Circulating Neuroactive Steroid Levels in a Patient With Schizophrenia Who Showed Periodic Catatonia.

Catatonia is an abnormal psychological and behavioral state related to stress. The treatment strategy suggests the involvement of neuroactive steroids in its pathophysiology. We report a hospitalized patient with schizophrenia in whom a catatonic state occurred 7 times in 5.5 years. Blood levels of steroid hormones and adrenocorticotropic hormone (ACTH) were measured during the catatonic state and in the intervals between catatonic states (non-catatonic states). Cortisol and dehydroepiandrosterone sulfate (DHEAS) were significantly higher during catatonia than in the non-catatonic state. Cortisol significantly correlated with the ACTH level, whereas blood DHEAS and progesterone correlated only during the non-catatonic state. In addition, the cortisol to DHEAS ratios did not differ between catatonic and non-catatonic states. Although the correlating elevations of ACTH and cortisol implied activation of the hypothalamic-pituitary-adrenal axis (HPA-axis) in the catatonic state, DHEAS levels did not seem to increase in a manner dependent on the HPA-axis or the production of progesterone. The results suggest that the catatonic state was a neuroendocrinological state of HPA-axis activation with comparable increases in DHEAS levels.

The Lack of Alterations in Metabolites in the Medial Prefrontal Cortex and Amygdala, but Their Associations with Autistic Traits, Empathy, and Personality Traits in Adults with Autism Spectrum Disorder: A Preliminary Study.

Proton magnetic resonance spectroscopy (1H-MRS) has shown inconsistent alterations in brain metabolites of adults with autism spectrum disorder (ASD). We investigated brain metabolites in the medial prefrontal cortex and amygdala of 24 drug-naive adults with ASD and no intellectual disability and 24 non-ASD control subjects, using 3 T 1H-MRS. Adults with ASD showed no significant differences from control in glutamate, glutamate plus glutamine, N-acetylaspartate, glycerophosphorylcholine plus phosphorylcholine, creatine plus phosphocreatine, or myo-inositol in either region. However, ASD subjects did show significant correlations of localized brain metabolites with autistic traits, empathy deficits, and personality traits using the Autism-Spectrum Quotient, Questionnaire of Cognitive and Affective Empathy, Interpersonal Reactivity Index, and NEO Personality Inventory-Revised. These findings should be taken as preliminary or exploratory.

Associations among autistic traits, cognitive and affective empathy, and personality traits in adults with autism spectrum disorder and no intellectual disability.

Reported empathy deficits in autism spectrum disorder (ASD) could be attributable to other ASD-related features. We evaluated 28 ASD adults with no intellectual disability and 24 age-matched non-ASD control subjects using the Autism-Spectrum Quotient (AQ), Questionnaire of Cognitive and Affective Empathy (QCAE), Interpersonal Reactivity Index (IRI), and NEO Personality Inventory-Revised (NEO). Compared to the controls, ASD participants showed lower scores for perspective taking, online simulation, cognitive empathy, and peripheral responsivity on the QCAE, and lower scores for perspective taking and empathic concern on the IRI. Within the ASD group, the AQ scores showed significant relationships with perspective taking, online simulation and cognitive empathy on the QCAE, and perspective taking on the IRI. The ASD group also showed higher scores for neuroticism and lower scores for extraversion on the NEO compared to the controls. However, there were no relationships between AQ scores and NEO factors within the ASD group. Multiple regression analysis with stepwise linear regression demonstrated that perspective taking score on the QCAE and extraversion score on the NEO were good predictor variables to autistic traits on the AQ. These findings help us to understand empathy and personality traits in ASD adults with no intellectual disability.

Allopregnanolone induces antidepressant-like effects through BDNF-TrkB signaling independent from AMPA receptor activation in a rat learned helplessness model of depression.

Allopregnanolone (ALLO, 3α5α-tetrahydroprogesterone) was found to be effective for depressed patients. Animal models of depression indicate that ALLO is associated with the pathophysiology of depression. Traditional antidepressant drugs produce antidepressant effects via the monoamine system, with consequent up-regulation of brain-derived neurotrophic factor (BDNF). This study was designed to examine whether the antidepressant effects of ALLO involve BDNF-TrkB signaling or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation on the learned helplessness paradigm. The antidepressant-like effect of ALLO infusion into the cerebral ventricle was blocked by coinfusion of TrkB inhibitor ANA-12, but not by co-administration of AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX). Thus, the antidepressant-like effect of ALLO involves BDNF signaling independent from AMPA receptor activation.

Monoaminergic balances predict non-depression-like phenotype in Learned Helplessness Paradigm.

Monoamine neuronal system abnormality is hypothesized to be the neurochemical pathology in depression, as it is supported by the efficacy of conventional antidepressants. The learned helplessness paradigm generates depression-like (LH) and non-depression-like (non-LH) behavioral models. Examination of the neurochemical states accompanying such distinct behavioral phenotypes can facilitate investigations of the mechanisms underlying resilience and the search for new strategies for depression prevention and therapy. Here, we measured the levels of monoamines, including noradrenaline (NA), serotonin (5-HT), and dopamine (DA), and their metabolites in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), hippocampus, nucleus accumbens (NAc), amygdala, and striatum in LH, non-LH, and non-manipulated (naïve) rats. Compared with LH rats, non-LH rats showed lower 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and NA turnovers in the amygdala and higher 5-HT levels in the NAc. Compared with naïve rats, non-LH rats showed increased DA and homovanillic acid (HVA) levels in the amygdala and increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus and NAc, whereas LH rats exhibited increased HVA levels and DA turnovers in the hippocampus, decreased 5-HIAA levels in the mPFC, increased DA turnovers in the OFC, and decreased DA turnovers in the amygdala. Comparison between LH and non-LH suggest that suppressed amygdaloid NA activity and elevated 5-HT activity in the NAc are related to stress resilience. Changes that occurred in LH or non-LH rats when compared with those in naïve rats suggest that suppressed DA activity in the hippocampus and OFC; elevated DA activity in the amygdala; and facilitated 5-HT activity in the hippocampus, mPFC, and NAc are phenomena related to the expression of a non-depression-like phenotype.

Hypothalamic Monoaminergic Pathology in a Neurodevelopmental Rat Model Showing Prenatal 5-Bromo-2'-Deoxyuridine Treatment-Induced Hyperactivity and Hyporeproductivity.

OBJECTIVE: Prenatal treatment of rats with 5-bromo-2'-deoxyuridine (BrdU) is a neurodevelopmental model showing hyperactivity and impaired sexual activity. Human neurodevelopmental disorders, such as autism, exhibit sex-related pathology, but sex-related neurodevelopment has not been fully investigated in this model. We conducted this study to facilitate the understanding of the pathophysiology of neurodevelopmental disorders. METHODS: Pregnant rats received 50 mg/kg BrdU on gestational days 9-15. The tissue content of dopamine (DA), serotonin (5-HT), and their metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were measured in male and female offspring at 3 weeks (juveniles) and 10 weeks (adults) of age. RESULTS: Prenatally BrdU-treated rats had reduced DA metabolism or DA content in the hypothalamus from the juvenile through the adult period without sex differences, but sex-specific striatal DA abnormalities emerged after maturation. A reduction in 5-HT metabolism was measured in the hypothalamus without sex differences throughout development. Developmental alterations in the striatal 5-HT states were sex-dependent. Temporal changes in DA or 5-HT metabolism were found in the frontal cortex and midbrain. CONCLUSION: The sex-specific influence of a genotoxic factor on the development of the DA and 5-HT systems was clarified in the hypothalamus and striatum. The results suggest that the observed sex dependence and region specificity are related to the pathology of social dysfunction in neurodevelopmental disorders.

Switching to aripiprazole for the treatment of residual mutism resulted in distinct clinical courses in two catatonic schizophrenia cases.

OBJECTIVES: The efficacy of a partial agonist for the dopamine D2 receptor, aripiprazole, for catatonia in schizophrenia has been reported. METHODS: We report distinct clinical courses in challenging aripiprazole to treat residual mutism after severe catatonic symptoms improved. RESULTS: In the first case, mutism was successfully treated when the patient was switched from olanzapine to aripiprazole. In contract, switching to aripiprazole from risperidone aggravated auditory hallucinations in the second case. CONCLUSIONS: We will discuss the benefits and risks of using aripiprazole for the treatment of catatonic schizophrenia and the possibility of dopamine supersensitivity psychosis.

Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial.

BACKGROUND: This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. METHODS: We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. RESULTS: Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P < 0.001; and 12.5 vs. 81.8 %, P = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased (χ2 = 8.5, df = 3, P = 0.036) and serum mature BDNF levels were temporarily significantly decreased (F = 3.5, df = 2.4, P = 0.027) in the responders of both groups at week 24. CONCLUSION: This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled.

Risperidone long-acting injectable in the treatment of treatment-resistant schizophrenia with dopamine supersensitivity psychosis: Results of a 2-year prospective study, including an additional 1-year follow-up.

UNLABELLED: Dopamine supersensitivity psychosis (DSP) resulting from antipsychotic treatment is related to treatment-resistant schizophrenia (TRS), and its treatment has not been established to date. Maintaining thoroughly stable occupancy of the dopamine D2 receptor by risperidone long-acting injectable (RLAI) is one strategy for treatment. In this study, RLAI was given as an adjunctive medication to oral antipsychotic(s), which were switched partially and gradually to RLAI in 108 treatment-resistant patients for an additional 1-year follow-up in a 2-year study, and to compare the effects in 72 patients with a DSP history (DSP group) and 36 patients without this history (NonDSP group). Although both groups showed significant improvements in the total Brief Psychotic Rating Scale (BPRS) score during the follow-up period, greater improvement was observed for the DSP group than the NonDSP group. High doses (> 850 mg chlorpromazine-dose combined of oral antipsychotics and RLAI) did not significantly change in both groups throughout the study period; however, extrapyramidal symptoms, including tardive dyskinesia, were significantly improved only in the patients with DSP. This study strongly suggested that the RLAI treatment, even with only partial switching, provides relief from refractory symptoms, particularly for patients with a history of DSP. CLINICAL TRIAL REGISTRATION: http://www.umin.ac.jp/:UMIN000008487.

Distinct effects of the serotonin-noradrenaline reuptake inhibitors milnacipran and venlafaxine on rat pineal monoamines.

Monoamine systems are involved in the pathology and therapeutic mechanism of depression. The pineal gland contains large amounts of serotonin as a precursor for melatonin, and its activity is controlled by noradrenergic sympathetic nerves. Pineal diurnal activity and its release of melatonin are relevant to aberrant states observed in depression. We investigated the effects on pineal monoamines of serotonin-noradrenaline reuptake inhibitors, which are widely used antidepressants. Four days of milnacipran treatment led to an increase in noradrenaline and serotonin levels, whereas 4 days of venlafaxine treatment reduced 5-hydroxyindoleacetic acid levels; both agents induced an increase in dopamine levels. Our data suggest that milnacipran increases levels of the precursor for melatonin synthesis by facilitating the noradrenergic regulation of pineal activity and that venlafaxine inhibits serotonin reuptake into noradrenergic terminals on the pineal gland.

Mother/offspring co-administration of the traditional herbal remedy yokukansan during the nursing period influences grooming and cerebellar serotonin levels in a rat model of neurodevelopmental disorders.

Neurodevelopmental impairment in the serotonergic system may be involved in autism spectrum disorder. Yokukansan is a traditional herbal remedy for restlessness and agitation in children, and mother-infant co-administration (MICA) to both the child and the nursing mother is one of the recommended treatment approaches. Recent studies have revealed the neuropharmacological properties of Yokukansan (YKS), including its 5-HT1A (serotonin) receptor agonistic effects. We investigated the influence of YKS treatment on behavior in a novel environment and on brain monoamine metabolism during the nursing period in an animal model of neurodevelopmental disorders, prenatally BrdU (5-bromo-2'-deoxyuridine)-treated rats (BrdU-rats). YKS treatment did not influence locomotor activity in BrdU-rats but reduced grooming in open-field tests. YKS treatment without MICA disrupted the correlation between locomotor behaviors and rearing and altered levels of serotonin and its metabolite in the cerebellum. These effects were not observed in the group receiving YKS treatment with MICA. These data indicate a direct pharmacological effect of YKS on the development of grooming behavior and profound effects on cerebellar serotonin metabolism, which is thought to be influenced by nursing conditions.

Personality traits as predictors for the outcome of lithium augmentation in treatment-resistant depression.

The NEO Personality Inventory-Revised (NEO) and the Temperament and Character Inventory (TCI) were administered to patients with treatment-resistant depression (n=21) before lithium augmentation. Analysis showed that the poor outcome group (n=11) had lower openness scores on the NEO, and lower cooperativeness scores on the TCI compared with the good outcome group (n=10). These findings may be predictors of poor responsiveness to lithium augmentation in the treatment of antidepressant-resistant depression.

A study of remitted and treatment-resistant depression using MMPI and including pessimism and optimism scales.

BACKGROUND: The psychological aspects of treatment-resistant and remitted depression are not well documented. METHODS: We administered the Minnesota Multiphasic Personality Inventory (MMPI) to patients with treatment-resistant depression (n = 34), remitted depression (n = 25), acute depression (n = 21), and healthy controls (n = 64). Pessimism and optimism were also evaluated by MMPI. RESULTS: ANOVA and post-hoc tests demonstrated that patients with treatment-resistant and acute depression showed similarly high scores for frequent scale (F), hypochondriasis, depression, conversion hysteria, psychopathic device, paranoia, psychasthenia and schizophrenia on the MMPI compared with normal controls. Patients with treatment-resistant depression, but not acute depression registered high on the scale for cannot say answer. Using Student's t-test, patients with remitted depression registered higher on depression and social introversion scales, compared with normal controls. For pessimism and optimism, patients with treatment-resistant depression demonstrated similar changes to acutely depressed patients. Remitted depression patients showed lower optimism than normal controls by Student's t-test, even though these patients were deemed recovered from depression using HAM-D. CONCLUSIONS: The patients with remitted depression and treatment-resistant depression showed subtle alterations on the MMPI, which may explain the hidden psychological features in these cohorts.

A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis.

OBJECTIVE: Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP. METHOD: This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression-Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively. RESULTS: While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (≥20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group. CONCLUSIONS: It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP. CLINICAL TRIALS REGISTRATION: UMIN (UMIN000008487).

Low openness on the revised NEO personality inventory as a risk factor for treatment-resistant depression.

BACKGROUND: Recently, we reported that low reward dependence, and to a lesser extent, low cooperativeness in the Temperature and Character Inventory (TCI) may be risk factors for treatment-resistant depression. Here, we analyzed additional psychological traits in these patients. METHODS: We administered Costa and McCrae's five-factor model personality inventory, NEO Personality Inventory-Revised (NEO-PI-R), to antidepressant-treatment resistant depressed patients (n=35), remitted depressed patients (n=27), and healthy controls (n=66). We also evaluated the relationships between scores on NEO and TCI, using the same cohort of patients with treatment-resistant depression, as our previous study. RESULTS: Patients with treatment-resistant depression showed high scores for neuroticism, low scores for extraversion, openness and conscientiousness, without changes in agreeableness, on the NEO. However, patients in remitted depression showed no significant scores on NEO. Patients with treatment-resistant depression and low openness on NEO showed positive relationships with reward dependence and cooperativeness on the TCI. CONCLUSIONS: Many studies have reported that depressed patients show high neuroticism, low extraversion and low conscientiousness on the NEO. Our study highlights low openness on the NEO, as a risk mediator in treatment-resistant depression. This newly identified trait should be included as a risk factor in treatment-resistant depression.

Personality traits as risk factors for treatment-resistant depression.

BACKGROUND: The clinical outcome of antidepressant treatment in patients with major depressive disorder (MDD) is thought to be associated with personality traits. A number of studies suggest that depressed patients show high harm avoidance, low self-directedness and cooperativeness, as measured on the Temperament and Character Inventory (TCI). However, the psychology of these patients is not well documented. METHODS: Psychological evaluation using Cloninger's TCI, was performed on treatment-resistant MDD patients (n = 35), remission MDD patients (n = 31), and age- and gender-matched healthy controls (n = 174). RESULTS: Treatment-resistant patients demonstrated high scores for harm avoidance, and low scores for reward dependence, self-directedness, and cooperativeness using the TCI, compared with healthy controls and remission patients. Interestingly, patients in remission continued to show significantly high scores for harm avoidance, but not other traits in the TCI compared with controls. Moreover, there was a significant negative correlation between reward dependence and harm avoidance in the treatment-resistant depression cohort, which was absent in the control and remitted depression groups. CONCLUSIONS: This study suggests that low reward dependence and to a lesser extent, low cooperativeness in the TCI may be risk factors for treatment-resistant depression.

Differential levels of brain amino acids in rat models presenting learned helplessness or non-learned helplessness.

RATIONALE: Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). OBJECTIVES: We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. METHODS: LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. RESULTS: The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. CONCLUSIONS: The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression.

Add-on Lamotrigine Treatment for Subsyndromal Depression after Manic or Mixed States in Bipolar Disorder Improved the Quality of Life.

Two cases of patients experienced subsyndromal depression after manic or mixed hypomanic and depressive episodes due to bipolar I (case 1) and II (case 2) disorders prior to the use of lamotrigine. Case 1 showed episodes of mood switching induced by antidepressants and seasonal mood instability. Case 2 showed hippocampal atrophy and a persistent dull headache that preceded the use of lamotrigine. Both were successfully treated with add-on lamotrigine therapy, and the dull headache was effectively treated with olanzapine. Both patients improved in social activity and work performance after these add-on treatments. Thus, add-on treatment with lamotrigine alone or in combination with olanzapine was an effective strategy to improve the quality of life in bipolar depression. Subsyndromal depression that present after the disappearance of the manic or mixed state was suggested to be practical indication for the use of lamotrigine.

Abnormal brain function of the rat neonate in a prenatal 5-bromo-2'-deoxyuridine (BrdU)-induced developmental disorder model.

Neonatal brain function was investigated in a prenatal BrdU-induced developmental disorder model, which has been reported to exhibit behavioral abnormalities such as locomotor hyperactivity, impaired learning and memory, and lower anxiety in offspring. After 1h home cage deprivation we observed an increase in the number of c-Fos (neuronal activity marker) immunoreactive cells in several brain regions of the olfactory and stress-related areas in normal neonates at 11 days. Next, pregnant rats were exposed to 50mg/kg of BrdU from gestation days 9-15, and their offspring at 11 days were home-cage deprived. Compared to vehicle control, the number of c-Fos immunoreactive cells in BrdU group was found to be decreased in the piriform cortex and locus coeruleus, which are known to play an important role in neonatal learning and memory. We also analyzed Pearson product-moment correlation coefficient of the number of c-Fos immunoreactive cells, focusing on the piriform cortex and locus coeruleus versus numerous other brain areas (11 areas including amygdala). Numerous significant correlations were observed in the vehicle control group, however, correlations of the locus coeruleus disappeared in the BrdU group. By observing c-Fos immunoreactivity after home cage deprivation our study uncovers abnormal brain functions as early as postnatal day 11 in this disorder model. Based on these results, we propose a new histological approach for functional characterization of developmental disorder models.