Papers by Kenji Hashimoto
BMC psychiatry, Sep 15, 2016
Maternal depression can be harmful to both mothers and their children. Omega-3 polyunsaturated fa... more Maternal depression can be harmful to both mothers and their children. Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been investigated as an alternative intervention for pregnant women with depressive symptoms because of the supporting evidence from clinical trials in major depression, the safety advantage, and its anti-inflammatory and neuroplasticity effects. This study examines the efficacy of omega-3 PUFA supplementation for pregnant women with depressive symptoms in Taiwan and Japan, to provide evidence available for Asia. The rationale and protocol of this trial are reported here. The Synchronized Trial on Expectant Mothers with Depressive Symptoms by Omega-3 PUFAs (SYNCHRO) is a multicenter, double-blind, parallel group, randomized controlled trial. Participants will be randomized to either the omega-3 PUFAs arm (1,200 mg eicosapentaenoic acid and 600 mg docosahexaenoic acid daily) or placebo arm. Primary outcome is total score on the Hamilton Rating Scale for...
Expert opinion on therapeutic targets, Nov 28, 2016
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is one of the most attractive antide... more The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is one of the most attractive antidepressants since this drug causes rapid-onset and sustained antidepressant effects in treatment resistant patients with depression. There are unanswered questions about how ketamine induces its rapid and sustained antidepressant actions. This key article suggests that (2R,6R)-HNK (hydroxynorketamine), a major metabolite of (R)-ketamine, shows antidepressant effects in rodent models of depression, indicating that the metabolism of (R)-ketamine to (2R,6R)-HNK is pivotal in its antidepressant action. Here these findings are put into context and their significance is discussed.
Acta neuropsychiatrica, Jan 29, 2015
Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the p... more Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p<0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p<0.001). This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of ...
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 2012
European Journal of Nuclear Medicine and Molecular Imaging, 2002
Annals of Nuclear Medicine, 1989
The biodistribution of 3 H-PK 11195, an antagonist of the peripheral-type benzodiazepine receptor... more The biodistribution of 3 H-PK 11195, an antagonist of the peripheral-type benzodiazepine receptors, was studied in mice. High accumulations of radioactivity in the heart, lung, spleen, kidney and adrenal were observed after intravenous injection of tracer amounts of 3 H-PK 11195 into the mice. The radioactivity in the heart, lung, spleen, kidney and adrenal was significantly decreased by the coadministration of carrier PK 11195, which indicated that PK 11195 specifically binds to the receptors. No radioactive metabolites were observed in the heart, lung and brain 20 min after intravenous administration of 3H-PK 11195. The accumulation of 3H-PK 11195 in the lung was not affected by pretreatment with either a-methyl benzylamine or imipramine, suggesting that 3 H-PK 11195 specifically binds to the receptors. The ratios of radioactivity of the kidney, adrenal and spleen to blood increased as a function of time, whereas that of the lung and heart rapidly reached to a steady state. 11 C-PK 11195 was synthesized by the N-methylation of desmethyl precursor yielding more than 100 mCi with high specific activity (more than 1.4 Ci/pmol). The labeling and purification procedure was completed within 23 min after the end of bombardment (EOB). The 11 C-PK 11195 solution for injection seems to have a high potential for the in vivo study of the peripheral-type benzodiazepine receptors in the living human by means of positron emission tomography (PET).
Psychopharmacology, 2015
Accumulating evidence suggests involvement of the glutamatergic system in the biological mechanis... more Accumulating evidence suggests involvement of the glutamatergic system in the biological mechanisms of posttraumatic stress disorder (PTSD), but few studies have demonstrated an association between glutamatergic system abnormalities and PTSD diagnosis or severity. We aimed to examine whether abnormalities in serum glutamate and in the glutamine/glutamate ratio were associated with PTSD diagnosis and severity in severely injured patients at risk for PTSD and major depressive disorder (MDD). This is a nested case-control study in TPOP (Tachikawa project for prevention of posttraumatic stress disorder with polyunsaturated fatty acid) trial. Diagnosis and severity of PTSD were assessed 3 months after the accidents using the Clinician-Administered PTSD Scale. The associations of glutamate levels and the glutamine/glutamate ratio with diagnosis and severity of PTSD and MDD were investigated by univariate and multiple linear regression analyses. Ninety-seven of 110 participants (88 %) completed assessments at 3 months. Serum glutamate levels were significantly higher for participants with full or partial PTSD than for participants without PTSD (p = 0.049) and for participants with MDD than for participants without MDD (p = 0.048). Multiple linear regression analyses showed serum glutamate levels were significantly positively associated with PTSD severity (p = 0.02) and MDD severity (p = 0.03). The glutamine/glutamate ratio was also significantly inversely associated with PTSD severity (p = 0.03), but not with MDD severity (p = 0.07). These findings suggest that the glutamatergic system may play a major role in the pathogenesis of PTSD and the need for new treatments targeting the glutamatergic system to be developed for PTSD.
Neuroscience Letters, 2016
The current diagnostic tests for mood disorders, including major depressive disorder (MDD) and bi... more The current diagnostic tests for mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), have limitations. Inflammatory markers, growth factors, and oxidative stress markers are involved in the pathophysiology of mood disorders. A multi-assay biological diagnostic test combining these biomarkers might improve diagnostic efficiency. The plasma levels of soluble tumor necrosis factor receptor 2 (sTNFR2), epidermal growth factor (EGF), and myeloperoxidase were measured in 40 MDD patients, 40 BD patients and 40 controls in a Japanese population. We also investigated the plasma levels of these markers in 40 patients with schizophrenia to determine the utility of these markers in differential diagnosis. The plasma levels of sTNFR2 were significantly higher in BD and schizophrenia patients than in controls. The plasma levels of EGF and myeloperoxidase were significantly higher in patients with BD than in controls. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and mood disorders was 69.2%, with a sensitivity and specificity of 62.5% and 82.5%, respectively. The correct classification rate obtained from discriminant analysis with sTNFR2 and EGF between controls and BD was 85.0%, with a sensitivity and specificity of 77.6% and 92.5%, respectively. Our results suggest that sTNFR2 and EGF could be biological markers of BD. Further studies are needed to determine the utility of these markers in diagnostic tests for mood disorders.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008
Fluvoxamine as a sigma-1 receptor agonist improved cognitive impairments in a patient with schizo... more Fluvoxamine as a sigma-1 receptor agonist improved cognitive impairments in a patient with schizophrenia
Annals of General Psychiatry, 2009
Background: Psychotic depression is a clinical subtype of major depressive disorder. A number of ... more Background: Psychotic depression is a clinical subtype of major depressive disorder. A number of clinical studies have demonstrated the efficacy of the combination of an antidepressant (for example, a tricyclic antidepressant or selective serotonin reuptake inhibitor (SSRI)) and an atypical antipsychotic or electroconvulsive therapy in treating psychotic depression. In some cases, the clinician or patient may prefer to avoid antipsychotic drugs altogether because of the risk of extrapyramidal side effects (EPS) in patients with psychotic depression treated with these drugs. Methods: We report five cases where fluvoxamine monotherapy was effective in the patients with psychotic depression. Results: The scores on the Hamilton Depression (HAM-D) scale and the Brief Psychiatric Rating Scale (BPRS) in the five patients with psychotic depression were reduced after fluvoxamine monotherapy. Conclusion: Doctors should consider fluvoxamine monotherapy as an alternative approach in treating psychotic depression because it avoids the risk of EPS from antipsychotic drugs.
Neuropsychopharmacology, 2007
The present study was undertaken to examine whether the second generation antibiotic drug minocyc... more The present study was undertaken to examine whether the second generation antibiotic drug minocycline attenuates behavioral changes (eg, acute hyperlocomotion and prepulse inhibition (PPI) deficits) in mice after the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (dizocilpine). Dizocilpine (0.1 mg/kg)-induced hyperlocomotion was significantly attenuated by pretreatment with minocycline (40 mg/kg). Furthermore, the PPI deficits after a single administration of dizocilpine (0.1 mg/kg) were attenuated by pretreatment with minocycline (10, 20, or 40 mg/kg), in a dose-dependent manner. Moreover, in vivo microdialysis study in the free-moving mice revealed that pretreatment with minocycline (40 mg/kg, i.p.) significantly attenuated the increase of extracellular dopamine (DA) levels in the frontal cortex and striatum after administration of dizocilpine (0.1 mg/kg), suggesting that the inhibition of dizocilpine-induced DA release by minocycline may, at least in part, be implicated in the mechanism of action of minocycline with respect to dizocilpine-induced behavioral changes in mice. These findings suggest that minocycline could attenuate behavioral changes in mice after the administration of the NMDA receptor antagonist dizocilpine. Therefore, it is possible that minocycline would be a potential therapeutic drug for schizophrenia.
European archives of psychiatry and clinical neuroscience, Jan 8, 2017
The transcription factor Keap1-Nrf2 signaling plays a key role in the oxidative stress which is i... more The transcription factor Keap1-Nrf2 signaling plays a key role in the oxidative stress which is involved in psychiatric disorders. In the learned helplessness (LH) paradigm, protein levels of Keap1 and Nrf2 in the prefrontal cortex and dentate gyrus of hippocampus from LH (susceptible) rats were lower than control and non-LH (resilience) rats. Furthermore, protein expressions of Keap1 and Nrf2 in the parietal cortex from major depressive disorder, schizophrenia, and bipolar disorder were lower than controls. These results suggest that Keap1-Nrf2 signaling might contribute to stress resilience which plays a key role in the pathophysiology of psychiatric disorders.
Scientific reports, Jan 2, 2017
Accumulating evidence suggests a role of the ephrin receptor EphA4 and the downstream protein eph... more Accumulating evidence suggests a role of the ephrin receptor EphA4 and the downstream protein ephexin1 in synaptic plasticity, which is implicated in depression. We examined whether EphA4-ephexin1 signaling plays a role in the pathophysiology of depression, and the antidepressant-like effect of EphA4 inhibitor rhynchophylline. We found increased ratios of p-EphA4/EphA4 and p-ephexin1/ephexin1 in the prefrontal cortex (PFC) and hippocampus but not in the nucleus accumbens (NAc), of susceptible mice after social defeat stress. Furthermore, the p-EphA4/EphA4 ratio was higher in the parietal cortex of depressed patients compared with controls. Systemic administration of rhynchophylline, produced a rapid antidepressant-like effect in a social defeat stress model by inhibiting EphA4-ephexin1 signaling and activating brain-derived neurotrophic factor-TrkB signaling in the PFC and hippocampus. Pretreatment with rhynchophylline before each social defeat stress could prevent the onset of the ...
European archives of psychiatry and clinical neuroscience, 2016
Effects of a single bilateral infusion of R-enantiomer of ketamine in rat brain regions of learne... more Effects of a single bilateral infusion of R-enantiomer of ketamine in rat brain regions of learned helplessness model of depression were examined. A single bilateral infusion of R-ketamine into infralimbic (IL) portion of medial prefrontal cortex (mPFC), CA3 and dentate gyrus (DG) of the hippocampus showed antidepressant effects. By contrast, a single bilateral infusion of R-ketamine into prelimbic (PL) portion of mPFC, shell and core of nucleus accumbens, basolateral amygdala and central nucleus of the amygdala had no effect. This study suggests that IL of mPFC, CA3 and DG of hippocampus might be involved in the antidepressant actions of R-ketamine.
European archives of psychiatry and clinical neuroscience, Jan 19, 2016
Using learned helplessness (LH) model of depression, we measured protein expression of brain-deri... more Using learned helplessness (LH) model of depression, we measured protein expression of brain-derived neurotrophic factor (BDNF) pro-peptide, BDNF precursors (proBDNF and preproBDNF) in the brain regions of LH (susceptible) and non-LH rats (resilience). Expression of preproBDNF, proBDNF and BDNF pro-peptide in the medial prefrontal cortex of LH rats, but not non-LH rats, was significantly higher than control rats, although expression of these proteins in the nucleus accumbens of LH rats was significantly lower than control rats. This study suggests that regional differences in conversion of BDNF precursors into BDNF and BDNF pro-peptide by proteolytic cleavage may contribute to stress resilience.
The Open Clinical Chemistry Journal, 2009
D-Alanine, one of D-amino acids present in the mammalian brain, is a selective and potent agonist... more D-Alanine, one of D-amino acids present in the mammalian brain, is a selective and potent agonist at the Nmethyl-D-aspartate (NMDA) receptors. Like D-serine, D-alanine is reported to be effective in the treatment of schizophrenia. However, orally given D-alanine is metabolized substantially by D-amino acid oxidase (DAAO), diminishing its oral bioavailability. In this study, we studied the effects of oral D-alanine administration with or without the novel DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO), on the extracellular D-alanine levels in the brain and on the prepulse inhibition (PPI) deficits after administration of the NMDA receptor antagonist dizocilpine. Co-administration of CBIO (30 mg/kg) with D-alanine (100 mg/kg), but not D-alanine (100 mg/kg) alone, significantly attenuated dizocilpine (0.1 mg/kg)-induced PPI deficits in mice. The in vivo microdialysis study of the conscious and free moving mice revealed that co-administration of CBIO (30 mg/kg) significantly increased extracellular levels of D-alanine in the frontal cortex after oral administration of D-alanine (100 mg/kg). These findings suggest that co-administration of CBIO can increase the bioavailability of D-alanine after oral administration of D-alanine, and that co-administration of CBIO can enhance the efficacy of D-alanine on dizocilpine-induced PPI deficits. Therefore, combination of D-alanine and a DAAO inhibitor such as CBIO offers new therapeutic potential for treatment of schizophrenia.
PloS one, 2013
The clinical outcome of antidepressant treatment in patients with major depressive disorder (MDD)... more 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 wa...
Pharmacology, biochemistry, and behavior, 2012
Previous studies have indicated that minocycline might function as an antidepressant drug. The ai... more Previous studies have indicated that minocycline might function as an antidepressant drug. The aim of this study was to evaluate the antidepressant-like effects of minocycline, which is known to suppress activated microglia, using learned helplessness (LH) rats (an animal model of depression). Infusion of minocycline into the cerebral ventricle of LH rats induced antidepressant-like effects. However, infusion of minocycline into the cerebral ventricle of naïve rats did not produce locomotor activation in the open field tests, suggesting that the antidepressant-like effects of minocycline were not attributed to the enhanced locomotion. LH rats showed significantly higher serotonin turnover in the orbitofrontal cortex and lower levels of brain-derived neurotrophic factor (BDNF) in the hippocampus than control rats. However, these alterations in serotonin turnover and BDNF expression remained unchanged after treatment with minocycline. On the contrary, minocycline treatment of LH rats ...
Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased t... more Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased the K d , but not B max , values of [ 3 H]1,3-dipropyl-8-cyclopentylxanthine ([ 3 H]DPCPX) binding to adenosine A 1 receptors in the prefrontal cortex and hippocampus, but not striatum, of rat brain. However, subchronic treatment with PCP (10 mg/kg, i.p., once daily for 11 days) did not alter the K d and B max values of [ 3 H]DPCPX binding to adenosine A 1 receptors in these three regions. Subchronic treatment with MAP or PCP did not alter the B max and K d values of [ 3 H]2-p-(2-carboxyehyl)phenethylamino-5Ј-N-ethylcarboxyamidoadenosine ([ 3 H]CGS21680) binding to adenosine A 2A receptors in the striatum. Furthermore, subchronic treatment with MAP or PCP significantly decreased the specific binding of [ 3 H]CGS21680 to adenosine A 2A receptors in the hippocampus, but not in the prefrontal cortex. Thus, these results suggest that MAP and PCP may produce differential effects on the adenosine A 2A receptors, but not adenosine A 1 receptors in rat brain.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 31, 2014
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), s... more Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression. In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined. LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effe...
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Papers by Kenji Hashimoto