Hitoshi Maeshima

Executive dysfunction in medicated, remitted state of major depression

BACKGROUND Past neuropsychological studies on depression have documented executive dysfunction and it has been reported that some dysfunction persists even after depressive symptoms disappear. Studies have shown a correlation between cerebrovascular lesions and executive dysfunction in depression among the elderly. The aim of the present study was to focus on executive functions in remitted major depressive disorder (MDD) patients, and to investigate whether remitted young and elderly patients show different patterns of executive dysfunction, and to ascertain the relationships with vascular lesions. METHODS Subjects were 79 inpatients with MDD and 85 healthy controls. Each subject received Wisconsin Card Sorting Test (WCST), Stroop test, and Verbal Fluency Test (VFT) in a remitted state. Both the MDD and control groups were divided into young and elderly groups, and the performances between 4 groups were compared. RESULTS For Stroop test, the scores of the MDD group were significantly lower than controls. In addition, as for VFT, the scores for the elderly MDD group were significantly lower than the other groups. Multiple regression analysis showed that VFT scores were affected by the presence of vascular lesions. CONCLUSIONS The results of the present study demonstrated that executive dysfunction remained even in a remitted state in MDD patients, but the patterns of impairment were different between young and elderly patients. The results also suggested that vascular lesions affect executive dysfunction, particularly in elderly depressive patients.

Serum amyloid β protein in young and elderly depression: a pilot study

Background:  Depression may increase the risk of developing Alzheimers disease (AD). Recent large cohort studies have also shown that a low plasma amyloid β (Aβ)‐42 level combined with a high Aβ40 level increases the risk of developing AD, suggesting plasma Aβ42/40 ratio as useful for identifying risk of developing mild cognitive impairment and AD. Although several studies have examined Aβ levels in the peripheral blood of elderly individuals with depression, results have been inconsistent. Furthermore, no results have been described for younger depression.

Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (S) levels in medicated patients with major depressive disorder compared with controls

BACKGROUND There is accumulating evidence regarding gender differences in clinical symptoms or response to antidepressants in patients with depression. However, less attention has been given to sex differences in the underlying biological mechanisms of depression. The adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), play a critical role in controlling affect, mood, and anxiety. Changes in serum adrenal androgen levels have been reported in conditions pertaining to stress as well as in psychiatric disorders. The objective of the present study was to investigate differences in serum levels of adrenal androgens in male and female patients with major depressive disorder (MDD). METHODS Participants included 90 inpatients with MDD at the psychiatric ward of Juntendo University Koshigaya Hospital who were receiving antidepressants. Serum levels of DHEA and DHEA-S were assessed at the time of admission. Matched controls (based on sex and age) included 128 healthy individuals. First, data from male and female MDD patients and controls were compared. Second, correlations between serum hormone levels and scores on the Hamilton Rating Scale for Depression (HAM-D) of patients with MDD were assessed by gender. In addition, effects of various factors on adrenal androgens were analyzed using multiple regression analysis. RESULTS Serum DHEA levels were significantly increased in both male and female MDD patients compared with controls. Serum levels of DHEA-S in male patients were significantly decreased compared with male controls, whereas no significant differences were seen in female patients and controls. No significant correlations among adrenal androgens were observed in male patients with MDD, whereas significant positive correlations were found in both male and female controls. No significant correlations were seen between adrenal androgens and HAM-D scores in male or female patients. Multiple regression analysis showed that both hormones were affected by the age at onset of depression. LIMITATIONS All subjects in the present study were on antidepressant medications. CONCLUSIONS Elevated levels of serum DHEA may be associated with the biological pathophysiology of depression, as DHEA administration has been found to be effective for the treatment of depression. Findings of differential changes in DHEA-S levels in men compared with women may suggest distinct characteristics of these hormones between men and women with depression. However, DHEA/DHEA-S may be a poor indicator for evaluating severity of depression.

Heterogeneity of elderly depression: increased risk of Alzheimer's disease and Aβ protein metabolism.

Epidemiological studies have proposed that depression may increase the risk for Alzheimers disease (AD), even in patients with early-onset depression. Although metabolism of amyloid β protein (Aβ) in elderly depression received attention in terms of their correlation, there is a serious heterogeneity in elderly depression in terms of age at onset of depression. Moreover, it is unknown whether early-onset major depressive disorder (MDD) has a long-term effect on the involvement of Aβ metabolism and later development of AD. Thus, we evaluated serum Aβ40 and Aβ42 levels, the Aβ40/Aβ42 ratio in 89 elderly (≥60 years of age) inpatients with MDD and 81 age-matched healthy controls, and compared them among patients with early-onset (<60 years) and late-onset (≥60years) MDD and controls. The results showed that the serum Aβ40/Aβ42 ratio was significantly higher in patients with both early- and late-onset MDD than in controls (early-onset, p=0.010; late-onset, p=0.043), and it is of great interest that the serum Aβ40/Aβ42 ratio was negatively correlated with the age at MDD onset (R=-0.201, p=0.032). These results suggest that an earlier onset of MDD may have a more serious abnormality in Aβ metabolism, possibly explaining a biological mechanism underlying the link between depression and AD.

Metabolism of amyloid-β protein may be affected in depression.

OBJECTIVE Epidemiologic studies have demonstrated that a history of depression increases the risk of developing Alzheimers disease, particularly among individuals with early-onset depression. On the other hand, recent studies have suggested that a higher amyloid-β protein (Aβ)40 to Aβ42 ratio may be associated with the future onset of Alzheimers disease. Our objective was to assess whether the pathophysiology of early-onset depression may involve or affect Aβ metabolism. METHOD In this extension of a case-control pilot study, 193 inpatients with DSM-IV major depressive disorder (MDD) (mean age = 55.9 years) from the Juntendo Koshigaya Hospital, Saitama, Japan, and 413 healthy controls from the community (mean age = 56.6 years) were recruited between May 2004 and April 2009. Serum Aβ40 and Aβ42 levels, Aβ40/Aβ42 ratio, and other clinical and biological factors were compared between controls and patients in 3 age groups: young (< 40 years), middle-aged (≥ 40 to < 65 years), and elderly (≥ 65 years). Depressive symptoms were assessed with the Hamilton Depression Rating Scale. All patients were receiving antidepressant medication at the time of the study, and doses of current antidepressants were converted to an equivalent imipramine dose. RESULTS The serum Aβ40/Aβ42 ratio was significantly higher in MDD patients than controls in all age groups (young: P = .003; middle-aged: P < .001; elderly: P = .006). These differences were also observed in noncarriers of the apolipoprotein E ε4 allele. CONCLUSIONS Our findings suggest that Aβ metabolism may be affected in depression; these findings also possibly answer the question of why even early-onset depression is a risk factor for developing Alzheimers disease.

Association analysis of glycine- and serine-related genes in a Japanese population of patients with schizophrenia.

Differences in the levels of the glutamate-related amino acids glycine and serine in brain/plasma between schizophrenic patients and normal subjects and changes in the plasma concentrations of these amino acids according to the clinical course have been reported. It has been hypothesized that glycine and serine metabolism may be altered in schizophrenia. In fact, some genes related to the metabolism of these amino acids have been suggested to be candidate genes for schizophrenia. Thus, we performed a genomic case-control analysis of amino acid metabolism-related genes in Japanese patients with schizophrenia. Case-control genetic association analysis of PHGDH, SHMT1, SRR, and DAO was performed. In addition, the effect of the various genotypes resulting from these four genes on changes in plasma amino acid levels in schizophrenia was assessed. The genetic case-control analysis showed that no individual single-nucleotide polymorphism (SNP) in any of the four genes was associated with schizophrenia; only the two (rs3918347-rs4964770, P=0.0009) and three (rs3825251-rs3918347-rs4964770, P=0.002) SNP-based haplotype analysis of the DAO gene showed an association with schizophrenia even after correction for multiple testing. None of the genotypes studied was associated with changes in the plasma glycine and l- and d-serine levels during the schizophrenic clinical course. The DAO gene may be a susceptibility locus for schizophrenia.

Significance of Measurements of Peripheral Carbonyl Stress Markers in a Cross-sectional and Longitudinal Study in Patients With Acute-stage Schizophrenia

Altered peripheral carbonyl stress markers, high levels of serum pentosidine, which accumulates following carbonyl stress, and low levels of pyridoxal (vitamin B6), which detoxifies reactive carbonyl compounds, have been reported in a cross-sectional study of chronic schizophrenia. However, changes in the levels of these compounds in patients with schizophrenia have not been investigated in a longitudinal study. To clarify whether these markers may be biological markers that reflect the clinical course of the disease, the serum levels of these compounds were investigated in a cross-sectional and a longitudinal study. One hundred and thirty-seven acute-stage Japanese patients were enrolled. Among these, 53 patients were followed from the acute stage to remission. A portion of patients in the acute stage (14 cases, 10.2%) showed extremely high pentosidine levels. These levels were not associated with the severity of symptoms but were associated with antipsychotic dose amounts. Pyridoxal levels were lower in schizophrenia and increased according to the clinical course of the illness. Furthermore, 18 patients with decreased pyridoxal levels according to the clinical course showed that the greater the decrease in pyridoxal levels, the lesser the improvement in symptoms. Thus, extremely high pentosidine levels in a portion of patients may be caused by higher daily antipsychotic doses, whereas pyridoxal levels were lower in schizophrenia and increased according to the clinical course. Patients with decreasing pyridoxal levels during the clinical course showed less improvement in symptoms. Carbonyl stress markers may also be therapeutic biological markers in some patients with schizophrenia.

Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: Class-specific influence by tricyclic antidepressants and newer antidepressants

Patients with major depressive disorder (MDD) are known to present with cognitive deficits; however, the presence of these deficits in the remitted state have been inconsistent. One of the most important factors potentially contributing to inconsistencies between studies may be the influence of medications. To explore the influence of antidepressants on cognitive performance in remitted MDD, we evaluated memory and executive functions using Wechsler Memory Scale-Revised and Stroop Color and Word Test, and compared performance among 50 medicated (29 treated with tricyclic antidepressants [TCA], 21 treated with selective serotonin reuptake inhibitors or serotonin noradrenalin reuptake inhibitors) and 19 medication-free MDD patients and 31 controls. The results showed that all 3 MDD groups had significantly lower performance for verbal memory compared with controls. Both medicated groups showed significantly lower performance for visual memory compared with controls; however, the medication-free group did not differ from controls. For the executive function, only the TCA group showed a significantly lower performance compared with controls. These results suggest that cognitive impairment remained even in remitted patients with MDD, however, part of this impairment may be influenced by class-specific antidepressant side effects.

Association study between Disrupted-in-Schizophrenia-1 (DISC1) and Japanese patients with treatment-resistant schizophrenia (TRS)

Treating the 20-30% of patients with schizophrenia whose symptoms are resistant to antipsychotic treatment, a condition known as treatment-resistant schizophrenia (TRS), can be problematic. Recently, an association between Disrupted-in-Schizophrenia-1 (DISC1), a candidate susceptibility gene for schizophrenia, and TRS was reported. Associations between three missense SNPs, rs3738401 (Q264R), rs6675281 (L607F), and rs821616 (S704C) in DISC1, especially rs3738401, showed strong significance. Thus, the main aim of our current study was to examine if the reported possible functional polymorphisms in DISC1 were related to Japanese TRS. First, DISC1 was re-investigated in 485 Japanese patients with schizophrenia and 660 healthy controls with a case-control study using four candidate SNPs, rs751229, rs3738401, rs821597, and rs821616. DISC1 was not associated with schizophrenia in the Japanese population. Second, we investigated whether these SNPs contributed to TRS in 127 inpatients with schizophrenia (35 patients; TRS and 92 patients; non-TRS). The genotypic distributions of these four SNPs were not significantly different between TRS and non-TRS in either genotypic or recessive models of minor alleles. In addition, clinical variables, such as improvement in clinical symptoms, duration of hospitalization, and total antipsychotics dose amounts, were not different among the genotypes of these SNPs. Taken together, results showed that DISC1 had no apparent degree of association with Japanese patients with schizophrenia as a candidate susceptibility gene for disease per se or TRS.

Association analysis between functional polymorphism of the rs4606 SNP in the RGS2 gene and antipsychotic-induced Parkinsonism in Japanese patients with schizophrenia: Results from the Juntendo University Schizophrenia Projects (JUSP)

Antipsychotic-induced extrapyramidal symptoms (AIEPSs) are commonly recognized side effects of typical 1st generation antipsychotics, and considerable variability is seen in the susceptibility of individual patients to AIEPSs. Regulator of G-protein signaling 2 (RGS2) proteins regulate intracellular signaling and second messenger activation of molecules including dopamine, serotonin, and acetylcholine receptors, all of which appear to be involved in the pathophysiology of AIEPSs. Previous studies have shown an association between AIEPSs in schizophrenia and RGS2, especially the minor G allele of single nucleotide polymorphism (SNP) rs4606 (+2971C>G) in RGS2, and have suggested a possible protective effect by the G allele on AIEPSs. In this study, we investigated whether the rs4606 SNP in RGS2 alone also showed an effect on AIEPSs by utilizing the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) in 103 Japanese patients with schizophrenia. In the assumed G allele recessive model, sialorrhea and total Parkinsonism scores were significantly higher in subjects with the GG genotype than in subjects with other genotypes. Other clinical variables were not significantly different among the various genotype groups. Controlling for clinical variables as covariates, a one-way analysis of covariance found no association between rs4606 genotypes and DIEPSS scores. Taken together, these results, although preliminary, suggest that rs4606 does not affect AIEPSs in Japanese subjects.