Differences between bipolar and unipolar depression on Rorschach testing.

BACKGROUND: The bipolar-unipolar distinction in patients with a major depressive episode is the most important issue related to the diagnosis and treatment of mood disorders, but remains unresolved. This study was undertaken to compare bipolar and unipolar depression on Rorschach testing using the Comprehensive System with reference to healthy Japanese controls. METHODS: Patients with bipolar or unipolar depression who had undergone the Rorschach test for routine clinical purposes were followed up naturalistically for a long period. Based on diagnostic confirmation after long-term follow-up, scores on this test for patients with bipolar and unipolar depression were compared with those published elsewhere for healthy Japanese controls. RESULTS: The bipolar depression group showed significantly higher scores or positive findings in five variables of the Rorschach test, ie, WSum6, DR2 > 0, (CF + C) > FC + 2, PureC > 1, and Populars > 7, as assessed using the Comprehensive System, than did the unipolar depression group and healthy controls. These scores did not differ between the unipolar depression and control groups. CONCLUSION: The results of this study show thought disorder or cognitive slippage and marked laxness in modulating emotion in bipolar depression, indicating the psychopathological characteristics of bipolar disorder.

Abnormalities in extracellular glycine and glutamate levels in the striatum of sandy mice.

OBJECTIVE: Glycine regulates glutamatergic neurotransmission, and several papers have reported the relationship between glycine and schizophrenia. The dysbindin-1 (DTNBP1: dystrobrevin-binding protein 1) gene is related to glutamatergic neurotransmission and has been found to be a strong candidate gene for schizophrenia. In this study, we clarified the relationship between dysbindin, glutamate, and glycine with in vivo microdialysis methods. METHODS: We measured extracellular glycine and glutamate levels in the striatum of sandy (sdy) mice using in vivo microdialysis methods. Sdy mice express no dysbindin protein owing to a deletion in the dysbindin-1 gene. In addition, we measured changes in those amino acids after methamphetamine (METH) administration. RESULTS: The basal levels of extracellular glycine and glutamate in the striatum of sdy mice were elevated. These extracellular glutamate levels decreased gradually after METH administration and were not subsequently different from those of wild-type mice. CONCLUSIONS: These results suggest that dysbindin might modulate glycine and glutamate release in vivo.

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

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

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

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

Developmental GABAergic deficit enhances methamphetamine-induced apoptosis.

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

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

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

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

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

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

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

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

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

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

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

Effects of behavioral and neurochemical changes on adult excitotoxic lesion of the ventral hippocampus.

BACKGROUND: The postmortem and magnetic resonance imaging studies for schizophrenic patients showed neuropathological abnormalities including neuron loss and volume reduction in ventral hippocampus (VH), some longitudinal studies suggest these changes may be a neurodegenerative process. OBJECTIVES: The present study examined the effects of adult bilateral VH lesions on a dopaminergic stimulant, methamphetamine (METH)-induced and an N-methyl-(D)-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801)-induced behavioral and neurochemical changes in rats, in order to evaluate a potential of adult VH lesion animals for a model of schizophrenia. METHODS: To study the behavioral effects after bilateral VH lesions in adult rats, locomotor activity was measured individually by an infra-red sensor. Extracellular concentrations of dopamine in the nucleus accumbens (NAc) were measured using in vivo brain microdialysis. RESULTS: The bilateral adult VH lesion rats showed a significant enhanced hyperlocomotion in response to METH but no changes to MK-801 and phencyclidine; while bilateral adult VH lesion enhanced METH-induced increasing dopamine levels in the NAc. CONCLUSIONS: The bilateral adult VH lesions enhanced locomotor activity, which related to increased dopamine releases in the NAc, induced by a dopaminergic stimulant; these findings may suggest a potential of adult VH lesion animal for a model reflecting dopamine D2 receptor antagonist-responsive pathophysiology of schizophrenia by way of neurodegenerative processes.

Different effects of a single and repeated administration of clozapine on phencyclidine-induced hyperlocomotion and glutamate releases in the rat medial prefrontal cortex at short- and long-term withdrawal from this antipsychotic.

Clozapine is a prototype of atypical antipsychotics that has a profile not only to block D(2)/5-HT(2A) receptors but also to enhance N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. This study hypothesized different effects between a single and repeated administration of clozapine on NMDA receptor-mediated neurotransmission, and examined effects of these treatments of clozapine on a non-competitive NMDA receptor antagonist, phencyclidine (PCP)-induced hyperlocomotion and acute increases in glutamate levels in the medial prefrontal cortex (mPFC), after short- and long-term withdrawal from this antipsychotic. Locomotor activity and extracellular levels of glutamate were measured by an infrared sensor and in vivo microdialysis respectively. A single administration of clozapine attenuated PCP-induced hyperlocomotion and blocked PCP-induced increases in glutamate levels in the mPFC at 48 hours, but not 11 days after the injection of clozapine. Repeated administration of clozapine attenuated PCP-induced hyperlocomotion not only at 48 hours, but also 11 days after the last injection of clozapine, with blocking PCP-induced increases in glutamate levels in the mPFC. Both a single and repeated administration of clozapine had no effect on methamphetamine (METH)-induced hyperlocomotion at 48 hours or 11 days after the treatment of clozapine. Considering fast dissociation of clozapine from dopamine D(2) receptors and no effect of a single or repeated administration of clozapine on METH-induced hyperlocomotion, the attenuated PCP-induced hyperlocomotion by a single and repeated clozapine treatments cannot be explained by clozapine occupancy of dopamine D(2) receptors. Repeated but not a single administration of clozapine inhibited a 5-HT(2A/2C) agonist, DOI-induced increases in the mPFC 11 days after the last injection of clozapine. These findings suggest that subchronically treated clozapine-induced long-lasting downregulation of 5-HT(2A) receptors may block the enhanced PCP-induced neurochemical and behavioral changes.

Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.

RATIONALE: Neurodevelopmental deficits of parvalbumin-immunoreactive gamma-aminobutyric acid (GABA)ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). METHODS: GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. RESULTS: Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbumin-immunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbumin-immunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP-induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. CONCLUSIONS: These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.

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.

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.

[Treatment of "the premonitory state of schizophrenia" with atypical antipsychotics].

"Premonitory symptoms and signs" before the full-blown stage of schizophrenia are recognized as abnormal expressions (signs) and symptoms of "early schizophrenia", as described by Nakayasu (1990). The following conclusions were derived from my examination of the effects of atypical antipsychotics on six patients suffering from 'the premonitory symptoms and signs' in 'the premonitory state of schizophrenia'. 1) Even though hyperventilation, fatigue and a depressive state existed in the foreground at the first medical examination, we suspected 'the premonitory state of schizophrenia', and investigated symptoms of 'early schizophrenia' as described by Nakayasu, in cases in which abnormal expressions such as stiff facial expression and specific tense and perplexed attitude were observed. 2) In cases in which 'the premonitory symptoms and signs' were observed, we introduced treatment with atypical antipsychotics as soon as possible. Hyperventilation and a depressive state, which were considered to be induced by 'the premonitory state of schizophrenia', disappeared as a result of the improvement of 'the premonitory symptoms and signs' by the atypical antipsychotics. 3) Risperidone, perospirone, and olanzapine were effective for so-called "positive early symptoms". Risperidone, which is expected to have an acute effect, was effective in cases in which early intervention was necessary. When a depressive state was secondarily induced by risperidone, a change to perospirone was useful. Furthermore, when risperidone and perospirone were not sufficiently effective, olanzapine improved 'the premonitory symptoms and signs'. 4) In cases in which so-called "negative early symptoms" and a decrease in the energy-potential, such as emotional blunting, were observed, olanzapine induced improvement. 5) In 'the premonitory state of schizophrenia', treatment with atypical antipsychotics should be maintained, for both the improvement of 'the premonitory symptoms and signs' and the prevention of progression to the full-blown stage. The dose and duration of the treatment with antipsychotics should be carefully modified, with consideration for the specificity of the life cycle and life events for each patient. In conclusion, treatment with atypical antipsychotics was useful for both the improvement of 'the premonitory symptoms and signs of schizophrenia' and the prevention of the development of pathogenesis.

Effect of MS-153 on the development of behavioral sensitization to stereotypy-inducing effect of phencyclidine.

The present study examined the effects of a novel compound, MS-153 [(R)-(-)-5-methyl-1-nicotinyl-2-pyrazoline], which has an ability to enhance glutamate uptake and inhibit glutamate release, on the development of behavioral sensitization to phencyclidine (PCP). MS-153 (10 and 100 mg/kg) enhanced stereotypy induced by a single injection of PCP (7.5 mg/kg). Repeated administration of PCP (20 mg/kg, once every day for 5 days) enhanced stereotypy-inducing effects of PCP (7.5 mg/kg) when tested 4 days after the withdrawal from the repeated PCP treatment, indicating the development of behavioral sensitization. MS-153 given 60 and 120 min after the PCP treatments blocked the development of behavioral sensitization to stereotypy-inducing effects of PCP. These results suggest that the attenuation of glutamatergic neural transmission enhances acute effect of PCP, but in contrast, blocks the behavioral sensitization to PCP.