Serum levels of brain-derived neurotrophic factor in remission, but not the acute phase, may predict the development from depression to dementia.

OBJECTIVES: Depression may be a risk factor or a prodromal symptom of dementia, and decreased serum levels of brain-derived neurotrophic factor (BDNF) have been observed in both depression and dementia. The aim of the present study was to determine whether serum levels of BDNF in the remitted or acute phase of depression predicted the transition from depression to dementia. METHODS: Serum levels of BDNF were measured in the acute phase of depression (n = 204) and after remission (n = 117), and we followed (mean: 24.3 months) the participants to assess the subsequent onset of dementia or mild cognitive impairment (MCI). RESULTS: Serum levels of BDNF after remission, but not those in the acute depressive phase, predicted the future development of dementia or MCI. CONCLUSIONS: Patients with low serum BDNF levels, even after depression remission, might have an increased risk of developing dementia. These findings suggest a potential association between residual low serum BDNF levels after remission and the prodromal state of dementia, or the involvement of BDNF in the transition from depression to dementia. However, given that this study is low-powered and preliminary, interpretation of the results should be approached with caution.

Increased Serum Levels of α-Synuclein in Patients With Major Depressive Disorder.

OBJECTIVE: Epidemiologic studies have demonstrated that depression is a risk factor for dementia. In particular, dementia with Lewy bodies (DLB) has been noted to be highly relevant to depression. It has been suggested that α-synuclein (α-syn), a major component of Lewy bodies, is related to the onset and progression of DLB. To investigate the relationship between depression and DLB, we compared serum α-syn levels of patients with depression to those of healthy subjects. METHODS: The subjects were 103 inpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or DSM-5 major depressive disorder (MDD) and 132 healthy comparisons. Patients were recruited from Juntendo Koshigaya Hospital, Saitama, Japan, between June 2010 and November 2016. Serum α-syn levels were measured using an enzyme-linked immunosorbent assay kit. Serum α-syn levels were compared using a 2 (age group [<60 years versus ≥60 years]) × 2 (diagnosis [MDD versus comparison]) analysis of variance. RESULTS: There was no significant main effect of age (F = 1.167, df = 1, 231, p = 0.281). There was a significant main effect of diagnosis (F = 44.657, df = 1, 231, p <0.001), with higher α-syn levels in the MDD group versus the healthy comparison group, regardless of age. CONCLUSION: The present results suggest that depression may affect the metabolism of α-syn; there is a possibility that depression is not only a prodromal symptom of DLB but also a causal risk factor for DLB.

Renal concerns relative to the use of lithium in geriatric bipolar disorder patients.

BACKGROUND: Lithium is a first-line treatment for bipolar disorder in geriatric patients; however, it has long been associated with potentially significant renal consequences, including chronic kidney disease (CKD). METHODS: We reviewed the available evidence to characterize the effects of lithium on renal function, provide a consensus on periodic monitoring, and propose criteria for transitioning an older patient with bipolar disorder and renal issues to an alternate medication. RESULTS: Although the evidence on lithium use, duration, and dosage on progression of CKD and end-stage renal disease in geriatric patients is mixed, there is solid evidence that patients receiving lithium generally have a reduced glomerular filtration rate compared with controls. The current guidelines for monitoring lithium use in geriatric patients are nearly sufficient, but adherence in clinical practice frequently falls short. Alternative medications for bipolar disorder in geriatric patients are generally considered safe and effective, but do not have the strength of evidence that exists in the general adult population. CONCLUSIONS: Currently, there is no compelling evidence that lithium should be avoided in geriatric patients; however, prudent monitoring strategies are recommended, with a strong consideration of transitioning geriatric patients with poor tolerance to an alternative medication.

Serum brain-derived neurotrophic factor levels and personality traits in patients with major depression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. Previous studies have demonstrated lower serum BDNF levels in patients with major depressive disorder (MDD) and reported an association between BDNF levels and depression-related personality traits in healthy subjects. The aim of the present study was to explore for a possible association between peripheral BDNF levels and personality traits in patients with MDD. METHODS: In this cross-sectional study, a total of 123 inpatients with MDD (Diagnostic and Statistical Manual for Mental Disorders, 4th edition) at the Juntendo University Koshigaya Hospital were recruited. Serum levels of BDNF were measured. Personality traits were assessed using the 125-item short version of the Temperament and Character Inventory (TCI). RESULTS: Multiple regression analysis adjusted for age, sex, body mass index, dose of antidepressant, and depression severity showed that TCI Self-Directedness (SD) scores were negatively associated with serum BDNF levels (ß = -0.23, p = 0.026). CONCLUSIONS: MDD patients who have low SD did not show the reduction in serum BDNF levels that is normally associated with depressive state. Our findings suggest that depression-related biological changes may not occur in these individuals.

Duration of last depressive episode may influence serum BDNF levels in remitted patients with major depression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) may have an important role in the pathophysiology of depression. Previous studies indicate that serum BDNF levels were lower in patients with depression and increased after treatment with antidepressants. However, results of studies on serum BDNF levels in remitted patients with depression have been inconsistent. The purpose of the present study was to determine which factors influence the alteration of serum BDNF levels in depression in the remitted state. METHODS: Serum BDNF levels were evaluated in 75 remitted inpatients with major depressive disorder (MDD) and 108 controls. Multiple regression analyses were conducted using serum BDNF levels as the dependent variable; and the number of episodes, Hamilton Rating Scale for Depression score at admission, or duration of last depressive episode as independent variables. RESULTS: Serum BDNF levels were lower in remitted patients with MDD than in controls (P < .001). Multiple regression analysis showed a significant effect between the duration of the last depressive episode and serum BDNF levels (P < .022). CONCLUSIONS: Serum BDNF levels in remitted patients with MDD did not recover to the level of healthy controls, and lower serum BDNF levels were influenced by a longer duration of last depressive episode. It is possible that persistent hippocampal reduction in remitted depression may be caused by lower BDNF levels associated with a longer duration of the last depressive episode.

Clinical course and serum amyloid ß levels in elderly patients with major depressive disorder.

BACKGROUND: Depression is known to be a risk factor for Alzheimer's disease (AD). Changes in amyloid ß protein (Aß) metabolism have been speculated as a factor contributing to the transition from depression to AD. The aim of this study is to reveal the time course and state-dependency of Aß metabolism. METHODS: Serum Aß levels in 277 elderly (≥60 years) patients with depression (both early- and late-onset) were measured at admission, immediately after remission, and 1 year after remission, and compared them with 178 healthy subjects. RESULTS: The analysis revealed decreased Aß42 levels and increased Aß42/40 ratios in elderly patients with depression at admission compared with healthy subjects. These changes in the acute phase of depression were not normalized immediately after remission; however, they recovered to healthy levels 1 year after remission. LIMITATIONS: There is a possibility that the results may be influenced by antidepressants. CONCLUSIONS: These results suggest that altered Aß metabolism caused by depression may ameliorate, although after a lengthy period of time after remission. Our findings also suggest that the AD-related pathological changes caused or increased by depression can be reduced by maintaining remission for an extended period of time.

No association between glutathione-synthesis-related genes and Japanese schizophrenia.

AIMS: Schizophrenia is a major psychiatric disorder with complex genetic, environmental, and psychological causes, and oxidative stress may be involved in the pathogenesis of the disease. Glutathione (GSH), one of the main cellular non-protein antioxidants and redox regulators, and altered GSH levels have been reported in various regions in patients with schizophrenia. Three enzymes are responsible for GSH synthesis: glutamate cysteine ligase modifier (GCLM), glutamate cysteine ligase catalytic subunit (GCLC), and glutathione synthetase (GSS). Previously, positive associations between GCLM and schizophrenia were reported in Europeans, but not in the Japanese population. Thus, in this study, we investigated the association between the GSH synthesis genes (GCLM, GCLC, and GSS) and schizophrenia in Japanese individuals. METHODS: Seventeen single-nucleotide polymorphisms (SNP) in GCLM, GCLC, and GSS were genotyped in 358 patients with schizophrenia and in 359 controls. RESULTS: No SNP showed a significant association between their allelic or genotypic frequencies and schizophrenia. Case-control haplotype association analysis using windows of two or three SNP showed no significant associations with schizophrenia. The case-control haplotype analyses based on the ascertained linkage disequilibrium blocks also showed no significant associations in any genes with schizophrenia. CONCLUSIONS: The three primary GSH synthesis genes do not have an apparent degree of association with schizophrenia in the Japanese population.

Apolipoprotein E4 increases the risk of depression recurrence.

BACKGROUND: Possession of the ε4 allele of apolipoprotein E (APOE4) is related to the incidence of depression in old age. We investigated whether the presence of APOE4 is also associated with subsequent depression recurrence in a wide range of age groups. METHODS: Altogether, 163 patients with major depressive disorder (MDD) after remission were recruited between August 2004 and March 2016 and followed up prospectively. The patients were divided into two groups: APOE4 carriers and non-carriers. We compared the time to recurrence of depression between the two groups. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the effect of the APOE4 allele on risk of a depression recurrence. RESULTS: Cumulative probability of developing a depression recurrence was higher in APOE4 carriers than non-carriers. Presence of an APOE4 allele remained significantly associated with the incidence of depression recurrence. LIMITATIONS: All patients were treated with one or two different antidepressants, which may have had different effects on patients with MDD. Second, participants in the present study comprised patients with both first and multiple episodes of MDD. Third, we did not have the statistical power to perform a stratified analysis in consideration of heterozygous or homozygous genotypes of APOE4. CONCLUSION: Possession of an APOE4 allele may increase the risk of depression recurrence.

Plasma alanine levels increase in patients with schizophrenia as their clinical symptoms improve-Results from the Juntendo University Schizophrenia Projects (JUSP).

UNLABELLED: Since oral administration of d-alanine, an agonist that binds to the glycine site of N-methyl-d-aspartate (NMDA) receptors, improves the positive and cognitive symptoms of patients with schizophrenia, measurement of endogenous plasma alanine levels could serve as a clinical marker for schizophrenia severity and improvement. Mean plasma alanine levels were compared in healthy controls and patients with schizophrenia during the clinical course of the disease. METHODS: eighty-one Japanese patients with schizophrenia and 50 age- and gender-matched healthy controls were studied. Plasma alanine levels were measured twice, during the acute stage and during the remission stage, using high-performance liquid chromatography. On admission, lower plasma alanine levels in patients with schizophrenia were accompanied by more severe schizophrenic symptoms, especially positive symptoms. The plasma alanine levels in patients with schizophrenia increased significantly from the time of admission to discharge, when they were significantly higher than control levels. An increase in plasma alanine levels from the acute stage to the remission stage of schizophrenia was correlated with improvement in symptoms. Drug-naïve patients did not show a significant difference in plasma alanine levels when compared with healthy controls. The measurement of plasma alanine levels may be a therapeutic marker for schizophrenia.

Serum levels and mutual correlations of amyloid ß in patients with depression.

AIM: Epidemiological studies have shown that depression is a risk factor for Alzheimer's disease (AD). Although the biological mechanism underlying the link between depression and AD is unclear, altered amyloid ß (Aß) metabolism in patients with depression has been suggested as a potential mechanism. Results from previous studies of Aß metabolism in patients with depression have been inconsistent, and Aß polymerization, which is a crucial process in AD pathology, has not previously been assessed. METHODS: Serum levels of Aß40, Aß42 and Aß oligomers were evaluated in 104 inpatients with major depressive disorder (MDD) and 132 healthy control individuals. RESULTS: Lower serum Aß42 levels were observed in patients with MDD, but there was no difference in serum Aß oligomer levels between the MDD group and the healthy control group, even in older adults. Interestingly, serum Aß oligomer levels in patients with MDD were dependent on serum Aß42 levels, regardless of age, and this relationship was not observed in the control group. CONCLUSIONS: These results suggest that Aß42 is more prone to aggregation and polymerization in patients with depression than in healthy individuals, suggesting a possible mechanism underlying the transition from depression to AD. Geriatr Gerontol Int 2020; 20: 125-129.

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.

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

BACKGROUND: Depression may increase the risk of developing Alzheimer's disease (AD). Recent large cohort studies have also shown that a low plasma amyloid beta (Abeta)-42 level combined with a high Abeta40 level increases the risk of developing AD, suggesting plasma Abeta42/40 ratio as useful for identifying risk of developing mild cognitive impairment and AD. Although several studies have examined Abeta levels in the peripheral blood of elderly individuals with depression, results have been inconsistent. Furthermore, no results have been described for younger depression. METHODS: Serum Abeta40, Abeta42 level and Abeta40/42 ratio were evaluated using enzyme-linked immunosorbent assay in 60 patients with major depressive disorder (MDD) and 60 healthy controls. The results were analyzed in two age groups (young, <60 years; elderly, >or=60 years). RESULTS: Serum Abeta40 level was significantly higher in young MDD patients compared to young controls (P < 0.001), but it was not significantly deferent in the elderly group. Serum Abeta42 level did not differ significantly in both young and elderly groups. Abeta40/42 ratio was significantly higher in both young (P < 0.001) and elderly (P < 0.001) patients with MDD compared to controls. CONCLUSIONS: Serum Abeta40/42 ratio was significantly higher in MDD patients than in controls, and this difference was seen for both elderly and young subjects. This may suggest that even young subjects with MDD undergo pathological changes in the very early stage of amyloid deposition.

Serum levels of TDP-43 in late-life patients with depressive episode.

BACKGROUND: Recent reports have suggested a relationship between affective disorder including depression and bipolar disorder (BP) and frontotemporal dementia (FTD). TAR DNA binding protein (TDP) -43 is a protein found in the brain and peripheral fluid of patients with FTD. To examine a possible association between affective disorders and FTD, serum levels of TDP-43 were evaluated in late-life patients with major depressive episode (MDE). METHODS: The subjects were 74 late-life (≥50 years old) inpatients with DSM-IV or -5 MDE (58 had major depressive disorders and 16 had BP) and 58 healthy subjects. Patients were recruited from Juntendo Koshigaya Hospital, Saitama, Japan, between January 2005 and May 2017. Serum TDP-43 levels were measured using an ELISA kit. RESULTS: Serum levels of TDP-43 were significantly higher in the MDE group than the control group independent of age and sex. LIMITATIONS: All patients were on antidepressant medication. CONCLUSIONS: Our finding suggests that some depressive patients may be in a prodromal stage of FTD or very-early stage of FTD comorbid with depression.

Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP).

OBJECTIVES: Based on the hypothesis of NMDA receptor hypofunction in schizophrenia, plasma glycine, L-serine, and D-serine levels have been studied, since they could serve as biological markers. However, changes over time in the levels of these amino acids in schizophrenic patients have not been investigated. To clarify the mean plasma glycine, L-serine, and D-serine levels in patients with schizophrenia, levels of these amino acids were compared between healthy controls and patients with schizophrenia. The plasma levels of these amino acids during the clinical course of schizophrenia were also compared. METHODS: Eighty-nine Japanese patients with schizophrenia and 50 age- and gender-matched healthy controls were studied. Plasma glycine, L-serine, and D-serine levels and their ratios were measured twice, during the acute stage and during the remission stage, using high-performance liquid chromatography. RESULTS: The admission plasma glycine, L-serine, and D-serine levels of schizophrenic patients were higher than those of healthy controls. There were no significant differences between drug-naïve patients and healthy controls in the admission levels of the plasma amino acids, but chronically medicated patients had higher admission plasma glycine and D-serine levels. Only the D-serine level and the D-/L-serine ratio were markedly significantly increased in schizophrenic patients from the time of admission to the time of discharge as their clinical symptoms improved. In addition, the increase in the plasma D-serine levels of drug-naïve patients was correlated with improvements in positive symptoms. CONCLUSIONS: Plasma amino acid levels, especially D-serine levels, could be useful as a "therapeutic" or "clinical state" marker in patients with acute schizophrenia.

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.

Glucocorticoid may influence amyloid ß metabolism in patients with depression.

Epidemiological studies have demonstrated that depression may be a risk factor for Alzheimer's disease (AD); however, the biological mechanisms of the transition from depression to AD are still not clear. Changes of amyloid ß protein (Aß) metabolism and increased glucocorticoid (GC) levels have been found in both depression and AD. Moreover, several studies in animal models have demonstrated that GC administration changes Aß metabolism. To reveal whether GC affects amyloid metabolism in patients with depression, we evaluated serum levels of Aß40, Aß42 and cortisol at admission in 187 inpatients with major depressive disorder (MDD) and 224 healthy comparisons. Additionally, we re-evaluated the serum levels of Aßs in 27 patients with MDD 1 year later. The results of multiple regression analyses revealed that serum cortisol and Aß levels are not correlated at the time of admission. However, serum cortisol levels at admission correlated with serum Aß42 levels and Aß40/Aß42 ratio 1 year later. These findings suggest that increased cortisol in patients with MDD may influence the metabolism of Aß over prolonged periods of time.

Increased plasma glutamate by antipsychotic medication and its relationship to glutaminase 1 and 2 genotypes in schizophrenia -- Juntendo University Schizophrenia Projects (JUSP).

Disturbed glutamatergic neurotransmission has become recognized as a key component in the pathophysiology of schizophrenia. The change in serum/plasma glutamate with the use of antipsychotic medication has been studied and may be a possible clinical marker. In the present study, we examined plasma glutamate concentration, including a comprehensive investigation of its involvement with clinical course of schizophrenia and a genomic analysis. We performed a case-control genetic association analysis of the glutaminase 1 (GLS) and 2 (GLS2) genes. In addition, the difference in plasma glutamate concentration between the "acute stage" and "remission stage", and the effect of genotypes of SNPs within the two genes were assessed. The genetic association analysis of the GLS and GLS2 genes showed no association with schizophrenia. Plasma glutamate was increased with antipsychotic medication at "remission stage". Although GLS and GLS2 are not likely genetic risk factors for schizophrenia, changes in plasma glutamate concentration might be connected with clinical course of schizophrenia.

Residual memory impairment in remitted depression may be a predictive factor for recurrence.

OBJECTIVE: Memory impairment in remitted depression is reported to be related to the number of previous depressive episodes. A recent report hypothesized that each depressive episode increases the risk of memory impairment during remission, which further increases the risk of recurrence. We investigated whether the risk for recurrence increased as a function of memory impairment at remission. METHOD: One hundred ten participants with DSM-IV-TR major depressive disorder (MDD) after remission (defined as a score ≤ 7 on the Hamilton Depression Rating Scale) were recruited between April 2004 and March 2012 and were followed up prospectively. All patients were divided into 2 groups: those who had memory impairment and those who had no memory impairment after remission. (Memory impairment was determined with the Wechsler Memory Scale-Revised.) The time to recurrence of depression (a score ≥ 4 on the Clinical Global Impressions-Severity of Illness scale) was compared between the groups prospectively. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio (HR) estimates for a multivariate model were conducted to examine the risk of recurrence by presence of memory impairment after remission. RESULTS: One hundred nine participants completed this study. In the follow-up period, recurrence occurred in 25 (55.6%) of the 45 patients with memory impairment and 21 (32.8%) of the 64 patients with no memory impairment. In the Kaplan-Meier survival estimates for time to incidence of recurrence in patients with and without memory impairment, the cumulative probability of developing a recurrence for patients with memory impairment was higher than for patients with no memory impairment (log-rank test: χ(2)1 = 4.63, P = .03). Survival analysis was also performed using Cox proportional hazards regression in a multivariate model. The presence of memory impairment remained significantly associated with incidence of recurrence (HR = 2.55; 95% CI, 1.30-4.99; P = .006). CONCLUSIONS: The presence of residual memory impairment in patients with remitted MDD may increase the risk of recurrence.

Psychomotor agitation in major depressive disorder is a predictive factor of mood-switching.

BACKGROUND: The relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression. METHODS: We identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients (n=74), and (2) non-agitated patients (n=115). These groups were prospectively followed and compared by time to mood-switching. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation. RESULTS: During follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan-Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ(2)=7.148, df=1, p=0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18-7.51). LIMITATIONS: We did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching. CONCLUSIONS: The main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.

Temperament and character as predictors of recurrence in remitted patients with major depression: a 4-year prospective follow-up study.

The aim of the present study was to examine whether the specific personality traits, Harm-Avoidance (HA) and Self-Directedness (SD) as measured by the Temperament and Character Inventory (TCI), were predictive for subsequent depressive episodes in remitted patients with major depressive disorders (MDDs) over a 4-year follow-up. A total of 109 inpatients with MDD participated in this study. The subjects completed the TCI when they were assessed to be in remission. They were divided into high or low HA groups and high or low SD groups, as discriminated by the quartile value. A total of 69 patients were followed-up over a 4-year period or until recurrence. Both Kaplan-Meier analysis and Cox׳s proportional hazards regression analysis indicated that patients with a low SD score had a significantly shorter time to recurrence from remission than patients with a high SD score even when some prognostic predictors were controlled for. In contrast, HA was not found to be a predictor of recurrence for future depressive episodes. A part of MDD patients with low scores in Self-Directedness are likely to develop depression over a subsequent period of time. Interventions that improve SD may help to delay recurrence of depression in MDD patients.