Kunitoshi Kamijima

Reliability and validity of Japanese version of the Mini‐International Neuropsychiatric Interview

Abstract  The Mini‐International Neuropsychiatric Interview (MINI) is a short, structured diagnostic interview used as a tool to diagnose 16 axis I (Diagnostic and Statistical Manual) DSM‐IV disorders and one personality disorder. Its original version was developed by Sheehan and Lecrubier. We translated the MINI into Japanese, and investigated the reliability and validity of the Japanese version of MINI. Eighty‐two subjects participated in the validation of the MINI versus the Structured Clinical Interview for DSM‐III‐R (SCID‐P). One hundred and sixty‐nine subjects participated in the validation of the MINI versus an experts professional opinion. Seventy‐seven subjects were interviewed by two investigators and subsequently readministered by a third interviewer blind to the results of initial evaluation 1–2 days later. In general, kappa values indicated good or excellent agreement between MINI and SCID‐P diagnoses. Kappa values indicated poor agreement between MINI and experts diagnoses for most diagnoses. Interrater and test–retest reliabilities were good or excellent. The mean durations of the interview were 18.8 min for MINI and 45.4 min for corresponding sections of SCID‐P. Overall, the results suggest that the MINI Japanese version succeeds in reliably and validly eliciting symptom criteria used in making DSM‐III‐R diagnoses, and can be performed in less than half the time required for the SCID‐P.

Assessment of the Dexamethasone/CRH Test as a State-Dependent Marker for Hypothalamic-Pituitary-Adrenal (HPA) Axis Abnormalities in Major Depressive Episode: A Multicenter Study

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary–adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.

THE PATIENT HEALTH QUESTIONNAIRE, JAPANESE VERSION : VALIDITY ACCORDING TO THE MINI-INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW-PLUS

To validate the Japanese version of the Patient Health Questionnaire against the Mini-International Neuropsychiatric Interview-Plus in Japan 131 patients in 4 primary care settings and 2 general hospital settings participated. These patients completed the Patient Health Questionnaire and returned it to their physician within 48 hr. Subsequently, the subjects underwent a diagnostic evaluation interview based on the Mini-International Neuropsychiatric Interview-Plus by an interviewer blind to the results of the Patient Health Questionnaire screening. The Patient Health Questionnaire diagnosis was characterized using kappa values between 0.70 and 1.0 for Somatoform Disorder, Major Depressive Disorder, Panic Disorder, Bulimia Nervosa, Alcohol Abuse/Dependence, and Premenstrual Disorder. Sensitivities, specificities, and negative predictive values were very good (between 0.84 and 1.0) for the first 4 diagnoses but not Alcohol Abuse/Dependence or Premenstrual Disorder, as were the Positive predictive values (between 0.78 and 1.0). Findings show very good concordance of the Japanese version of the Patient Health Questionnaire with the Japanese version of the Mini-International Neuropsychiatric Interview–Plus.

A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity

Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles (‘A1’ allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5–5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.

Steady-state plasma levels of nortriptyline and its hydroxylated metabolites in Japanese patients: impact of CYP2D6 genotype on the hydroxylation of nortriptyline.

The authors investigated the impact of the CYP2D6 genotype on steady-state concentrations of nortriptyline (NT) and its metabolites, trans-10-hydroxynortriptyline (EHNT) and cis-10-hydroxynortriptyline in a Japanese population of psychiatric patients. Forty-one patients (20 men and 21 women) were orally administered nortriptyline hydrochloride. The allele frequencies of the CYP2D6*5 and CYP2D6*10 were 4.9% and 34.1%, respectively. Significant differences in NT concentrations corrected for dose and weight were observed between the subjects with no mutated alleles and those with one mutated allele (mean +/- SD for no mutated alleles vs. one mutated allele: 70.3 +/- 25.4 vs. 98.4 +/- 36.6 ng/mL x mg(-1) x kg(-1); t = 2.54, dcf = 33, p < 0.05) and between the subjects with no mutated alleles and two mutated alleles (no mutated alleles vs. two mutated alleles: 70.3 +/- 25.4 vs. 147 +/- 31.1 ng/mL x mg(-1) x kg(-1); t = 5.87, df = 19, p < 0.0001). Also, a significant difference in the NT/EHNT ratio, which is representative of the hydroxylation ratio of NT, was observed between the subjects with no mutated alleles and those with two mutated alleles (no mutated alleles vs. two mutated alleles: 0.82 +/- 0.30 vs. 2.71 +/- 0.84; t = 7.86, df = 19, p < 0.0001). Multiple regression analysis showed that the number of mutated alleles of CYP2D6, which was the only significant factor, accounted for 41% and 48% of the variability in log(NT corrected for dose and weight) and log(NT/EHNT), respectively.

A missense polymorphism (S205L) of the low-affinity neurotrophin receptor p75NTR gene is associated with depressive disorder and attempted suicide.

Several lines of evidence have implicated that neurotrophins play an important role in the pathophysiology of mood disorders. This study examined whether a common missense polymorphism (S205L) of a gene encoding the p75NTR, the low‐affinity receptor for neurotrophins, is associated with depressive disorder in a Japanese sample of 164 patients and the same number of controls matched for age and sex. There were significant differences in the genotype distribution and allele frequency between the cases and controls. The minor allele (L205) was significantly decreased in the patients than in the controls (P < 0.05, odds ratio 0.54, 95% CI 0.31–0.94), suggesting that this allele may have a protective effect against the development of major depression. Furthermore, this association was more strongly observed in the patients with a history of attempted suicide than those without such a history. Our results suggest that the S205L polymorphism of the p75NTR gene is involved in the pathogenesis of depressive disorder and suicidal behavior.

Differential expression of VAMP2/synaptobrevin-2 after antidepressant and electroconvulsive treatment in rat frontal cortex

The biological basis for the therapeutic mechanisms of depression is still unknown. We have previously performed expressed-sequence tag (EST) analysis to identify some molecular machinery responsible for antidepressant effect. Then, we developed our original cDNA microarray, on which cDNA fragments identified as antidepressant-related genes/ESTs were spotted. In this study, with this microarray followed by Western blot analysis, we have demonstrated the induction of vesicle-associated membrane protein 2(VAMP2/synaptobrevin-2) in rat frontal cortex not only after chronic antidepressant treatment, but also after repeated electroconvulsive treatment. On the other hand, expression of SNAP-25 and syntaxin-1 was not changed by these treatments. These components make a soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor complex with VAMP2 and mediate the synaptic vesicle docking/fusion machinery. In conclusion, it is suggested that VAMP2/synaptobrevin-2 plays important roles in the antidepressant effects. Our results may contribute to a novel model for the therapeutic mechanism of depression and new molecular targets for the development of therapeutic agents.

The differential ACTH responses to combined dexamethasone/CRH administration in major depressive and dysthymic disorders.

In a preliminary study, we performed the combined dexamethasone/CRH test on patients with major depressive and dysthymic disorders as well as healthy controls. The ACTH response was significantly enhanced in the major depression group compared to the control group and tended to be heightened compared to the dysthymia group. The cortisol response was not significantly different among the three groups. We assume that major depression and dysthymia are neuroendocrinologically distinct disorders, although whether the difference is quantitative or qualitative remains to be examined.

Genes for interleukin‐2 receptor β chain, interleukin‐1 β, and schizophrenia: No evidence for the association or linkage

We studied a CA repeat polymorphism of the interleukin-2 receptor beta chain (IL-2RB) gene and a C/-514/T variation of the interleukin-1 beta (IL-1B) gene in Japanese schizophrenia patients. Both a case-control association study (54 patients and 54 controls) and a linkage study using six multiplex families (the number of the affected > or =4 in each family) were employed. No evidence for the association or the linkage was obtained either for the IL-2RB or IL-1B gene.