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.

A Personal Historical Perspective on Psychiatry in Japan During the Last 4 Decades.

After graduating from University of Tsukuba in 1982, I joined the Department of Psychiatry at the same university. Due to the anti-psychiatry social movement and reports of incidents involving violence against in-hospital patients at psychiatric hospitals, psychiatric associations in Japan faced questions related to ethical awareness, making it a challenging environment for conducting clinical research. For this reason, the first half of my journey─my 20 years at the University of Tsukuba─was spent conducting basic research on animal models of schizophrenia. With respect to the onset of schizophrenia, I studied dopamine and related neuropeptides in the brain, as well as abnormalities in neurotransmission in the excitatory and inhibitory amino acid neurotransmission systems. In April 2002, I was appointed as a Department Chair at Juntendo University Koshigaya Hospital. I was responsible for overseeing many medical staff, including the clinical education of practicum students and resident physicians, as well as the training of psychiatric specialists. I was also involved in the management and operation of medical services provided at the mental health clinic that had 350 outpatients per day and saw the admission and discharge of 500 patients annually. Meanwhile, I became actively involved in activities related to perinatal mental health. In 2018, I was appointed as the Director of the Japanese Society of Perinatal Mental Health and worked diligently to improve medical care related to perinatal mental health in Japan through the development of perinatal mental health guidelines.

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.

Clinical guide for women with mental health problems during the perinatal period.

Pregnancy and childbirth have various effects on the physical as well as mental aspects of women. Therefore, appropriate considerations must be given to the mental health of pregnant women. The Guideline Review Committee of the Japanese Society of Psychiatry and Neurology launched a liaison meeting for the Japanese Society of Psychiatry and Neurology and the Japan Society of Obstetrics and Gynecology, with a view to creating a "Clinical guide for women with mental health problems during the perinatal period" by cooperation of these two fields. After repeated discussions with input from both academic societies, they jointly formulated the "Clinical guide for women with mental health problems during the perinatal period: Overview" in May 2020, and reported its "Detailed Contents" in April 2021. We hope that this guide, which is the English overview of the detailed guide, will contribute to the mental health of pregnant women, facilitating healthy pregnancies and childbirth.

Identification of 22q11.2 deletion in a patient with schizophrenia and clinically diagnosed Rubinstein-Taybi syndrome.

Background: Rubinstein-Taybi syndrome (RTS) is a rare autosomal-dominant disease. Almost all cases are sporadic and attributed to de novo variant. Psychotic symptoms in RTS are rare and have been reported in only a few published cases. On the other hand, 22q11.2 deletion syndrome is the most common chromosomal microdeletion in humans. The 22q11.2 deletion is well recognized as a risk factor for schizophrenia. Here, we present a schizophrenic psychosis case clinically diagnosed as RTS but resolved as carrying 22q11.2 deletion by genomic analysis. Case presentation: A 38-year-old Japanese male was admitted to our hospital due to psychotic symptoms. He had been diagnosed with RTS based on physical characteristics at the age of 9 months. On admission, we performed whole exome sequencing. He had no pathogenic variant in CREBBP or EP300. We detected 2.5 Mb deletion on 22q11.2 and one rare loss-of-function variant in a loss-of-function-constrained gene (MTSS1) and three rare missense variants in missense-constrained genes (CELSR3, HERC1, and TLN1). Psychotic symptoms were ameliorated by the treatment of risperidone. Conclusion: The psychiatric manifestation and genomic analysis may be a clue to detecting 22q11.2 deletion syndrome in undiagnosed patients. The reason for similarity in physical characteristics in 22q11.2 deletion syndrome and RTS remains unresolved. The 22q11.2 deletion and HERC1 contribute to the patient's phenotype.

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.

The long-term prognosis of hippocampal neurogenesis and behavioral changes of offspring from rats exposed to valproic acid during pregnancy.

AIM: In pregnant women with epilepsy, it is essential to balance maternal safety and the potential teratogenicity of anticonvulsants. Recently, growing evidence has indicated that valproic acid (VPA) can produce postnatal congenital malformations and impair cognitive function. However, the mechanisms underlying cognitive dysfunction in long-term prognoses remain unclear. METHODS: Pregnant Wistar rats received daily intraperitoneal injections of VPA (200 mg/kg/day) from embryonic day 12.5 until birth. On postnatal day (PD) 149, the rats received an injection of bromodeoxyuridine (BrdU). On PD 150, the rats were subjected to the open field (OF), elevated plus-maze (EPM), and Y-maze tests. After behavioral testing, perfusion fixation was performed and the brain was dissected for immunohistochemistry. RESULTS: A significant marked decrease was seen in the number of BrdU-positive cells in the dentate gyrus of offspring of VPA-treated dams compared to those of control. However, no significant differences in hyperactivity were found based on the results of the OF test among the offspring on PD 150 of 200 VPA-treated dams. In addition, no significant differences were seen in the EPM test. CONCLUSION: The behavioral abnormality observed in young offspring of VPA-treated dams was not significantly different from that of controls in adult offspring on PD 150. However, compared with controls, the number of BrdU-positive cells in VPA-treated rats was halved. The findings suggest that the behavioral abnormality seems to improve as they grow, even if some structural abnormalities may remain in the central nervous system.

Prevalence of perinatal depression among Japanese men: a meta-analysis.

INTRODUCTION: Perinatal depression is a widely discussed mental illness that occurs not only in women, but also in men. A previous international meta-analysis of the prevalence of paternal perinatal depression suggested that cross-cultural variables or socioeconomic environment may influence paternal depression. However, it is not clear that these data are general enough to apply to Japanese men, and there are few review articles about perinatal depression among this demographic. The purpose of our study is to provide a reliable estimate of the prevalence of perinatal depression among Japanese men. METHOD: We searched two databases, PubMed and ICHUSHI, to identify studies with data on the prevalence of prenatal or postpartum depression among Japanese men. Data were extracted from reports published from January 1994 to June 2018. The period prevalence of paternal perinatal depression among Japanese men was investigated. A subgroup analysis of gender differences in perinatal depression was also performed. RESULTS: We reviewed 1,379 abstracts, retrieved 33 articles and ultimately included 15 studies. The period prevalence of paternal prenatal depression in men was 8.5% (95% CI 3.3-20.3%). Moreover, the period prevalence of postpartum depression in men was 9.7% (95% CI 7.4-12.8%) within the first month, 8.6% (95% CI 5.5-13.3%) in postpartum months 1-3, 13.2% (95% CI 11.6-15.0%) in postpartum months 3-6 and 8.2% (95% CI 1.3-38.0%) in postpartum months 6-12. We also found that the prevalence of prenatal depression was significantly lower in men than in women. However, the prevalence of postpartum depression was not significantly different between men and women. CONCLUSIONS: The prevalence of perinatal depression among Japanese men peaked at 3-6 months after birth, and its overall prevalence was approximately 10%. These results were similar to those of an international meta-analysis on perinatal depression. Notably, we found that the prevalence of postpartum depression was as high in men as it was in women. Therefore, it is suggested that healthcare workers should be more watchful for paternal perinatal depression in the postpartum period than in the prenatal period.

Prevalence of perinatal depression among Japanese women: a meta-analysis.

BACKGROUND: Perinatal depression is one of the important mental illnesses among women. However, not enough reviews have been done, and a certain consensus has not been obtained about the prevalence of perinatal depression among Japanese women. The purpose of our study is to reveal the reliable estimates about the prevalence of perinatal depression among Japanese women. METHOD: We searched two databases, PubMed and ICHUSHI, to identify studies published from January 1994 to December 2017 with data on the prevalence of antenatal or postnatal depression. Data were extracted from published reports. RESULTS: We reviewed 1317 abstracts, retrieved 301 articles and included 123 studies. The point prevalence of postpartum depression at 1 month was 14.3% incorporating 108,431 Japanese women. The period prevalence of depression at pregnancy was 14.0% in the second trimester and 16.3% in the third trimester. The period prevalence of postpartum depression was 15.1% within the first month, 11.6% in 1-3 months, 11.5% in 3-6 months and 11.5% in 6-12 months after birth. We also identified that compared with multiparas, primiparas was significantly associated with a higher prevalence of postpartum depression; the adjusted relative risk was 1.76. CONCLUSIONS: The prevalence of postpartum depression at 1 month after childbirth was found to be 14.3% among Japanese women. During pregnancy, the prevalence of depression increases as childbirth approaches, and the prevalence of depression was found to decrease in the postpartum period over time. In addition, we found that the prevalence of postpartum depression in primiparas was higher than that in multiparas. Hence, we suggest that healthcare professionals need to pay more attention to primiparas than multiparas regarding postpartum depression.

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.

Prenatal exposure to valproic acid is associated with altered neurocognitive function and neurogenesis in the dentate gyrus of male offspring rats.

In pregnant women with epilepsy, it is imperative to balance the safety of the mother and the potential teratogenicity of anticonvulsants, which could cause impairments such as intellectual disability and cleft lip. In this study, we examined behavioral and hippocampal neurogenesis alterations in male offspring of rats exposed to valproic acid (VPA) during pregnancy. Pregnant Wistar rats received daily intraperitoneal injections of VPA (100 mg/kg/day or 200 mg/kg/day) from embryonic day 12.5 until birth. At postnatal day 29, animals received an injection of bromodeoxyuridine (BrdU). At postnatal day 30, animals underwent the open field (OF), elevated plus-maze, and Y-maze tests. After behavioral testing, animals were decapitated, and their brains were dissected for immunohistochemistry. Of the offspring of the VPA200 mothers, 66.6% showed a malformation. In the OF test, these animals showed locomotor hyperactivity. In the elevated plus-maze, offspring of VPA-treated mothers spent significantly more time in the open arms, irrespective of the treatment dose. The number of BrdU-positive cells in the dentate gyrus of the offspring of VPA-treated mothers increased significantly in a dose-dependent manner compared with the control. A significant positive correlation between spontaneous locomotor activity in the OF and BrdU-positive cell counts was observed across groups. In conclusion, VPA administration during pregnancy results in malformations and attention-deficit/hyperactivity disorder-like behavioral abnormalities in the offspring. An increase in cell proliferation in the hippocampus may underlie the behavioral changes observed. Repeated use of high doses of VPA during pregnancy may increase the risk of neurodevelopmental abnormalities dose dependently and should be carefully considered.

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.

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.

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.

Electroconvulsive stimulation transiently enhances the permeability of the rat blood-brain barrier and induces astrocytic changes.

The blood-brain barrier (BBB) plays important roles in both the physiological and pharmacological state of the brain. Transiently enhancing the permeability of the BBB may allow use of more types of medications for neuropsychiatric diseases. Several studies have demonstrated that seizures cause a transient decrease in BBB integrity. We studied the timing of BBB changes following seizures and the role of astrocytes in this process. Rats received 10 applications of electroconvulsive stimulation (ECS). They were then infused with sodium fluorescein, a fluorescent substance that rarely passes the BBB, via the inferior vena cava. After 120min of circulation, the amount of sodium fluorescein in the brain was measured by two methods in vivo fluorescence imaging (total radiant efficiency) and the brain concentration of sodium fluorescein. To assess any changes to the BBB, we measured S100Β in serum, which is a standard marker of BBB breakdown that is expressed by astrocytes. We also examined ultrastructural changes following ECS. Total radiant efficiency and the brain concentration of sodium fluorescein were significantly increased in treated rats compared to controls when sodium fluorescein was injected immediately after ECS but not when the injection was performed more than 15 min after ECS. Astrocytic endfeet showed swelling around brain capillaries following ECS. In conclusion, ECS transiently enhances the permeability of the BBB, which may be accompanied by changes in astrocytic endfeet.

Serum Levels of Albumin-ß-Amyloid Complex in Patients with Depression.

OBJECTIVE: Epidemiologic studies have demonstrated that suffering from depression may be a risk for Alzheimer disease (AD). As a possible biologic mechanism underlying the transition from depression to AD, it has been speculated that pathologic changes in ß-amyloid (Aß) metabolism are involved. To further understand the peripheral kinetics of amyloid in patients with depression, we investigated serum levels of free Aß and albumin-bound Aß. METHODS: Seventy inpatients with DSM-IV major depressive disorder (MDD) and 81 healthy individuals (the comparison group) were recruited between June 2012 and February 2014. Serum Aß40 and Aß42 levels, Aß40/Aß42 ratio, and serum levels of albumin-Aß complexes (SLAACs) were compared between the comparison group and patients in two age groups comprising younger (<60 years) and elderly (≥60 years) people. RESULTS: SLAAC was decreased in older patients with MDD but not in younger patients. The serum-free Aß40/Aß42 ratio was higher in patients with depression, even in younger patients. CONCLUSION: Our findings suggest that free Aß and the albumin-bound Aß reflect a different serum amyloid kinetics in depression. We speculate that serum-free Aß reflects changes in amyloid metabolism in patients suffering from depression and albumin-bound Aß reflects AD pathology and may be a potential predictor of the prodromal stage of AD.

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.

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.

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.