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Shin Nakagawa

Publications and source records attributed to Shin Nakagawa.

At least 19 recordsLinked to original sources
PubMed2006

Long-term outcome of antidepressant-refractory depression: the relevance of unrecognized bipolarity.

BACKGROUND: The long-term outcome of antidepressant-refractory depression is not well known. Therefore, the present study investigated the long-term outcome of 26 antidepressant-refractory patients with depression, whom we had studied and treated in 1995. METHODS: Before being classified as nonresponse, these patients had been treated adequately with at least two tricyclic or heterocyclic antidepressants (a minimum of the equivalent of 150 mg of imipramine for 4 weeks). In 1995, 21 of 26 patients were diagnosed with unipolar depression, while 5 were diagnosed with bipolar depression. Mean follow-up was 5.7 years (range: 1-7 years) and changes in diagnosis, remission and treatment efficacy were evaluated. RESULTS: Following the long-term follow-up, 13 patients achieved full remission and demonstrated high social functioning (mean GAF score, 91). A further four depressed patients experienced full remission; however, subsequent recurrence was observed. In total, 17 of 26 patients experienced remission at least once during the long-term follow-up period despite the chronic depressive episodes observed at study entry. Adjuvant treatment with lithium, dopamine receptor agonists or thyroid hormone was effective for promoting full remission. Among the 21 patients initially diagnosed with unipolar depression in 1995, diagnoses were changed to bipolar disorder in 5 cases. LIMITATIONS: This naturalistic study had a relatively small sample size and treatment was not controlled. CONCLUSIONS: Long-term follow-up revealed that a substantial proportion of antidepressant-refractory depression is comprised of bipolar disorders. In addition, augmentation therapies are effective for promoting full remission among chronically depressed patients without a risk of serious side effects.

Adult↗
PubMed2006

Effect of combined treatment with noradrenaline and serotonin reuptake inhibitors on conditioned freezing.

To clarify the therapeutic interaction between serotonin and noradrenaline reuptake inhibition on fear, this study examined the acute and subchronic effects of combined treatment with the selective serotonin reuptake inhibitor citalopram and the selective noradrenaline reuptake inhibitor reboxetine on the expression of conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks). After fear conditioning was achieved with footshocks, the drugs were administered to rats and freezing behavior, as an index of fear, was observed in the shock chamber. Acute and subchronic treatment with citalopram was reproducibly anxiolytic against conditioned freezing. Acute reboxetine worsened conditioned freezing and reversed the acute anxiolytic effects of citalopram, but this anxiogenic effect of noradrenaline reuptake inhibition was not observed after subchronic treatment. These results suggest that adding noradrenaline reuptake inhibitors to serotonin reuptake inhibitors adversely affects fear, at least with acute treatment.

Analysis of Variance↗
PubMed2006

Target brain sites of the anxiolytic effect of citalopram, a selective serotonin reuptake inhibitor.

The purpose of the present study was to elucidate the brain regions in which citalopram, a selective serotonin reuptake inhibitor (SSRI), exerts its anxiolytic effects in conditioned fear stress (CFS) in rats, an animal model of anxiety. The effect of citalopram on CFS-induced c-Fos expression was investigated using immunohistochemistry. Systemic administration of citalopram attenuated contextual CFS-induced c-Fos expression in the secondary motor cortex, primary somatosensory cortex, and basolateral nucleus of the amygdala. Among these regions the basolateral nucleus of the amygdala is a likely candidate region in which citalopram exerts its anxiolytic effect.

Amygdala↗
PubMed2006

Effect of co-administration of subchronic lithium pretreatment and acute MAO inhibitors on extracellular monoamine levels and the expression of contextual conditioned fear in rats.

We investigated the effects of clorgyline [a selective MAO (monoamine oxidase inhibitor)-A inhibitor] and lazabemide (a selective MAO-B inhibitor) on extracellular serotonin, dopamine and noradrenaline concentrations in the medial prefrontal cortex after 1-week treatment with subchronic 0.2% or 0.05% Li2CO3 (p.o.) and the effects on expression of contextual conditioned fear, previously reported to be reduced by facilitation of serotonin neurotransmission. As compared to normal diet controls, the subchronic 0.2% Li2CO3 group showed significantly higher levels of extracellular serotonin, but not noradrenaline. No changes were observed in the 0.05% Li2CO3 group. Acute clorgyline (10 mg/kg) treatments combined with subchronic 0.2% Li2CO3 treatments showed significant increases in extracellular serotonin concentrations, but not in dopamine or noradrenaline, as compared with clorgyline treatment alone. There was an additive effect with combined treatment of subchronic 0.2% Li2CO3 and acute clorgyline on the reduction of conditioned freezing, an index of conditioned fear, and this was not observed with subchronic 0.05% Li2CO3. These behavioral data indicate the functional significance of increased extracellular serotonin concentrations due to combined use of a MAO-A inhibitor with subchronic lithium. Effects of lazabemide (10 mg/kg) on extracellular monoamine concentrations and conditioned fear were slight or negligible, and were not affected by subchronic lithium treatment. The present study suggests that lithium augmentation of the antidepressant effect of MAO inhibitors is mediated by additional increases in the extracellular serotonin concentrations induced by MAO-A inhibition and suggests that the anxiolytic action of MAO inhibitors may be enhanced by lithium.

Animals↗
PubMed2006

5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala.

Evidence from preclinical and clinical studies has shown that 5-HT(1A) receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT(1A) receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT(1A) receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT(1A) receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats. These results reveal that both intrahippocampal and intraamygdala injections of flesinoxan decreased the expression of conditioned freezing, while injections into the medial prefrontal cortex did not. In addition, intraamygdala injection of flesinoxan attenuated the increased defecation induced by conditioned fear, but injections into the hippocampus and medial prefrontal cortex failed. These results suggest that flesinoxan exerts its anxiolytic actions in the fear conditioning through stimulations of the postsynaptic 5-HT(1A) receptors in the hippocampus and amygdala.

Amygdala↗
PubMed2006

Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study.

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary-adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

Adult↗
PubMed2006

Lithium response and Val66Met polymorphism of the brain-derived neurotrophic factor gene in Japanese patients with bipolar disorder.

Lithium is a first-line agent for the treatment of bipolar disorder. A significant association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder has been reported. We investigated whether this polymorphism is associated with the response to lithium treatment in Japanese patients with bipolar disorder. Patients had been treated with lithium carbonate for more than 1 year, and the response was retrospectively evaluated. No significant differences were found in the genotype distribution or allele frequency between responders and non-responders. Our results suggested that the brain-derived neurotrophic factor Val66Met polymorphism might not greatly contribute to the efficacy of lithium in bipolar disorder.

Adult↗
PubMed2005

Subchronic milnacipran treatment increases basal extracellular noradrenaline concentrations in the medial prefrontal cortex of rats.

In this study, we investigated the acute effects of milnacipran, a serotonin-noradrenaline reuptake inhibitor, following subchronic treatment with milnacipran (30 mg/kg periorally for 7 days) on extracellular noradrenaline, dopamine and serotonin concentrations in the medial prefrontal cortex. Subchronic administration of milnacipran produced significantly higher basal levels of extracellular noradrenaline. Acute milnacipran administration following subchronic milnacipran treatment for 7 days produced a greater increase in extracellular noradrenaline than a single dose of milnacipran alone. The present results suggest that subchronic milnacipran treatment enhances noradrenergic neural transmission beyond that achieved with acute administration of milnacipran alone, but has no effect on serotonergic or dopaminergic neural transmission.

Administration, Oral↗
PubMed2005

Effect of a dopamine D1/5 receptor antagonist on haloperidol-induced inhibition of the acquisition of conditioned fear.

This study examined the effects of combined treatment with the typical antipsychotic drug haloperidol and dopamine D1/5 receptor antagonist SCH 23390 on the acquisition of contextual conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks), compared with those of various antipsychotic adjuvants, which may increase the effects of antipsychotic drugs. Rats were treated subcutaneously with haloperidol (3 mg/kg) combined with SCH 23390 (0.03 mg/kg) and were given fear conditioning by 5 min footshocks in shock chambers 30 min after the injection. One week after the footshocks, the rats were tested in the same shock chamber without shocks and freezing behavior was observed as an index of fear and anxiety. Haloperidol significantly inhibited the acquisition of conditioned freezing. SCH 23390 combined with haloperidol inhibited the acquisition of conditioned freezing more than either drug alone did. These results suggest that combined dopamine D2-like receptor antagonism and dopamine D1-like receptor antagonism is a promising and effective strategy to increase antipsychotic effects.

Analysis of Variance↗
PubMed2005

Effect of milnacipran on extracellular monoamine concentrations in the medial prefrontal cortex of rats pre-treated with lithium.

Antidepressants are effective in most patients with depression, but sometimes have sub-optimal effects. Thus, there is a need to use more powerful antidepressants when dealing with treatment-resistant cases. Lithium carbonate is widely used for this purpose. We investigated the acute effects of milnacipran, a serotonin-noradrenaline reuptake inhibitor, on extracellular serotonin, dopamine and noradrenaline concentrations, in the rat medial prefrontal cortex. The effects of milnacipran were examined in rats following 7 days of treatment with lithium, and in untreated controls. The lithium group had significantly greater basal levels of extracellular serotonin than the control group. Milnacipran (3 mg/kg) combined with lithium treatment caused a greater increase in extracellular noradrenaline and dopamine levels than milnacipran alone. Milnacipran (3 and 30 mg/kg) combined with lithium treatment also caused a greater increase in extracellular serotonin levels than milnacipran alone. Thus, lithium might augment the antidepressant effects of serotonin-noradrenaline reuptake inhibitors by augmenting serotonin release.

Animals↗
PubMed2005

A possible association between the -116C/G single nucleotide polymorphism of the XBP1 gene and lithium prophylaxis in bipolar disorder.

Bipolar disorder (BPD) is a severe, chronic, and life-threatening illness, and its pathogenesis remains unclear. Recently, a functional polymorphism (-116C/G) of the X-box binding protein 1 (XBP1) gene was reported to be a genetic risk factor for BPD. Moreover, the endoplasmic reticulum stress responses were impaired in cultured lymphocytes from BPD patients with the -116G allele and only valproate rescued such impairment among three major mood stabilizers. In this context, we hypothesized that BPD patients with different genotypes respond differently to mood stabilizers. We investigated the association between the -116C/G polymorphism of the XBP1 gene and lithium response in Japanese patients with BPD. We found that lithium treatment is more effective among BPD patients with the -116C allele carrier than in patients homozygous for the -116G allele. The association between the -116C/G polymorphism and clinical efficacy of mood stabilizers should be further investigated in a prospective study with a larger sample.

Adult↗
PubMed2004

Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala.

Selective serotonin reuptake inhibitors are first-line treatment for most anxiety disorders, but their mechanism of anxiolytic action has not been clarified. Selective serotonin reuptake inhibitors are anxiolytic in conditioned fear stress (re-exposure to an environment paired previously with inescapable electric footshocks). To clarify the brain regions where selective serotonin reuptake inhibitors act, we examined the effect of microinjection of the selective serotonin reuptake inhibitor, citalopram, into the amygdala, medial prefrontal cortex and mediodorsal nucleus of the thalamus on freezing behavior, an index of fear, induced by conditioned fear stress. Bilateral injection of citalopram into the amygdala before testing reduced freezing significantly, while bilateral injection into the medial prefrontal cortex or mediodorsal nucleus of the thalamus did not. These results suggest that the anxiolytic effect of a selective serotonin reuptake inhibitor in conditioned fear is mediated by its effect in the amygdala, and support the hypothesis of serotonin function in anxiety by which facilitation of serotonin neurotransmission decreases anxiety.

Amygdala↗
PubMed2004

Single footshock attenuates c-Fos expression induced by 5-HT2A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rat brain.

Administration of 3 mg/kg 5-hydroxytryptamine2A/2C (5-HT2A/2C) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced c-Fos expression in all areas of the rat neocortex. The single footshock 24 h before DOI administration significantly attenuated DOI-induced c-Fos expression in layer IV of the primary somatosensory cortex. These changes in c-Fos expression suggest an adaptational change in the somatosensory cortex by acute stress.

Amphetamines↗
PubMed2004

Effect of mediodorsal thalamic nucleus lesion on contextual fear conditioning in rats.

Much evidence from animal and clinical studies has shown that the mediodorsal nucleus of the thalamus (MD) is related to various types of memory, such as visual recognition, object-reward association, spatial working, and reference memory; however, few studies have investigated its role in emotion-related learning and memory processes. This study compared the effect of pre- and posttraining bilateral lesions of the mediodorsal thalamic nucleus with those of the amygdala on contextual conditioned fear. Both pre- and posttraining amygdala lesions almost eliminated conditioned freezing, and significantly blocked postshock freezing when behavioral tests were performed immediately after footshocks, reconfirming previous studies that the amygdala is implicated in the learning of Pavlovian conditioning. Both pre- and posttraining lesions of the mediodorsal nucleus of the thalamus significantly attenuated conditioned freezing but had no effect on postshock freezing. In contrast to lesions of the amygdala, those of the mediodorsal thalamic nucleus failed to alter the increased defecation induced by conditioned fear stress. Our results suggest that the mediodorsal nucleus of the thalamus has an important role in acquisition, consolidation or retrieval in Pavlovian contextual fear conditioning. Possible neural circuits, incorporating the amygdala, MD, and hippocampus, and the functional similarity of the MD and hippocampus in contextual fear conditioning, are also discussed.

Amygdala↗
PubMed2004

Effect of co-administration of lithium and reboxetine on extracellular monoamine concentrations in rats.

We investigated the effect of reboxetine, a selective noradrenaline reuptake inhibitor, 7 days after treatment with subchronic lithium on extracellular noradrenaline, dopamine and serotonin (5-HT) concentrations in the medial prefrontal cortex. Acute treatment with reboxetine significantly increased extracellular concentrations of noradrenaline and dopamine, but did not alter 5-HT concentrations. Subchronic lithium increased basal levels of extracellular 5-HT, but not noradrenaline or dopamine. Co-administration of reboxetine and lithium treatment increased the extracellular concentrations of noradrenaline, dopamine and 5-HT, though reboxetine alone increased the extracellular levels of noradrenaline and dopamine only. Thus, combined lithium and reboxetine produces an additive effect neurochemically rather than their interaction.

Administration, Oral↗
PubMed2004

[Biological basis of anxiety disorders and serotonergic anxiolytics].

Selective serotonin reuptake inhibitors (SSRIs) have wide indications for the treatment of anxiety disorders, including panic disorder, generalized anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder and social anxiety disorder in addition to depression. Until recently, no animal model has been available for screening the anxiolytic effect of SSRIs and studying its mechanism of action. We have investigated the relationship between serotonin neurotransmission and anxiety using conditioned fear stress (CFS), an animal model of anxiety. CFS increased serotonin neurotransmission in the medial prefrontal cortex and amygdala. In behavioral pharmacological studies, SSRIs, serotonin1A agonists and monoamine oxidase inhibitors, which are assumed to facilitate serotonin neurotransmission, decreased conditioned freezing, an index of anxiety or fear, in CFS. In vivo microdialysis studies showed that serotonin neurotransmission in the medial prefrontal cortex increased after recovery from the freezing behavior. Microinjection of SSRI to the basolateral nucleus of the amygdala reduced conditioned freezing, indicating that the amygdala is one of target brain sites of anxiolytic action of SSRIs. Furthermore, CFS-induced c-Fos expression in the basolateral nucleus of the amygdala was reduced by SSRI pretreatment. Taken together, recent studies indicate that facilitation of brain serotonin neurotransmission decreases anxiety in agreement with the clinical evidence.

Animals↗