Skip to main content

Abstract

Objective:

Despite the high frequency of depression in the first year following stroke, few studies have predicted risk of depression after the acute and subacute stroke periods. The aim of this study was to identify, in the acute and subacute periods, measures that would predict major depression during the first year after stroke.

Methods:

Study subjects were inpatients with ischemic stroke aged 20–85 years within 6 weeks of onset. Patients were evaluated at baseline and at 3, 6, 9, and 12 months. Patients were diagnosed with major depression using the Structured Clinical Interview for DSM-IV. The severity of depressive symptoms was measured with the Patient Health Questionnaire-9 (PHQ-9) and the Montgomery-Åsberg Depression Rating Scale (MADRS).

Results:

Of the 152 potential patients who met inclusion criteria, 49 had follow-up evaluations; one patient with major depression in the acute and subacute periods was excluded from the analysis. Among the remaining 48 patients, the number of those with major depression during the first year of stroke onset was five (10.4%). Patients who developed major depression had significantly more depressive symptoms in the acute and subacute stroke phase as assessed by both the PHQ-9 and MADRS. Patients with PHQ-9 scores ≥9 in the acute and subacute stroke phases were significantly more likely to develop major depression in a chronic phase of stroke.

Conclusions:

The self-administered PHQ-9 can identify patients in the acute and subacute stroke periods who are at increased risk for developing major depression during the first year after stroke.
Stroke was the third leading cause of mortality in Japan in 2017 (1). In 2019, those over age 65 accounted for 28.4% of the total population in Japan, which ranked first among 201 countries (2, 3).
In large cohorts exceeding 25,000 people, poststroke depression has been found to occur in approximately 30% of survivors during the first year following stroke (4). Depression following stroke has been shown in numerous studies to impair both cognitive and motor recovery as well as increase mortality for as long as 10 years following acute stroke (510).
Although several studies have found that antidepressant medications can prevent the development of depression (11, 12), many patients are reluctant to take antidepressants before they are depressed. Thus, methods to predict the risk of developing depression after acute stroke are needed. However, very few studies have tried to identify reliable methods for predicting the development of depression after the acute stroke period.
The present study was designed to examine frequency and risks of major depression after ischemic stroke. We tested the hypothesis that subsyndromal depressive symptoms during the acute and subacute stroke periods would predict the development of major depression during the chronic 1-year period following stroke. The aim of this study, therefore, was to assess the reliability of standardized instruments during the acute and subacute stroke periods to predict patients’ likelihood of developing major depression during the first year chronic stage following stroke.

Methods

Participants

Study subjects were enrolled and followed between July 2014 and March 2019 from inpatients at the Department of Neurology, Tokai University Hospital, with ischemic stroke aged 20–85 years within 6 weeks of onset. Patients were excluded if they had impairment of consciousness, history of dementia, another form of brain injury or aphasia with severe comprehension deficits, or cognitive impairment due to stroke that impaired their ability to understand informed consent or mental status questions. In addition, patients were excluded if they met DSM-IV criteria for alcohol or substance abuse or dependence within the 24 weeks prior to enrollment or if they met DSM-IV criteria for schizophrenia or other psychotic disorders. The patients were examined at initial evaluation (i.e., within 6 weeks of stroke onset) and 3, 6, 9, and 12 months after the ischemic stroke. Depression, cognition, and quality of life were assessed at each of these visits. To predict onset of major depression during the chronic stage of the first year after stroke, patients with major depression in the acute and subacute stroke periods (i.e., within 6 weeks of stroke onset) were excluded from the analysis.
The Institutional Review Board for Clinical Research of the Tokai University School of Medicine approved this study. Written consent was obtained from all enrollees.

Neurological Evaluations

At least two neurologists diagnosed an ischemic stroke based on a complete physical and neurological examination, and MRI brain scans. The severity of the stroke was assessed using the National Institutes of Health Stroke Scale (13).

Assessment for Depression

The patients were examined using the Structured Clinical Interview for DSM-IV (SCID) (14, 15) mood and anxiety disorder section. The diagnosis of major depression developing for the first time after stroke was based on symptoms elicited by the SCID and DSM-IV criteria.
The severity of depressive symptoms was objectively assessed using the Japanese version of the Montgomery-Åsberg Depression Rating Scale (MADRS); it comprises 10 items, each of which is scored on a scale that ranges from 0 to 6 (16, 17). The MADRS has been used widely in clinical double-blind studies to assess the efficacy of various antidepressant therapies in Western countries (18).
The Patient Health Questionnaire (PHQ-9) Japanese version consists of questions about the nine symptom criteria upon which the DSM-IV major depression diagnosis is based (19, 20). The PHQ-9 is a self-administered questionnaire that asks patients to rate their symptoms of depression from 0 to 3 (0=not at all; 3=nearly every day) over the past 2 weeks. Total scores from 1 to 4 are categorized as minimal, from 5 to 9 mild, from 10 to 14 moderate, from 15 to 19 moderately severe, and from 20 to 27 severe (19). The PHQ-9 is widely used throughout the world to screen for depressive disorder and monitor depressive symptoms. The original version of the PHQ-9 has been translated into multiple languages and validated in numerous studies globally (2022).

Cognitive Assessment

Global cognitive impairment was assessed at all evaluations using the Japanese version of the Mini-Mental State Examination (23, 24). Scores may range from 0 to 30, with lower scores indicating greater impairment. In addition, the Frontal Assessment Battery, developed as a short bedside cognitive and behavioral battery to assess frontal lobe functions, was also administered (25, 26). The Frontal Assessment Battery consists of six items, and the score on each item ranges from 0 to 3. A higher score indicates better frontal lobe performance.

Assessment for Quality of Life

The 36-item Short Form Survey (SF–36) (27) is one of the most widely used generic health survey instruments. The Japanese version of the SF–36 (2830), which has been demonstrated to address issues of validity and comparability with the English version, was used to evaluate health-related quality of life. The SF–36 health questionnaire generates three scores: a physical component summary, a mental component summary, and a role/social component summary (31). All scores were transformed to fit a norm-based score of 50 and standard deviation of 10, with higher scores indicating better quality of life.

Statistical Analysis

This study used a prospective design. Continuous variables were presented as means and standard deviation according to the diagnosis of depression. Categorical variables were summarized by descriptive statistical methods. Continuous variables were compared using the Mann-Whitney U test, whereas categorical variables were compared using the Fisher’s exact test. For each mental, cognitive, or physical characteristic at baseline, a simple logistic regression model was applied to identify factors that predict the onset of depression (32). For each identified factor, the predictive performance of discrimination was evaluated by calculating area under the receiver operating characteristic curve (AUROC). The AUROC was tested to determine whether it was >0.5. The predictive performance of calibration was evaluated by using the Hosmer-Lemeshow test. Threshold value for each predictive factor was determined considering the values of sensitivity and specificity. In order to evaluate the influence of missing values for each predictive factor, multiple imputation was applied (33). All statistical tests were performed with two-sided significance level of 0.05 using SAS 9.4 (SAS Institute, Cary, N.C.).

Results

Participants

A total of 152 patients met inclusion criteria; of these, 99 refused informed consent. In addition, four withdrew their previously granted consent. To predict patients in the acute and subacute stroke periods who would develop major depression during the chronic period of the first year following stroke, one patient who had a diagnosis of major depression in the acute and subacute phase was excluded from the analysis. The remaining 48 patients were included in the analysis. The number of patients with major depression during the chronic first year after stroke onset was five (10.4%). The mean time from stroke to onset of major depression was 7.2 months. Demographic and clinical characteristics of depressed and nondepressed patients are presented in Table 1. Psychiatric history included previous psychiatric outpatient treatment or use of a psychotropic medication.
TABLE 1. Demographic and clinical characteristics of ischemic stroke patients with and without depression
CharacteristicWithout depression (total N=43)With depression (total N=5)pa
 N%N% 
Categorical variables     
 Male3581.4240.00.0716
 Employment1739.5120.00.6372
 Living alone37.000.01.0000
 Psychiatric history511.6360.00.0272
 Coronary artery disease818.600.00.5730
 Atrial fibrillation818.6120.01.0000
 Stroke characteristics    0.3233
  Large-artery atherosclerosis49.3240.0 
  Small-artery occlusion1841.9120.0 
  Cardioembolism818.6120.0 
  Other demonstrated cause1227.9120.0 
  Undetermined cause12.300.0 
Left-side lesions2148.8240.01.0000
 MeanSDMeanSD 
Continuous variables     
 Age (years)69.010.567.28.30.3355
 National Institutes of Health Stroke Scale3.84.14.05.60.5167
 Systolic blood pressure (mmHg)157.623.6174.836.80.3275
 Low-density lipoprotein cholesterol (mg/dl)123.430.7145.433.20.1613
 HbA1c (mg/dl)6.11.35.70.60.8259
a
Fisher’s exact test was used for categorical variables, and Mann-Whitney U test was used for continuous variables.

Depressive State, Cognitive and Physical Function, and Quality of Life in a Subacute Stroke Phase

The mental, cognitive, and physical characteristics of patients at baseline are summarized in Table 2. The patients who developed major depression during the first year had significantly higher scores at baseline on the MADRS and PHQ-9.
TABLE 2. Baseline severity of depression, cognitive impairment, and quality-of-life scores among patients with ischemic strokea
 Without depression (total N=43)With depression (total N=5) 
AssessmentMeanSDMeanSDpb
MADRS4.55.615.09.90.0102
PHQ–92.23.08.84.50.0056
MMSE26.93.329.60.50.0799
FAB12.83.314.61.50.2338
mRS1.61.42.01.60.5197
SF–36     
 PCS42.713.532.822.70.2118
 MCS58.510.549.612.50.1173
 RCS44.415.532.123.70.1725
a
FAB=Frontal Assessment Battery, MADRS=Montgomery-Åsberg Depression Rating Scale, MCS=mental component summary, MMSE=Mini-Mental State Examination, mRS=modified Rankin Scale, PHQ–9=Patient Health Questionnaire–9, SF–36=36-item Short Form Survey, PCS=physical component summary, QOL=quality of life, RCS=role-social component summary.
b
Test for odds ratio=1 in simple logistic regression.

Predictive Tools for Depression

The predictive performance of discrimination and calibration for the identified two factors are shown in Table 3. MADRS and PHQ-9 in the subacute stroke phase had good classification ability to discriminate those who developed depression during the first year because the AUROCs were 0.83 and 0.88 (i.e., significantly greater than 0.5 compared with random classification). In addition, the Hosmer-Lemeshow test was nonsignificant.
TABLE 3. Predictive performance of mental and physical characteristics among patients with ischemic strokea
VariableAUROC95% CIpbHosmer-Lemeshow test p
MADRS0.830.61, 1.000.00330.4444
PHQ–90.880.69, 1.000.00010.1646
a
AUROC=Area under the receiver operating characteristic curve, MADRS=Montgomery-Åsberg Depression Rating Scale, PHQ–9=Patient Health Questionnaire–9.
b
Test for AUROC=0.5,
Furthermore, the threshold values were determined to make sensitivity plus specificity maximum. The threshold value of MADRS was 11, and its specificity and sensitivity were 0.881 (37/42) and 0.800 (4/5), respectively. The positive predictive value (PPV) and the negative predictive value (NPV) were 0.444 (4/9) and 0.974 (37/38), respectively. The threshold value of PHQ-9 was 9, and its specificity and sensitivity were 0.921 (35/38) and 0.800 (4/5), respectively. The PPV and NPV were 0.571 (4/7) and 0.972 (35/36), respectively. There was one missing MADRS score and five missing PHQ-9 scores in the nondepressed group. Similar results were obtained by the multiple imputation approach, suggesting little influence of missing values. The Pearson correlation coefficient between MADRS and PHQ-9 was 0.64 (p<0.001).

Discussion

To our knowledge, this is the first study to demonstrate that both the PHQ-9 and MADRS in the acute and subacute phase of ischemic stroke (i.e., within 6 weeks poststroke) were able to predict major depression during the chronic first-year period with an accuracy >80%.
Previous studies have demonstrated the efficacy of antidepressants to prevent the development of depression during the first year after stroke (11) and to decrease the mortality rate for depressed patient up to 5 years after stroke (34). Therefore, one might logically ask why the acute and subacute prediction of major depression during the chronic poststroke period is useful in the clinical setting. Based on our prior randomized studies of antidepressants to treat poststroke depression, we found that eight out of 30 patients randomized to medication refused to take medications due to fear of side effects of medications and/or because they did not feel depressed at that time (35). Thus, a significant number of patients with stroke are resistant to taking medications. The current study, however, demonstrated a clear method to identify stroke patients at high risk for developing major depression in the chronic period after stroke. Clinicians, therefore, may monitor the patients who have increased risk of major depression in the chronic stroke phase.
The only other study that we are aware of to examine risk of future poststroke depression was done by Fuentes et al. (36). This study found that higher scores on the Hamilton Depression Rating Scale (HAM-D) was associated with a three times greater risk of poststroke depression at the 3-month follow-up. However, the HAM-D, similar to the MADRS, is based on a clinical interview that requires a trained clinician.
Among combined studies of 2,769 patients hospitalized for subacute stroke or rehabilitation, 21.6% were diagnosed with major depression (37). Furthermore, approximately 15% of patients who were not depressed at initial assessment developed depression during the first year following stroke (4). In Japan, Kaji et al. (38) examined incident depression among 100 patients at 2 to 5 weeks after onset of stroke using the Mini-International Neuropsychiatric Interview (MINI); they found that the prevalence of major depression was 5%. In addition, a multiple-center study examined incident depression among 373 patients in a subacute-chronic phase of stroke (1 month to 1 year after the onset of stroke) using the MINI, and found that the prevalence of major depression was 9.9% (39). In the current study, the prevalence of patients with major depression in the chronic phase of stroke (7 weeks to 1 year after onset of stroke) was 10.4%. In Japan, the prevalence of poststroke chronic onset major depression may be lower than that in the United States and European countries. Therefore, the PPV and NPV should be carefully interpreted for a different population of interest because the PPV and NPV are highly dependent on the prevalence. For the Japanese stroke patient population, we can interpret that the risk for depression increases from 10% to 57% if the score of PHQ-9 is ≥9. For a different population where the prevalence is higher, the PPV or NPV should be interpreted differently.
The present study had the following limitations that should be acknowledged. First, the number of cases was rather small because only one institution was involved. Second, almost two thirds of the patients who met inclusion criteria declined to sign a consent form and therefore could not be included. The reason why so many patients refused to participate is unclear, but most of the patients in this study lived around the Tokai University Hospital; they might have been afraid that neighbors might discover information about their stroke or depression. In any event, additional patients need to be studied to assess the accuracy of the cut-off scores derived from this study as well as the utility of each of these depression scales.
In conclusion, a PHQ-9 score ≥9 in the acute and subacute phase of stroke was associated with an increased risk of developing major depression during the chronic period of the first year following stroke. The self-administered PHQ-9 may be a beneficial tool to help clinicians to identify patients who are at increased risk of developing depression during the first year after stroke.

Acknowledgments

The authors thank Michiyo Iwamoto, Clinical Trial Center of Tokai University Hospital, and Shino Tsuji, Nursing Division of Tokai University Hospital.

References

1.
Health, Labour and Welfare Statistics Association: Health, Labour and Welfare Statistics Association: Annual Statistical Report of National Health Conditions in Japan. Tokyo, Health, Labour and Welfare Statistics Association, 2019 [In Japanese]
2.
UN Department of Economic and Social Affairs: World Population Prospects 2019, Population by Broad Age Groups–Both Sexes. New York, UN Department of Economic and Social Affairs, 2019. https://population.un.org/wpp/Download/Standard/Population
3.
UN Department of Economic and Social Affairs: World Population Prospects 2019: Data Booklet. New York, UN Department of Economic and Social Affairs, 2019. https://population.un.org/wpp/Publications/Files/WPP2019_DataBooklet.pdf
4.
Hackett ML, Köhler S, O’Brien JT, et al: Neuropsychiatric outcomes of stroke. Lancet Neurol 2014; 13:525–534
5.
Parikh RM, Robinson RG, Lipsey JR, et al: The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up. Arch Neurol 1990; 47:785–789
6.
Morris PL, Robinson RG, Andrzejewski P, et al: Association of depression with 10-year poststroke mortality. Am J Psychiatry 1993; 150:124–129
7.
Herrmann N, Black SE, Lawrence J, et al: The Sunnybrook Stroke Study: a prospective study of depressive symptoms and functional outcome. Stroke 1998; 29:618–624
8.
House A, Knapp P, Bamford J, et al: Mortality at 12 and 24 months after stroke may be associated with depressive symptoms at 1 month. Stroke 2001; 32:696–701
9.
Pohjasvaara T, Vataja R, Leppävuori A, et al: Depression is an independent predictor of poor long-term functional outcome post-stroke. Eur J Neurol 2001; 8:315–319
10.
Ayerbe L, Ayis S, Crichton SL, et al: Explanatory factors for the increased mortality of stroke patients with depression. Neurology 2014; 83:2007–2012
11.
Robinson RG, Jorge RE, Moser DJ, et al: Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. JAMA 2008; 299:2391–2400
12.
Tsai CS, Wu CL, Chou SY, et al: Prevention of poststroke depression with milnacipran in patients with acute ischemic stroke: a double-blind randomized placebo-controlled trial. Int Clin Psychopharmacol 2011; 26:263–267
13.
Kunitz SC, Gross CR, Heyman A, et al: The pilot Stroke Data Bank: definition, design, and data. Stroke 1984; 15:740–746
14.
First M, Spitzer R, Gibbon M, et al: The Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition. New York, Biometrics Research Department, New York State Psychiatric Institute, 2010
15.
Takahashi S, Kitamura T, Okano T: Seishinka Shindan Mensetsu Manual. [Japanese Version of the Structured Clinical Interview for DSM-VI-TR Axis I Disorders] Tokyo, Nihon Hyoronsha, 2010
16.
Montgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382–389
17.
Takahashi N, Tomita K, Higuchi T, et al: The inter-rater reliability of the Japanese version of the Montgomery-Asberg depression rating scale (MADRS) using a structured interview guide for MADRS (SIGMA). Hum Psychopharmacol 2004; 19:187–192
18.
Leucht S, Fennema H, Engel RR, et al: Translating the HAM-D into the MADRS and vice versa with equipercentile linking. J Affect Disord 2018; 226:326–331
19.
Kroenke K, Spitzer RL, Williams JB: The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606–613
20.
Muramatsu K, Miyaoka H, Kamijima K, et al: The Patient Health Questionnaire, Japanese version: validity according to the Mini-International Neuropsychiatric Interview-Plus. Psychol Rep 2007; 101:952–960
21.
Kroenke K, Spitzer RL, Williams JB, et al: The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry 2010; 32:345–359
22.
Muramatsu K, Miyaoka H, Kamijima K, et al: Performance of the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) for depression in primary care. Gen Hosp Psychiatry 2018; 52:64–69
23.
Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189–198
24.
Ideno Y, Takayama M, Hayashi K, et al: Evaluation of a Japanese version of the Mini-Mental State Examination in elderly persons. Geriatr Gerontol Int 2012; 12:310–316
25.
Dubois B, Slachevsky A, Litvan I, et al: The FAB: a Frontal Assessment Battery at bedside. Neurology 2000; 55:1621–1626
26.
Kugo A, Terada S, Ata T, et al: Japanese version of the Frontal Assessment Battery for dementia. Psychiatry Res 2007; 153:69–75
27.
Ware JE Jr, Sherbourne CD: The MOS 36-item Short-Form Health Survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30:473–483
28.
Fukuhara S, Bito S, Green J, et al: Translation, adaptation, and validation of the SF-36 Health Survey for use in Japan. J Clin Epidemiol 1998; 51:1037–1044
29.
Fukuhara S, Ware JE Jr, Kosinski M, et al: Psychometric and clinical tests of validity of the Japanese SF-36 Health Survey. J Clin Epidemiol 1998; 51:1045–1053
30.
Fukuhara S, Suzukamo Y: Manual of SF-36 v2, Japanese Version. Kyoto, Japan, Institute for Health Outcomes and Process Evaluation Research, 2015
31.
Suzukamo Y, Fukuhara S, Green J, et al: Validation testing of a three-component model of Short Form-36 scores. J Clin Epidemiol 2011; 64:301–308
32.
Meurer WJ, Tolles J: Logistic regression diagnostics: understanding how well a model predicts outcomes. JAMA 2017; 317:1068–1069
33.
Sterne JA, White IR, Carlin JB, et al: Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 2009; 338:b2393
34.
Robinson RG, Jorge RE, Long J: Prevention of poststroke mortality using problem-solving therapy or escitalopram. Am J Geriatr Psychiatry 2017; 25:512–519
35.
Robinson RG, Schultz SK, Castillo C, et al: Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry 2000; 157:351–359
36.
Fuentes B, Ortiz X, Sanjose B, et al: Post-stroke depression: can we predict its development from the acute stroke phase? Acta Neurol Scand 2009; 120:150–156
37.
Robinson R: The Clinical Neuropsychiatry of Stroke, 2nd ed. Cambridge, United Kingdom, Cambridge University Press, 2006
38.
Kaji Y, Hirata K, Ebata A: Characteristics of post-stroke depression in Japanese patients. Neuropsychobiology 2006; 53:148–152
39.
Kaji Y, Hirata K, Katayama Y, et al: Characteristics of post-stroke depression and treatment strategy in Japanese patients: a multi-center study. Neurol Ther 2017; 34:37–42 [in Japanese]

Information & Authors

Information

Published In

Go to The Journal of Neuropsychiatry and Clinical Neurosciences
Go to The Journal of Neuropsychiatry and Clinical Neurosciences
The Journal of Neuropsychiatry and Clinical Neurosciences
Pages: 43 - 48
PubMed: 33086923

History

Received: 9 April 2020
Revision received: 23 June 2020
Accepted: 29 July 2020
Published online: 22 October 2020
Published in print: Winter 2021

Keywords

  1. Depression
  2. Predictor
  3. Stroke
  4. PHQ-9
  5. MADRS
  6. Stroke and Other Cerebral Vascular Disease (Neuropsychiatric Aspects)
  7. Depression

Authors

Details

Katsunaka Mikami, M.D., Ph.D. [email protected]
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Takeshi Sudo, Ph.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Yasushi Orihashi, M.S.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Keitaro Kimoto, M.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Atsushi Mizuma, M.D., Ph.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Tsuyoshi Uesugi, M.D., Ph.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Reina Kawamura, M.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Kazunari Honma, M.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Eiichiro Nagata, M.D., Ph.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Kenji Yamamoto, M.D., Ph.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Shunya Takizawa, M.D., Ph.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Hideo Matsumoto, M.D., Ph.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).
Robert G. Robinson, M.D.
Department of Psychiatry, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mikami, Sudo, Kimoto, Yamamoto, Matsumoto); Teikyo Heisei University Graduate School of Clinical Psychology, Tokyo (Sudo); Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Orihashi); Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan (Mizuma, Uesugi, Kawamura, Honma, Nagata, Takizawa); Department of Neurology, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka, Japan (Honma), and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Robinson).

Notes

Send correspondence to Dr. Mikami ([email protected]).

Competing Interests

Dr. Mikami has received research grant support from Grant-in-Aid for Scientific Research, the Japanese Society for Probiotic Science, Otsuka Pharmaceutical, Shionogi & Co., and Taisho Pharmaceutical; honoraria from Eli Lilly, Meiji Holdings, Miyarisan Pharmaceutical, Otsuka Pharmaceutical, Shionogi & Co., Shire Japan, and Takeda Pharmaceutical; and consulting fees from Otsuka Pharmaceutical and Shionogi & Co. Dr. Orihashi has received consulting fees from the Association of Medical Education and Ethics, Daiichi Sankyo, and Kitasato Clinical Research Center. Dr. Kimoto has received research support from Otsuka Pharmaceutical, Shionogi & Co., and Taisho Pharmaceutical. Dr. Mizuma has received research support from SENSHIN Medical Research Foundation. Dr. Nagata has received research support from Scientific Research and personal fees from Daiichi Sankyo Co., Eisai Co., and Takeda Co. Dr. Yamamoto has received grant support from Eisai Co., Ltd.; grant support and personal fees from Otsuka Pharmaceutical Co., Ltd.; personal fees from Meiji Seika Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Pfizer Japan Inc., Mitsubishi Tanabe Corporation, Shionogi & Co., Eli Lilly and Company, EPS Holdings, Inc., Grant-in-Aid for Scientific Research. Dr. Takizawa has received research grant support from Scientific Research. Dr. Matsumoto has received research support from Aikou Hospital, Dainippon Sumitomo, Keyaki-no-mori Hospital, Kishi Byoin, KOIKE-YA, Kouzu Hospital, Mental Clinic Yokohama Minatomirai, Otsuka Pharmaceutical, Shionogi & Co., Soushu Hospital, Tanzawa Hospital; and honoraria from Astellas Pharma, Dainippon Sumitomo, Eli Lilly, Eisai, GlaxoSmithKline, Janssen, Meiji Seika Pharma, MSD and Mitsubishi Tanabe Pharma, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi & Co., and Yoshitomiyakuhin Corporation. The other authors report no financial relationships with commercial interests.

Funding Information

JSPS KAKENHI Grant Number JP26461774:
Tokai University School of Medicine Research Aid:
Supported by JSPS KAKENHI (grant JP26461774) and Tokai University School of Medicine Research Aid.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Get Access

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - Journal of Neuropsychiatry and Clinical Neurosciences

PPV Articles - Journal of Neuropsychiatry and Clinical Neurosciences

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share