[Show abstract][Hide abstract] ABSTRACT: It is often difficult to differentiate between the depressive states seen in late-life depression and late-onset Alzheimer’ disease (AD) in the clinical setting.
Thirty-four outpatients were recruited, all fulfilling the criteria of aged 65 years or above, scores of 14 or more on the Hamilton depression rating scale (HAM-D), and 26 or less on the Mini-Mental State Examination (MMSE). At the initial visit, they were administered the Neurobehavioral Cognitive Status Examination (COGNISTAT). At 1 month, a diagnosis of either senile depression (n = 24) or Alzheimer’ disease (n = 10) was made.
The COGNISTAT revealed that the late-life depression group showed significantly higher scores in orientation and comprehension subtests compared with the AD group. At the study endpoint (6 months after treatment), MMSE detected significant improvements in the late-life depression group (n = 15), but no changes in the late-onset AD group (n = 7). Scores for memory, similarities, and judgment on the second COGNISTAT were significantly improved in the depressed group, whereas calculation scores deteriorated significantly in the AD group.
The COGNISTAT could prove useful in differentiating late-life depression from late-onset AD, despite similar scores on MMSE.
Preview · Article · Dec 2016 · Annals of General Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Role of brain-derived neurotrophic factor (BDNF)-TrkB signaling in a learned helplessness (LH) model of depression was investigated. LH rats showed a reduction of BDNF in the medial prefrontal cortex (mPFC), CA3, and dentate gyrus (DG) of the hippocampus, whereas LH rats showed an increase in BDNF in the nucleus accumbens (NAc). Furthermore, levels of proBDNF, a BDNF precursor, were higher in the mPFC, but lower in the NAc, of LH rats. A single bilateral infusion of a TrkB agonist 7,8-DHF, but not a TrkB antagonist ANA-12, into the infralimbic (IL) of mPFC, DG, and CA3, but not the prelimbic (PrL) of mPFC, exerted antidepressant effects in LH rats. In contrast, a single bilateral infusion of ANA-12, but not 7,8-DHF, into the core and shell of NAc exerted antidepressant-like effects in LH rats, with more potent effects observed for the NAc core than for NAc shell. Interestingly, a single administration of 7,8-DHF (10mg/kg, i.p.) significantly improved a decreased phosphorylation of TrkB in the mPFC, CA3, and DG of LH rats. Additionally, ANA-12 (0.5mg/kg, i.p.) significantly improved an increased phosphorylation of TrkB in the NAc of LH rats. In conclusion, these results suggest that LH causes depression-like behavior by altering BDNF in the brain regions, and that proBDNF-BDNF processing and transport may be altered in the mPFC-NAc circuit of LH rats. Therefore, TrkB agonists might exert antidepressant effects by stimulating TrkB in the IL, CA3, and DG, while TrkB antagonists might exert antidepressant effects by blocking TrkB in the NAc.
No preview · Article · Sep 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)-TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF-TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF-TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
[Show abstract][Hide abstract] ABSTRACT: Treatment-resistant depression is a challenging problem in the clinical setting. Tipepidine has been used as a non-narcotic antitussive in Japan since 1959.
We administered tipepidine to 11 patients with treatment-resistant depression. Tipepidine was given for 8 weeks as an augmentation.
Tipepidine significantly improved depression scores on the Hamilton Rating Scale for depression. Add-on treatment with tipepidine significantly improved scores on the trail making test and Rey auditory verbal learning test. However, no changes were observed in blood concentrations of stress-related hormones (adrenocorticotropic hormone, cortisol, dehydroepiandrosterone sulphate) with tipepidine augmentation.
Tipepidine might be a potential therapeutic drug for treatment-resistant depression.
No preview · Article · Jul 2015 · Acta Neuropsychiatrica
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidences suggest that pro-inflammatory cytokines such as interleukin-6 (IL-6) play a role in the pathophysiology of depression. In the learned helplessness (LH) paradigm, ~35% rats are resilient to inescapable stress.
Levels of IL-6 in the serum and medial prefrontal cortex (mPFC) of LH rats (susceptible) and non-LH rats (resilience) were measured using enzyme-linked immunosorbent assay and western blot analysis, respectively.
Serum levels of IL-6 in the LH rats were significantly higher than those of control and non-LH rats. In contrast, tissue levels of IL-6 in the mPFC were not different among three groups.
The results suggest that peripheral IL-6 may contribute to resilience versus susceptibility to inescapable stress.
No preview · Article · May 2015 · Acta Neuropsychiatrica
[Show abstract][Hide abstract] ABSTRACT: Background:
Defective decision-making is a symptom of impaired cognitive function observed in patients with schizophrenia. Impairment on the Iowa Gambling Task (IGT) has been reported in patients with schizophrenia, but these results are inconsistent among studies.
We differentiated subjects based on whether they expressed certainty at having deciphered an advantageous strategy in the course of the task. We investigated this impairment using the IGT in patients with schizophrenia and performed analysis different to standard advantageous decks minus disadvantageous decks in all 100 card choices, [C+D]-[A+B](1-100). We examined the effects on behavior after receiving a big penalty.
Results were dependent on participants utilizing with or without certainty, the best strategy for positive gain. Schizophrenic patients without certainty failed to show card choice shift, from disadvantageous to advantageous decks. Differences in card choices on the IGT were clearly shown between patients with schizophrenia and normal controls by the use of improvement from block 1 to blocks 3-5, [C+D]-[A+B]([41-100]-[1-20]) (P<0.001), rather than by the composite value of blocks 3-5, [C+D]-[A+B](41-100) (P=0.011). The deficit of emotion-based learning in schizophrenia without uncertainty were related to scores on the SANS and S5 attention. In addition, S1 affective flattering and S4 anhedonia-asociality were also related to these deficits. For a while, normal controls showed a smooth shift from disadvantageous to advantageous decks after big penalties, with or without a certainty for strategy. However, patients with schizophrenia failed to show switching from disadvantageous to advantageous decks, even after big penalties, under the same conditions.
Our results highlight certainty of strategy and behavior after a big penalty, as two points of difference between patients with schizophrenia and normal controls in the accumulation of net scores.
No preview · Article · Mar 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Objective
This open-label study examined the effects of ramelteon on cognitive functions in 10 outpatients with schizophrenia.
Ramelteon (8 mg/day) was administered to 10 patients with schizophrenia for six months. The verbal fluency test, Trail-Making Test, the Wisconsin Card Sorting Test, the Stroop Test, the Digit Span Distraction Test, Iowa Gambling Task, the Rey Auditory Verbal Learning Test were evaluated at baseline and 6 months after treatment with ramelteon.
Ramelteon improved significantly the scores of Rey Auditory Verbal Learning Test. Additionally, ramelteon exerted improvements in the verbal fluency and Iowa Gambling Task in 4 patients.
Ramelteon could be a potential therapeutic drug, in adjunctive treatment of learning and memory deficits seen in patients with schizophrenia.
Full-text · Article · Dec 2014 · Clinical Psychopharmacology and Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Background
The psychological aspects of treatment-resistant and remitted depression are not well documented.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Several lines of evidence suggest that glial cell-line derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric and neurodegenerative disorders. In this study, we investigated the association between GDNF serum levels and the clinical status of medicated patients with schizophrenia. Sixty-three medicated patients with schizophrenia and 52 age- and sex-matched healthy controls were recruited. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Serum levels of GDNF were determined using an ELISA method. Serum levels of GDNF did not differ between schizophrenia patients and controls. Higher GDNF serum levels were associated with better performances on the Digit Span in healthy controls but not in schizophrenics. At the same time, higher GDNF serum levels were associated with severe attention deficits on the SANS subscale, in schizophrenics. Our preliminary study suggests that serum levels of GDNF may be an unsuitable biomarker for schizophrenia, although it may be associated with working memory in healthy controls and the pathophysiology of attention deficits in schizophrenia.
No preview · Article · May 2014 · Neuroscience Letters
[Show abstract][Hide abstract] ABSTRACT: A meta-analysis study reported serum brain-derived neurotrophic factor (BDNF) levels as a potential biomarker for schizophrenia. However, at the time, commercially available human ELISA kits were unable to distinguish between pro-BDNF (precursor BDNF) and mature BDNF, because of limited antibody specificity. Here, we used new ELISA kits, to examine serum levels of mature BDNF and matrix metalloproteinase-9 (MMP-9), which converts pro-BDNF to mature BDNF in schizophrenia. Sixty-three patients with chronic schizophrenia and 52 age- and sex-matched healthy controls were enrolled. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Neither serum mature BDNF nor MMP-9 levels differed between patients and controls. In male subgroups, serum MMP-9 levels of smoking patients were higher than those of non-smoking patients, but this was not observed in male controls or the female subgroup. In patients, serum mature BDNF levels were associated with SANS total scores and the Information subtest scores of the Wechsler Adult Intelligence Scale Revised (WAIS-R), while serum MMP-9 levels were associated with smoking and category fluency scores. These findings suggest that neither mature BDNF nor MMP-9 is a suitable biomarker for schizophrenia, although further studies using large samples are needed.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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).
We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression.
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.
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.
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.
No preview · Article · Apr 2013 · Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Cognitive impairments in schizophrenia are associated with suboptimal psychosocial performance. Several lines of evidence have suggested that endoplasmic reticulum protein sigma-1 receptors were involved in cognitive impairments in patients with schizophrenia and that the sigma-1 receptor agonist fluvoxamine was effective in treating cognitive impairments in animal models of schizophrenia and in some patients with schizophrenia. A randomized, double-blind, placebo-controlled, parallel trial of fluvoxamine adjunctive therapy in patients with schizophrenia was performed. A total of 48 patients with chronic schizophrenia were enrolled. Subjects were randomly assigned to an 8-week administration of add-on fluvoxamine (n = 24, titrated up to 150 mg/d) or placebo (n =24) in a total 12-week double-blind trial. The primary outcome measure was the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing visual memory, working memory, attention, and executive function. The secondary outcome measures were the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and the Montgomery-Åsberg Depression Rating Scale. Fluvoxamine was well tolerated. No significant time × group interaction effects were observed in the scores of the CANTAB, Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, or the Montgomery-Åsberg Depression Rating Scale. However, in secondary analyses, the change from baseline to end point on the Spatial Working Memory strategy score (executive function) of CANTAB improved in the fluvoxamine group. This study suggests no major benefit of fluvoxamine adjunctive therapy to improve cognitive impairments in patients with schizophrenia. Nevertheless, a further study using a large sample size will be needed to confirm the secondary analyses findings.
Full-text · Article · Aug 2012 · Journal of clinical psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Background: Among neurotransmitter influencing memory formation, the noradrenergic system has been recognized as an important system. Memory formation involves various regions including the prefrontal cortex, hippocampus, amygdala and septum. Method: We investigated the effects of milnacipran on passive avoidance task and evaluated Fos counting in the prefrontal cortex, hippocampus, septum, amygdala and nucleus accumbens. Results: The milnacip-ran-treated rats (20 mg/kg, 4 days) showed a significant decrease in the number of Fos-immunoreactive cells in the in-fralimbic portion of prefrontal cortex, the shell portion of nucleus accumbens and the CA1 region of hippocampus, but a significant increase in the Fos counts in the lateral septum with no changes in the Fos counts in the striatum and amyg-dala. The milnacipran-treated rats showed amelioration in memory extinction (although not statistically significant), but not in memory acquisition and consolidation in the passive avoidance test. Conclusion: The differential activation of the brain regions might be possible sites for ameliorating memory extinction as well as antidepressant effects.
Preview · Article · Jan 2012 · Journal of Behavioral and Brain Science