Validity of the Patient Health Questionnaire (PHQ)-9 and PHQ-2 in general internal medicine primary care at a Japanese rural hospital: a cross-sectional study.

OBJECTIVE: Two depression screening tools, Patient Health Questionnaire (PHQ)-9 and PHQ-2, have not had their validity examined in general internal medicine settings in Japan. We examined the validity of these screening tools. METHODS: A total of 598 outpatients of an internal medicine clinic in a rural general hospital were enrolled consecutively and stratified by PHQ-9 score. Seventy-five patients randomly selected and 29 patients whose results from the PHQ-9 were considered to be positive for depressive disorder were then interviewed with a semistructured interview, the Mini International Neuropsychiatric Interview. We calculated diagnostic accuracy of the PHQ-9 and PHQ-2 to detect major depression and that of the suicidality item of the PHQ-9 to detect suicidality using sampling weights with multiple imputations. RESULTS: Sensitivity and specificity for depression were 0.86 and 0.85, respectively, for the PHQ-9 with cutoff points of 4/5, and 0.77 and 0.95, respectively, for the PHQ-2 with cutoff points of 2/3. Sensitivity and specificity of the suicidality item of the PHQ-9 were 0.70 and 0.97, respectively. CONCLUSION: In internal medicine clinics in Japanese rural hospitals, the PHQ-2 with an optimal cutoff point for each setting plus the suicidality item of the PHQ-9 can be recommended to detect depression without missing suicidality.

Prevalence of depression among outpatients visiting a general internal medicine polyclinic in rural Japan.

OBJECTIVE: In Europe and the US, primary care has been anticipated in identifying untreated depression. Findings show a high prevalence of depression in such settings. However, the prevalence of depression in an internal medicine clinic in a rural area of Japan, which has a role in primary care, is unclear. METHOD: The prevalence of depression and comorbid psychiatric disorders among outpatients of an internal medicine clinic in a rural general hospital was measured by a structured interview using the Mini International Neuropsychiatric Interview. Outpatients were recruited consecutively and stratified by Patient Health Questionnaire-9 (PHQ-9) scores. Among 598 outpatients, we interviewed 75 randomly selected patients and 29 whose results of the PHQ-9 were positive. We estimated prevalence of depressive episode using age, sex, physical findings by internal medical doctors and PHQ-9 scores as covariates. RESULTS: The estimated prevalence of major and minor depressive episodes were 7.4% [95% confidence interval (CI): 3.4%-11.4%] and 6.8% (95% CI: 2.6%-10.9%), respectively. Among major depressed patients, 71.4% had current suicidal ideation. CONCLUSION: Given the high rate of depression and suicidality, identification of depression and collaboration between internal medical doctors in a rural area of Japan and mental health professionals are needed.

Factors associated with perceived feasibility and willingness of non-psychiatric doctors in Japan to treat depressed patients.

OBJECTIVES: We previously reported that many non-psychiatric doctors in Japan believe that treating depression was not part of their duties. Educational interventions must address motivation of physicians to play a role in depression care. In this study, we explored factors associated with perceived feasibility and willingness of non-psychiatric doctors in Japan to treat depression. METHODS: The study population included non-psychiatric doctors of the General Physician-Psychiatrist (G-P) Network group in Japan. We explored perceived feasibility and willingness to treat depressed patients, and examined preliminary associations with attitudes toward depression (the Depression Attitude Questionnaire: DAQ) and current depression treatment in routine medical practice. RESULTS: Responses were obtained from 56 non-psychiatric doctors (response rate: 35.4%). The doctors who scored high on the "Professional" and "Pessimism" subscale of the DAQ believed that treating depressed patients was not feasible (chi2 = 13.6, p < 0.01; chi2 = 7.3, p < 0.05, respectively) and were not willing to treat depressed patients (chi2 = 9.4, p < 0.01; chi2 = 6.6, p < 0.05, respectively) as part of their routine medical practice. The doctors who scored high on the "Professional" subscale referred fewer depressed patients to psychiatrists (r = -0.33, p < 0.05), and those who scored high on the "Pessimism" subscale recognized fewer depressed patients (r = -0.39, p < 0.01). CONCLUSIONS: The present study showed that attitudes toward depression were associated with perceived feasibility and willingness to treat depressed patients and with under-diagnosis of depression. Educational interventions optimized for these attitudes should be developed to improve recognition and treatment of depression in Japan.

Attitudes toward depression among Japanese non-psychiatric medical doctors: a cross-sectional study.

BACKGROUND: Under-recognition of depression is common in many countries. Education of medical staff, focusing on their attitudes towards depression, may be necessary to change their behavior and enhance recognition of depression. Several studies have previously reported on attitudes toward depression among general physicians. However, little is known about attitudes of non-psychiatric doctors in Japan. In the present study, we surveyed non-psychiatric doctors' attitude toward depression. METHODS: The inclusion criteria of participants in the present study were as follows: 1) Japanese non-psychiatric doctors and 2) attendees in educational opportunities regarding depression care. We conveniently approached two populations: 1) a workshop to depression care for non-psychiatric doctors and 2) a general physician-psychiatrist (G-P) network group. We contacted 367 subjects. Attitudes toward depression were measured using the Depression Attitude Questionnaire (DAQ), a 20-item self-report questionnaire developed for general physicians. We report scores of each DAQ item and factors derived from exploratory factor analysis. RESULTS: We received responses from 230 subjects, and we used DAQ data from 187 non-psychiatric doctors who met the inclusion criteria. All non-psychiatric doctors (n = 187) disagreed with "I feel comfortable in dealing with depressed patients' needs," while 60 % (n = 112) agreed with "Working with depressed patients is heavy going." Factor analysis indicated these items comprised a factor termed "Depression should be treated by psychiatrists" - to which 54 % of doctors (n = 101) agreed. Meanwhile, 67 % of doctors (n = 126) thought that nurses could be useful in depressed patient support. The three factors derived from the Japanese DAQ differed from models previously derived from British GP samples. The attitude of Japanese non-psychiatric doctors concerning whether depression should be treated by psychiatrists was markedly different to that of British GPs. CONCLUSIONS: Japanese non-psychiatric doctors believe that depression care is beyond the scope of their duties. It is suggested that educational programs or guidelines for depression care developed in other countries such as the UK are not directly adaptable for Japanese non-psychiatric doctors. Developing a focused educational program that motivates non-psychiatric doctors to play a role in depression care is necessary to enhance recognition and treatment of depression in Japan.

[Mental disorder and suicide prevention in patients with physical illness].

Suicide rate in Japan is 25/100,000 in a year. The rate is higher than those in other developed countries. Physical illness is a risk factor for suicide. To prevent suicide in patients with physical illness, identification of mental illness, such as depression, is important. In addition, palliative care for distressing physical and psychological symptoms is also important. In process of identification of mental illness and distressing physical symptoms, communications between medical staff and patients are essential. Enhancing communication skills of medical staff may be a key point to prevent suicide.

Multiple barriers against successful care provision for depressed patients in general internal medicine in a Japanese rural hospital: a cross-sectional study.

BACKGROUND: A general internist has an important role in primary care, especially for the elderly in rural areas of Japan. Although effective intervention models for depressed patients in general practice and primary care settings have been developed in the US and UK medical systems, there is little information regarding even the recognition rate and prescription rate of psychotropic medication by general internists in Japan. The present study surveyed these data cross-sectionally in a general internal medicine outpatient clinic of a Japanese rural hospital. METHODS: Patients were consecutively recruited and evaluated for major depressive disorder or any mood disorder using the Patient Health Questionnaire (PHQ). Physicians who were blinded to the results of the PHQ were asked to diagnose whether the patients had any mental disorders, and if so, whether they had mood disorders or not. Data regarding prescription of psychotropic medicines were collected from medical records. RESULTS: Among 312 patients, 27 (8.7%) and 52 (16.7%) were identified with major depressive disorder and any mood disorder using the PHQ, respectively. Among those with major depressive disorder, 21 (77.8%) were recognized by physicians as having a mental disorder, but only three (11.1%) were diagnosed as having a mood disorder.Only two patients with major depressive disorder (7.4%) had been prescribed antidepressants. Even among those (n = 15) whom physicians diagnosed with a mood disorder irrespective of the PHQ results, only four (26.7%) were prescribed an antidepressant. CONCLUSIONS: Despite a high prevalence of depression, physicians did not often recognize depression in patients. In addition, most patients who were diagnosed by physicians as having a mood disorder were not prescribed antidepressants. Multiple barriers to providing appropriate care for depressed patients exist, such as recognizing depression, prescribing appropriate medications, and appropriately referring patients to mental health specialists.

A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia.

INTRODUCTION: Glutamate dysfunction has been implicated in the pathophysiology of schizophrenia. The metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors. GRM7, the gene that encodes mGluR7, is expressed in many regions of the human central nervous system. The GRM7 gene is located on human chromosome 3p26, which has been suggested by linkage analysis to contain a susceptibility locus for schizophrenia. METHODS: We screened for mutations in all exons, exon/intron junctions, and promoter regions of the GRM7 gene in Japanese patients with schizophrenia and evaluated associations between the detected polymorphisms and schizophrenia. We examined the influence of one polymorphism associated with schizophrenia on the expression of GRM7 by dual-luciferase assay in transfected cells. RESULTS: Twenty-five polymorphisms/mutations were detected in GRM7. Case-control analysis revealed a potential association of a synonymous polymorphism (371T/C, rs3749380) in exon 1 with schizophrenia in our case-control study of 2293 Japanese patients with schizophrenia and 2382 Japanese control subjects (allelic p=0.009). Dual-luciferase assay revealed suppression of transcription activity by exon 1 containing this polymorphism and a statistically significant difference in the promoter activity between the T and C alleles. CONCLUSIONS: Our results support the possible association of a GRM7 gene polymorphism with genetic susceptibility to schizophrenia.

Autosomal linkage analysis of a Japanese single multiplex schizophrenia pedigree reveals two candidate loci on chromosomes 4q and 3q.

We analyzed a large multiplex schizophrenia pedigree collected in mid-eastern Japan using 322 microsatellite markers distributed throughout the whole autosome. Under an autosomal-dominant inheritance model, the highest pairwise LOD score (LOD = 1.69) was found at 4q (D4S2431: theta = 0.0), and LOD scores at two other loci 3q (ATA34G06) and 8q (D8S1128) were 1.62 and 1.46, respectively. In multipoint analysis, LOD scores of the regions on 4q and 3q remained at a similar level; however, the LOD score of the region on 8q apparently decreased. Additional dense map analysis revealed haplotypes on 4q and 3q regions shared by affected individuals. On chromosome 4q, the haplotype spanning about 8 centiMorgans (cM) was shared by four of six genotyped individuals with schizophrenia and one affected individual whose haplotype was estimated. On 3q, the haplotype spanning about 20 cM was shared by five genotyped individuals with schizophrenia. We obtained two candidate regions of major susceptibility loci for schizophrenia on chromosomes 3q and 4q.

Monoallelic and unequal allelic expression of the HTR2A gene in human brain and peripheral lymphocytes.

BACKGROUND: The 102T/C polymorphism of the serotonin 2A receptor (HTR2A) gene is reported to be associated with schizophrenia and other diseases and phenotypes. Altered HTR2A expression has been found in relation to several neuropsychiatric conditions, including depression and schizophrenia. Studies of expression of HTR2A messenger RNA (mRNA) and protein in postmortem brains suggest that the 102C allele might be less transcriptionally active than the T allele. However, equal expression of both alleles has also been reported. METHODS: We performed primer extension assays to measure relative expression of allele-specific HTR2A transcripts in mRNAs isolated from the prefrontal cortex of 31 individuals with schizophrenia and from peripheral lymphocytes (PBLs) of 31 healthy individuals heterozygous for 102T/C. We also examined the allele transmission pattern of HTR2A in PBLs of nine families. RESULTS: Analyses of DNA and mRNA revealed that 102C is expressed but at lower levels than 102T in brains. In contrast to the biallelic expression observed in brains, monoallelic expression of HTR2A was common in PBLs. However, a family study revealed that imprinting was not responsible for the monoallelic expression in PBLs. CONCLUSIONS: The present study revealed a tissue-specific modification of HTR2A expression, which makes allelic and epiallelic analyses necessary for genetic epidemiologic and pharmacogenomic studies of HTR2A.

A polymorphism in the PDLIM5 gene associated with gene expression and schizophrenia.

BACKGROUND: Results of recent DNA microarray analyses of postmortem brains of patients with schizophrenia revealed that expression of the PDZ and LIM domain 5 gene (PDLIM5) is increased. In the present study, we examined whether polymorphisms in PDLIM5 are associated with schizophrenia. METHODS: We screened for mutations in PDLIM5 in 24 Japanese patients with schizophrenia and evaluated the associations of the identified polymorphisms with schizophrenia in a Japanese case-control population (total samples, 278 schizophrenia patients and 462 control subjects). Expression of PDLIM5 was quantified by real-time quantitative polymerase chain reaction (PCR) in postmortem prefrontal cortex of 34 schizophrenia patients. Electrophoretic mobility shift assay (EMSA) was performed to examine whether a polymorphism influences nuclear protein binding. RESULTS: We identified 27 polymorphisms in PDLIM5 and found associations between polymorphisms (rs2433320 and rs2433322) in the 5' region of the gene and schizophrenia (p = .004). Real-time quantitative PCR revealed that these polymorphisms influenced gene expression (p = .007). An EMSA showed that the different alleles of the rs2433320 polymorphism bound differently to nuclear proteins. CONCLUSIONS: These results suggest that PDLIM5 might play a role in genetic susceptibility to schizophrenia.

Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility loci on chromosomes 1p, 14q, and 20p.

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Association between chromogranin b gene polymorphisms and schizophrenia in the Japanese population.

BACKGROUND: We found in previous work a significant association between schizophrenia and D20S95 on chromosome 20p12.3. In this study, we analyzed 10 microsatellite markers and found an association of schizophrenia with D20S882 and D20S905 that flank D20S95. The chromogranin B gene (CHGB) is 30 kb from D20S905. The chromogranin B (secretogranin I) belongs to a series of acidic secretory proteins that are widely expressed in endocrine and neuronal cells, and its cerebrospinal fluid levels have been reported to decrease in patients with chronic schizophrenia. METHODS: We screened for polymorphisms in CHGB with polymerase chain reaction direct sequencing methods in 24 Japanese schizophrenic patients and identified a total of 22 polymorphisms. Allelic and genotypic distributions of detected polymorphisms were compared between unrelated Japanese schizophrenic patients (n = 192) and healthy control subjects (n = 192). RESULTS: Statistically significant differences in the allelic distributions were found between schizophrenic patients and control subjects for 1058C/G (A353G) (corrected p = 7.7 x 10(-5)) and 1104A/G (E368E) (corrected p = 8.1 x 10(-6)). The 1058C/G and 1104A/G alleles were in almost complete linkage disequilibrium and were in linkage disequilibrium with D20S95. CONCLUSIONS: Results suggest that the CHGB variations are involved in the susceptibility to schizophrenia in our study population.

Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders.

BACKGROUND: The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of mood disorders. The GABRA1 gene encodes one of the subunits of GABA-A receptor and is located on human chromosome 5q34-q35, which is a region reportedly linked to mood disorders. We examined the GABRA1 gene as a candidate for mood disorders. METHODS: We performed mutation screening of GABRA1 in 24 Japanese bipolar patients and evaluated associations in Japanese case-control subjects consisting of 125 patients with bipolar disorder, 147 patients with depressive disorders, and 191 healthy control subjects. Associations were confirmed in the National Institute of Mental Health (NIMH) Initiative Bipolar Pedigrees, which consists of 88 multiplex pedigrees with 480 informative persons. RESULTS: We identified 13 polymorphisms in the GABRA1 gene. Nonsynonymous mutations were not found. Association of a specific haplotype with affective disorders was suggested in the Japanese case-control population (corrected p=.0008). This haplotype association was confirmed in the NIMH pedigrees (p=.007). CONCLUSIONS: These results indicate that the GABRA1 gene may play a role in the etiology of bipolar disorders.

Significant linkage to chromosome 22q for exploratory eye movement dysfunction in schizophrenia.

A genome-wide scan for a locus responsible for exploratory eye movement (EEM), which is quantitative and can be disturbed in association with schizophrenia, was performed. A 10-cM resolution genome-wide linkage analysis of the EEM disturbance with 358 highly polymorphic microsatellite markers in 38 nuclear families with 122 members (38 probands, 47 sibs, and 37 parents) including 58 sib-pairs yielded the suggestive linkage to the GCT10C10 marker on chromosome 22q11.2 (LOD = 2.48). Dense mapping with additional markers around the GCT10C10 marker yielded evidence for significant linkage between EEM disturbance and markers D22S429 and D22S310 on chromosome 22q12.1 (LOD score of 4.63) with suggestive evidence for the chromosome region 22q11.2-q12.1. Our findings suggest that a relatively small number of loci may control the schizophrenia-related quantitative EEM trait. We believe that identifying gene(s) on chromosome 22q associated with the EEM phenotype may forward our understanding of the etiology of schizophrenia.

Lack of evidence for associations between plasma platelet-activating factor acetylhydrolase deficiency and schizophrenia.

Platelet-activating factor (PAF) is a potent phospholipid mediator that plays various roles in neuronal function and brain development. It is involved in NMDA receptor function. Release and degradation of PAF is controlled by intracellular and plasma PAF-acetylhydrolase (PAFAH). The plasma PAFAH gene (PLA2G7) is located on chromosome 6p. A previous study showed weak associations of the Ile198Thr and Val379Ala polymorphisms of this gene with schizophrenia that did not reach statistical significance after correction for multiple comparisons. Another study showed that a functional alteration of the enzyme with these two polymorphisms is likely, but the magnitude may be modest. Approximately 4% of the Japanese population lack plasma PAFAH because of a loss-of-function mutation (Val279Phe) in the PAFAH gene. Thus, the Val279Phe mutation is useful for examining whether a causal relation exists between PAFAH function and schizophrenia. We looked for an association between the Val279Phe mutation and schizophrenia in 191 Japanese patients with schizophrenia and in 188 Japanese controls. Similar genotypic and allelic distributions were observed in the two groups. These observations indicate that functional differences in the plasma form of PAFAH do not play a substantial role in the etiology of schizophrenia. However, the present study leaves open the possibility that other isoforms are involved.

Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence.

Because retinoid cascades are involved in the regulation and development of the central nervous system, including dopaminergic neurons, retinoic acid signaling defects may contribute to schizophrenia and substances dependence. Retinoid X receptors (RXRs) form heterodimer complexes with nuclear-related receptor 1 (NURR1) or with peroxisome proliferator-activated receptors (PPARs). We examined 48 Japanese patients with schizophrenia and 32 patients with alcohol dependence to detect mutations in the retinoid X receptor beta gene (RXRB) on chromosome 6p21.3, the NURR1 gene (NR4A2) on chromosome 2q22-q23, and the PPAR alpha gene (PPARA) on chromosome 22q12.2-13.1. A Val95Ala polymorphism of the RXRB gene, a Val227Ala polymorphism in the PPARA gene, and two synonymous single-nucleotide and CA repeat polymorphisms in the 5' region and 3' untranslated region of the NR4A2 gene were identified. Extended case control samples did not suggest an association between the diseases and the RXRB or PPARA polymorphisms. However, they revealed a significant association between the NR4A2 gene haplotype and alcohol dependence, indicating that 2q22-q23 including the NR4A2 gene locus is a possible genomic region contributing to genetic susceptibility to alcohol dependence.