Utility and limitations of PHQ-9 in a clinic specializing in psychiatric care.

BACKGROUND: The Patient Health Questionnaire-9 (PHQ-9), despite its excellent reliability and validity in primary care, has not been examined for administration to psychiatric patients. This study assesses the accuracy of PHQ-9 in screening for major depressive episode and in diagnosing major depressive episode in patients of a psychiatric specialty clinic. METHODS: We compared operational characteristics of PHQ-9 as a screening and diagnostic instrument to DSM-IV-TR diagnosis by a trained psychiatrist as a reference standard. The reference criteria were "current major depressive episode" or "current major depressive episode with major depressive disorder". PHQ-9 was used with two thresholds: diagnostic algorithm and summary scores (PHQ-9 ≥ 10). The optimal cut-off points of PHQ-9 summary scores were analyzed using a receiver operational characteristics (ROC) curve. RESULTS: For "current major depressive episode", PHQ-9 showed high sensitivity and high negative predictive value at both thresholds, but its specificity and positive predictive value were low. For "current major depressive episode with major depressive disorder", PHQ-9 also showed high sensitivity and high negative predictive value at both thresholds, but the positive predictive value decreased more than that for "current major depressive episode". The ROC analysis showed the optimal cut-off score of 13/14 for "current major depressive episode". CONCLUSIONS: PHQ-9 is useful for screening, but not for diagnosis of "current major depressive episode" in a psychiatric specialty clinic.

Social Anxiety/Taijin-Kyofu Scale (SATS): development and psychometric evaluation of a new instrument.

BACKGROUND: Taijin-kyofu (TK), especially the 'convinced' subtype of TK (c-TK; also known as the 'offensive' subtype of TK), is described as a Japanese culture-bound syndrome similar to social anxiety disorder (SAD). Recently, in Western countries, the symptoms of c-TK have been investigated in patients with SAD. We developed the Social Anxiety/Taijin-Kyofu Scale (SATS), a 12-item structured clinician-rated instrument designed to rate the severity of TK symptoms, and examined its reliability and validity. METHODS: The SATS was administered to 15 patients with c-TK diagnosed using the traditional Japanese TK criteria. Interviews used to score patients' symptoms were recorded on videotape. Additionally, the Clinical Global Impression-Severity Scale (CGI-S) was administered to assess convergent validity. Interrater reliability was assessed on 15 videotaped interviews; the interviews were independently rated by 10 other raters. Test-retest re-liability was assessed on 15 videotaped interviews by the same rater at an interval of more than 4 weeks. RESULTS: The SATS had high internal consistency (Cronbach's α = 0.97) and good interrater reliability (ICC = 0.88-0.93) and test-retest reliability (ICC = 0.94-0.99). The SATS total score correlated with the CGI-S scores (r = 0.77, p < 0.0001). CONCLUSION: The SATS appears to be a reliable and valid measure of the symptoms of TK.

[Innovation of an animal model for the pathophysiology of schizophrenia].

The pharmacological treatment of schizophrenia now faces a turning point where we are preparing for the introduction of medications which have the mechanism of modulating glutamatergic neurotransmission, in contrast to antipsychotics which have the main mechanism of blocking and modulating D2-type dopamine receptor-mediated dopaminergic neurotransmission. In order to predict the effects of new medications modulating glutamatergic neurotransmission, we have to understand the pathophysiology of schizophrenia in the light of the dynamic time-axis. In the present review article, we have proposed a new "comprehensive progressive pathophysiology model" based on the "dopamine to glutamate hypothesis". Using this model, we distinguish the progressive pathophysiology-stage and subsequent residual-stage, to predict the effects of antipsychotics, mood stabilizers, and new glutamatergic modulators.

Olanzapine and risperidone block a high dose of methamphetamine-induced schizophrenia-like behavioral abnormalities and accompanied apoptosis in the medial prefrontal cortex.

This study aims to propose a comprehensive new model for schizophrenia, which shows PPI disruption at baseline state as an endophenotype, the development of cross-sensitization to an NMDA receptor antagonist, MK-801 as a clinical phenotype of the progression into treatment-resistance, and accompanied induction of apoptosis in the medial prefrontal cortex as a critical possibility during the progression. Repeated administration of a high dose of methamphetamine (METH) (2.5 mg/kg), which could increase glutamate levels in the medial prefrontal cortex (mPFC), induced TUNEL-positive cells in this region, accompanied development of behavioral cross-sensitization to MK-801 in response to a challenge injection of MK-801, and PPI disruption at baseline state without a challenge injection. Olanzapine (OLZ) (1.0 mg/kg) and risperidone (RIS) (0.1 mg/kg), which inhibited and remarkably attenuated METH (2.5 mg/kg)-induced increases in glutamate levels, respectively, blocked not only the induction of TUNEL-positive cells in the mPFC but also the accompanied development of above behavioral abnormalities. These findings suggest that repeating the METH-induced glutamate release produces behavioral abnormalities as a clinical phenotype of schizophrenia, accompanied apoptosis as a critical possibility during the progression, and suggest that sufficient dose of olanzapine and risperidone can block the development of these behavioral abnormalities and accompanied apoptosis during the progression.

Confirmation of the factorial structure of the Japanese short version of the TEMPS-A in psychiatric patients and general adults.

BACKGROUND: The Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A) is a 110-item questionnaire that assesses five affective temperaments. However, a valid shortened version is desired for large-scale investigations to enhance the compliance of respondents. METHODS: A confirmatory factor analysis was conducted among 320 psychiatric patients and 61 general adults. The participants completed the Japanese 39-item short version of the TEMPS-A, and a portion of the participants completed the 110-item version. An exploratory factor analysis with the principal factor method and varimax rotation was conducted to identify a more suitable model of the short version of the TEMPS-A. RESULTS: The confirmatory factor analysis revealed that the 39-item version exhibited a poor model fit. However, we found that the 18-item version exhibited a firm five-factor structure based on the exploratory factor analysis, and this model exhibited an acceptable model fit. It had good or acceptable internal consistency (Cronbach's αs: 0.672-0.819). LIMITATIONS: The majority of the subjects in the present study were patients, and the temperament data may have been affected by psychiatric symptoms. CONCLUSION: A firm five-factor structure was not found in the 39-item short version of the Japanese TEMPS-A. Therefore, an 18-item version was proposed. This new 18-item version of the TEMPS-A might be useful for clinical applications and large-scale investigations.

The moderator effects of affective temperaments, childhood abuse and adult stressful life events on depressive symptoms in the nonclinical general adult population.

BACKGROUND: We recently demonstrated in the structural equation modeling that four of five affective temperaments, as measured by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego auto-questionnaire version (TEMPS-A), are strong mediators between childhood abuse and depressive symptoms in the nonclinical general adult population. In this study, we hypothesized that affective temperaments, childhood abuse, and adult life events have moderator effects that interact with one another on depressive symptoms. The hierarchical multiple regression analysis was used to analyze this interaction model. METHODS: The 286 participants from the nonclinical general adult population were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), Life Experiences Survey (LES), TEMPS-A, and Child Abuse and Trauma Scale (CATS). The data were analyzed using hierarchical multiple regressions with interactions. RESULTS: Depressive temperament enhanced and hyperthymic temperament inhibited the depressogenic effects of childhood abuse, while irritable temperament enhanced and hyperthymic temperament inhibited the depressogenic effects of adult negative (stressful) life events. Adult positive life events had an inhibitory moderator effect on depressive symptoms that was increased by cyclothymic and anxious temperaments. Neglect, punishment, and total childhood abuse enhanced the effects of negative life events on depressive symptoms. LIMITATIONS: As the subjects of this study were nonclinical, the findings should not be generalized to patients with mood disorders. In this cross-sectional study, there may be interdependence between the measured variables. CONCLUSIONS: This study, using the hierarchical multiple regression analysis with interaction, demonstrated the positive and negative interactions between any two of affective temperaments, childhood abuse, and adult life events, and the influence on depressive symptoms in the nonclinical general adult population. Important moderator roles for affective temperaments, childhood abuse, and adult life events on depressive symptoms were suggested.

The structural equation analysis of childhood abuse, adult stressful life events, and temperaments in major depressive disorders and their influence on refractoriness.

BACKGROUND: Previous studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of a major depressive disorder (MDD). In this study, we tested our hypothesis that childhood abuse, affective temperaments, and adult stressful life events interact and influence the diagnosis of MDD. PATIENTS AND METHODS: A total of 170 healthy controls and 98 MDD patients were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), the Life Experiences Survey, the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire, and the Child Abuse and Trauma Scale (CATS). The data were analyzed with univariate analysis, multivariable analysis, and structural equation modeling. RESULTS: The neglect scores of the CATS indirectly predicted the diagnosis of MDD through cyclothymic and anxious temperament scores of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire in the structural equation modeling. Two temperaments - cyclothymic and anxious - directly predicted the diagnosis of MDD. The validity of this result was supported by the results of the stepwise multivariate logistic regression analysis as follows: three factors - neglect, cyclothymic, and anxious temperaments - were significant predictors of MDD. Neglect and the total CATS scores were also predictors of remission vs treatment-resistance in MDD patients independently of depressive symptoms. LIMITATIONS: The sample size was small for the comparison between the remission and treatment-resistant groups in MDD patients in multivariable analysis. CONCLUSION: This study suggests that childhood abuse, especially neglect, indirectly predicted the diagnosis of MDD through increased affective temperaments. The important role as a mediator of affective temperaments in the effect of childhood abuse on MDD was suggested.

The influence of childhood abuse, adult stressful life events and temperaments on depressive symptoms in the nonclinical general adult population.

BACKGROUND: Previous studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of major depression. We hypothesized that childhood abuse, affective temperaments, and adult stressful life events interact and influence depressive symptoms in the general adult population and tested this hypothesis in this study. METHODS: The 294 participants from the nonclinical general adult population were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), Life Experiences Survey (LES), Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS-A), and Child Abuse and Trauma Scale (CATS). The data were analyzed with single and multiple regressions and structural equation modeling (Amos 20.0). RESULTS: Childhood abuse indirectly predicted the severity of the depressive symptoms through affective temperaments measured by TEMPS-A in the structural equation modeling. Four temperaments - depressive, cyclothymic, irritable, and anxious - directly predicted the severity of depressive symptoms and the negative appraisal of life events during the past year. The negative appraisal of life events during the past year mildly, but significantly, predicted the severity of depressive symptoms. LIMITATIONS: The subjects of this study were nonclinical. The findings might not be generalized to patients with mood disorders. CONCLUSIONS: This study suggests that childhood abuse, especially neglect, indirectly increased depressive symptoms through increased affective temperaments, which, in turn, increase the negative appraisal of stressful life events. An important role of affective temperaments in the effect of childhood abuse and stressful life events on depressive symptoms was suggested.

Development and validation of a screening questionnaire for present or past (hypo)manic episodes based on DSM-IV-TR criteria.

BACKGROUND: We developed a self-reported questionnaire, the Manic Episode Screening Questionnaire (MES), based on the eight diagnostic criteria items of DSM-IV-TR (hypo)manic episodes. This study was designed to determine the optimal screening methods to identify bipolar disorders among mood disorder patients of a psychiatric specialty clinic. METHODS: In 95 mood disorder patients, we assessed the operational characteristics of the MES as a screening and diagnostic instrument using a DSM-IV-TR diagnosis by a trained psychiatrist as a reference standard. The reference criteria were bipolar disorders. MES was used with two methods: the diagnostic algorithm and the one-question method (question #1 only). The diagnostic algorithm was regarded as fulfilled if the answers to question #1 and three or more of questions #2 to #8 were "yes", corresponding to the DSM-IV-TR (hypo)manic episode criteria. In different subjects, the test-retest reliability of the MES was examined. RESULTS: The two methods of the MES showed high specificity (0.93-0.94), high positive predictive value (0.81-0.83) and high negative predictive value (0.88-0.90), but the sensitivity scored lower (0.68-0.75). The test-retest reliability was moderate: 0.75 for the diagnostic algorithm and 0.68 for the one-question method. LIMITATIONS: This study includes a small number of bipolar I patients. The findings might not be generalized to patients outside of this patient population. CONCLUSIONS: The MES is useful for the screening and diagnosis of bipolar disorders among mood disorder patients in psychiatric specialty clinics. The one-question method of the MES is more convenient to use than prior questionnaires and is here recommended.

Impaired integrity of the brain parenchyma in non-geriatric patients with major depressive disorder revealed by diffusion tensor imaging.

Diffusion tensor imaging (DTI) is considered to be able to non-invasively quantify white matter integrity. This study aimed to use DTI to evaluate white matter integrity in non-geriatric patients with major depressive disorder (MDD) who were free of antidepressant medication. DTI was performed on 19 non-geriatric patients with MDD, free of antidepressant medication, and 19 age-matched healthy subjects. Voxel-based and histogram analyses were used to compare fractional anisotropy (FA) and mean diffusivity (MD) values between the two groups, using two-sample t tests. The abnormal DTI indices, if any, were tested for correlation with disease duration and severity, using Pearson product-moment correlation analysis. Voxel-based analysis showed clusters with FA decrease at the bilateral frontal white matter, anterior limbs of internal capsule, cerebellum, left putamen and right thalamus of the patients. Histogram analysis revealed lower peak position of FA histograms in the patients. FA values of the abnormal clusters and peak positions of FA histograms of the patients exhibited moderate correlation with disease duration and severity. These results suggest the implication of frontal-subcortical circuits and cerebellum in MDD, and the potential utility of FA in evaluation of brain parenchymal integrity.

Developmental GABAergic deficit enhances methamphetamine-induced apoptosis.

RATIONALE: Neuroanatomical evidence suggests that GABAergic deficits and progressive cortical atrophy occur with schizophrenia. OBJECTIVE: To evaluate the hypothesis that neurodevelopmental deficits affect neurodegeneration occurring with schizophrenia, this study examined a novel animal model for schizophrenia-related neurodevelopmental GABAergic deficit in neurodegenerative progression. METHODS: The prenatal N-methyl-D-aspartate (NMDA) receptor hypofunction model that induces neurodevelopmental GABAergic deficit in the medial prefrontal cortex (mPFC) was used to examine whether adult offspring of Sprague-Dawley rats exhibited disruption of prepulse inhibition (PPI), enhancement of methamphetamine (METH) (2.5 mg/kg)-induced glutamate release in the mPFC and the emergence of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive neurons in this brain region. RESULTS: Offspring of dams exposed to NMDA receptor antagonist MK-801 on days 15-18 of pregnancy (MK-801 offspring) showed reduced density of parvalbumin-immunoreactive GABAergic interneurons in the mPFC, PPI disruption on postnatal days 63 (P63) and 35 (P35) and an enhanced METH (2.5 mg/kg)-induced glutamate release. Repeated administration of this psychostimulant increased the emergence of TUNEL-positive cells. CONCLUSION: These findings suggest that prenatal blockade of NMDA receptors induces a neurodevelopmental GABAergic deficit. The decrease in the density of GABAergic neurons might be related to disruption of sensorimotor gating (PPI), enhanced METH-induced release of glutamate in the mPFC and a repeated METH injection-induced increase in apoptosis in this region of the brain in adult animals.

Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats.

Lamotrigine (LTG) is sometimes co-administered with antipsychotic drugs for the treatment of schizophrenia. Nevertheless, the pharmacological basis of LTG use for schizophrenia has not been reported. Our group recently proposed a new psychostimulant animal model that might reflect the progressive pathophysiology of schizophrenia. Results obtained using that model show that LTG blocks the initiation and expression of repeated high-dosage methamphetamine-induced prepulse inhibition deficit in rats (Nakato et al., 2010, Neurosci. Lett. [25]). Using the model, the effect of LTG (30 mg/kg) on methamphetamine (METH, 2.5 mg/kg)-induced increases in extracellular glutamate levels in the medial prefrontal cortex (mPFC) was examined in this study. Then the effect of repeated co-administration of LTG (30 mg/kg) on repeated METH (2.5 mg/kg)-induced apoptosis in this region of rats was investigated. Results show that LTG (30 mg/kg) blocked the METH (2.5 mg/kg)-induced glutamate increase in the mPFC. Repeated co-administration of LTG (30 mg/kg) blocked the development of apoptosis induced by repeated administration of METH (2.5 mg/kg) in the mPFC. The LTG blocks histological abnormalities induced by repeated administration of METH, which suggests a mechanism of LTG that protects against progressive pathophysiology in schizophrenia.

Effects of aripiprazole and haloperidol on progression to schizophrenia-like behavioural abnormalities and apoptosis in rodents.

Aripiprazole (APZ) is considered a first-line medication for treating first and multiple episodes of schizophrenia, but its effect on preventing the progressive pathophysiology of schizophrenia remains unclear. This study examined the hypothesis that APZ blocks enhanced glutamate release in the medial prefrontal cortex (mPFC) during psychotic episodes of schizophrenia, thereby preventing progression of the pathophysiology. We examined effects of APZ on methamphetamine (METH)-induced increases in glutamate levels in the mPFC, and on repeatedly administered METH-induced progression to schizophrenia-like behavioural abnormalities involving cross-sensitization to the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, deficit of prepulse inhibition (PPI), and expression of TUNEL-positive cells. Additionally, we compared the preventive effects of APZ to those of a conventional antipsychotic: haloperidol (HPD). Results show that APZ (1.0 and 3.0 mg/kg) and HPD (0.1 mg/kg) each blocked METH (2.5 mg/kg)-induced increases in glutamate levels in the mPFC. Furthermore, APZ (3.0 mg/kg) and HPD (0.1 mg/kg), when co-administered repeatedly with METH, each prevented progression to schizophrenia-like behavioural and neuropathological abnormalities. Repeated co-administration of APZ (3.0 mg/kg) with saline did not induce apoptosis, although HPD (0.1 mg/kg) with saline did induce apoptosis. These results indicate that APZ and HPD prevented progressive pathophysiology, which is related to increased glutamate levels, and indicate that repeated administration of HPD, but not APZ, induced apoptosis under conditions without increased glutamate levels. These findings suggest the importance of using APZ and HPD in the appropriate stages of the glutamate-related pathophysiology of schizophrenia.

Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats.

We recently proposed a new psychostimulant animal model of the progressive pathophysiological changes of schizophrenia. Studies using that model produced a treatment strategy for preventing progression. Lamotrigine (LTG) blocks repeated high-dosage methamphetamine (METH)-induced initiation and expression of prepulse inhibition deficit and development of apoptosis in the medial prefrontal cortex (mPFC). Moreover, it inhibits METH-induced increases in extracellular glutamate levels in the mPFC (Nakato et al., 2011, Neurosci. Lett.). Abnormal behavior induced by METH or NMDA receptor antagonists is regarded as an animal model of schizophrenia. This study examined the effects of LTG on the development of behavioral sensitization to METH and cross-sensitization to dizocilpine (MK-801) by repeated administration of high-dose METH (2.5mg/kg, 10 times s.c.). Rats were injected repeatedly with LTG (30mg/kg) after 120min METH administration (2.5mg/kg). Repeated co-administration of LTG blocked the development of behavioral cross-sensitization to MK-801 (0.15mg/kg), but it did not prevent behavioral sensitization to METH (0.2mg/kg). The LTG-induced prevention of increased glutamate by high-dose METH might be related to the former finding. Combined results of our previous studies and this study suggest that LTG is useful to treat schizophrenia, especially at a critical point in its progression.

Long-term naturalistic follow-up of lithium augmentation: relevance to bipolarity.

BACKGROUND: Whether bipolarity (unrecognized bipolar disorder) is related to the treatment response to lithium augmentation in antidepressant-refractory depression remains unclear. This study of responders and non-responders to lithium augmentation of 29 antidepressant-refractory patients with major depression, whom we had studied during 1995-1997, compared the bipolar diagnosis at the follow-up based on diagnostic confirmation after long-term follow-up. METHODS: Before being classified as stage 2 treatment-resistant depression, these patients had been treated adequately with at least two tricyclic or heterocyclic antidepressants from different pharmacological classes (a minimum of the equivalent of 150 mg of imipramine for 4 weeks). During 1995-1997, 29 patients received lithium augmentation. Their treatment responses were recorded. Mean follow-up was 8.0 years (range, 1-13 years). Bipolar conversion and full remission were evaluated. RESULTS: After the long-term follow-up, diagnoses were changed to bipolar depression in 3 of 4 lithium responders and 3 of 25 lithium non-responders; lithium augmentation was more effective for unrecognized bipolar patients. Only the family history of bipolar disorder predicted subsequent bipolar conversion. LIMITATIONS: Treatment was not controlled in this naturalistic study, which had a small sample size. CONCLUSIONS: Results of this long-term follow-up study suggest that bipolarity is related to a positive response to lithium augmentation in stage 2 treatment-resistant major depression. The family history of bipolar disorder suggests false unipolar depression, and therefore indicates lithium responders.

Lamotrigine blocks the initiation and expression of repeated high-dose methamphetamine-induced prepulse inhibition deficit in rats.

Our group developed a new psychostimulant animal model reflecting some clinical aspects of schizophrenia better than the conventional model does. In this model, long-lasting prepulse inhibition (PPI) deficit at the basement state is induced via repeated administration of methamphetamine (METH, 2.5mg/kg) without challenge injection of this psychostimulant. This study elucidates the effects of lamotrigine (LTG, 30mg/kg) on the initiation and expression of a steady-state PPI deficit induced by the repeated METH administration. We assessed the effect of coadministration of LTG and METH on the initiation of PPI deficit. The LTG was injected 120min after each METH injection for 5 times on every alternate day and for an additional 5 times every day, amounting to a total of 10 times. After 11-13 days of the withdrawal period, we measured PPI using the SR-LAB system. Using other animals after 20min of LTG injection, we subsequently examined the effect of a single injection of LTG on the expression of PPI deficit caused by the repeated METH administration. The LTG blocked the initiation of PPI deficit induced by the repeated METH administration at 68dB of prepulse intensity, but had no effect on the startle amplitude. The LTG prevented the initiation and expression of neuroplastic PPI deficit detected at the baseline state without any METH challenge injection, which was induced by the repeated administration of this psychostimulant. Results suggest that LTG is useful for blocking progressive deterioration of neurocognitive function and recovering the neurocognitive deficit in schizophrenia.

Pramipexole for stage 2 treatment-resistant major depression: an open study.

OBJECTIVE: To examine the effectiveness and safety of adjunctive pramipexole in the treatment of stage 2 treatment-resistant major depressive disorder. METHODS: This study included patients with moderate or non-psychotic severe major depressive disorder according to DSM-IV-TR criteria despite at least two adequate treatment trials with antidepressants from different pharmacological classes. Pramipexole 0.25 to 2 mg daily was added to antidepressant therapy. Previous treatments were continued unchanged, but no new treatments were allowed. We conducted assessments at baseline and at weeks 2, 4, 6, and 8. We defined response as a 50% or greater reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Ten patients (4 men, 6 women) aged 43.7±11.4 years received pramipexole at mean dose of 1.3±0.6 mg/d. Mean MADRS scores improved significantly from baseline to endpoint (mean differences=11.4, 95% CI [4.1, 18.7], P=0.0064). At the endpoint, six of 10 (60%) were responders on MADRS (≥50% reduction). Two patients (20%) terminated early due to mild somatic and psychiatric adverse effects. CONCLUSION: These preliminary data suggest that the addition of pramipexole to antidepressant treatment may be effective and well tolerated in patients with stage 2 treatment-resistant major depressive disorder.