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.

Pramipexole for stage 2 treatment-resistant major depression: an open study.

OBJECTIVE: To examine the effectiveness and safety of adjunctive pramipexole in the treatment of stage 2 treatment-resistant major depressive disorder. METHODS: This study included patients with moderate or non-psychotic severe major depressive disorder according to DSM-IV-TR criteria despite at least two adequate treatment trials with antidepressants from different pharmacological classes. Pramipexole 0.25 to 2 mg daily was added to antidepressant therapy. Previous treatments were continued unchanged, but no new treatments were allowed. We conducted assessments at baseline and at weeks 2, 4, 6, and 8. We defined response as a 50% or greater reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Ten patients (4 men, 6 women) aged 43.7±11.4 years received pramipexole at mean dose of 1.3±0.6 mg/d. Mean MADRS scores improved significantly from baseline to endpoint (mean differences=11.4, 95% CI [4.1, 18.7], P=0.0064). At the endpoint, six of 10 (60%) were responders on MADRS (≥50% reduction). Two patients (20%) terminated early due to mild somatic and psychiatric adverse effects. CONCLUSION: These preliminary data suggest that the addition of pramipexole to antidepressant treatment may be effective and well tolerated in patients with stage 2 treatment-resistant major depressive disorder.

The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.

Pharmacokinetic interaction between tandospirone and fluvoxamine in the rat contextual conditioned fear stress model and its functional consequence: Involvement of cytochrome P450 3A4.

AIMS: In a previous study it was demonstrated that the anxiolytic action of tandospirone, a 5-hydroxytryptamine (5-HT)(1A) receptor agonist, is facilitated by cytochrome P450 (CYP) 3A4 inhibitors, such as ketoconazole and cimetidine. It is also known that fluvoxamine, a selective serotonin re-uptake inhibitor (SSRI), inhibits CYP3A4. The purpose of the present study was to clarify the pharmacokinetic interaction between tandospirone and fluvoxamine and to evaluate their combined effect in the rat anxiety model. METHODS: The anxiolytic action of co-administration of tandospirone and fluvoxamine was examined using the rat contextual conditioned fear stress model. After testing the conditioned fear, plasma concentrations of tandospirone and its major metabolite 1-(2-pyrimidyl) piperazine were determined. RESULTS: One day after fear conditioning, both tandospirone (60 mg/kg, p.o.) and fluvoxamine (60 mg/kg, p.o.) significantly inhibited conditioned freezing and their combination effect was additive. In addition, plasma concentration of tandospirone was increased by fluvoxamine. CONCLUSIONS: There is a CYP3A4-related drug-drug interaction between tandospirone and fluvoxamine. Therefore, fluvoxamine may facilitate the anxiolytic effect of tandospirone via CYP3A4 inhibition.

Depressive patients are more impulsive and inconsistent in intertemporal choice behavior for monetary gain and loss than healthy subjects--an analysis based on Tsallis' statistics.

OBJECTIVES: Depression has been associated with impaired neural processing of reward and punishment. However, to date, little is known regarding the relationship between depression and intertemporal choice (delay discounting) for gain and loss. This examination is potentially important for advances in neuroeconomics of intertemporal choice, because depression is associated with reduced serotonergic activities in the brain. DESIGN AND SETTING: We compared impulsivity and inconsistency in intertemporal choice for monetary gain and loss between depressive patients and healthy control subjects. METHODS: We conducted delay discounting tasks for gain and loss in depressed and healthy control subjects. We then quantified impulsivity and inconsistency in the delay discounting with parameters in the q-exponential discount function based on Tsallis' statistics. RESULTS: We observed that depressive patients were more impulsive and time-inconsistent in intertemporal choice action for gain and loss, in comparison to healthy controls. MAIN FINDINGS: Depressed patients were more irrational in temporal discounting. CONCLUSIONS: The usefulness of the q-exponential discount function for assessing the impaired decision-making by depressive patients was demonstrated. Furthermore, biophysical mechanisms underlying the altered intertemporal choice by depressive patients are discussed in relation to impaired serotonergic neural systems.

Effect of co-administration of a serotonin-noradrenaline reuptake inhibitor and a dopamine agonist on extracellular monoamine concentrations in rats.

Recent studies have shown that dopamine agonists are useful for the treatment of not only Parkinson's disease, but also major depressive disorders. However, while these dopamine agonists provide a new treatment strategy for major depressive disorders, such as treatment-resistant cases, the antidepressant effect of dopamine agonists has yet to be investigated. To examine the mechanism of the antidepressive effect of dopamine agonists, we investigated the acute effect of the dopamine receptor agonist, cabergoline, and the serotonin-noradrenaline reuptake inhibitor, milnacipran, on extracellular noradrenaline, dopamine and serotonin concentrations in the rat medial prefrontal cortex. There was a greater increase in extracellular noradrenaline concentrations when acute milnacipran (30 mg/kg intraperitoneally) was administered after acute high-dose cabergoline (1 and 2 mg/kg subcutaneously) than when acute milnacipran was administered following acute vehicle or low-dose cabergoline (0.25 mg/kg subcutaneously). There were no significant differences noted in the dopamine or serotonin concentrations. These results suggest that the addition of cabergoline has the potential to strengthen the antidepressant effects of milnacipran and that the mechanism of action of the antidepressive effect of dopamine agonists might be due to enhancement of induced increases of extracellular noradrenaline.

Long-term perospirone treatment with a single dose at bedtime in schizophrenia: relevant to intermittent dopamine D2 receptor antagonism.

Perospirone, a serotonin 5-HT2A and dopamine D2 receptor antagonist, is metabolized to ID-15036 by CYP3A4 and the elimination half-life (T1/2) for the latter is longer than the former. The active metabolite ID-15036 is an 8-times weaker D2 antagonist than perospirone, although it has a high affinity for 5-HT2A receptor. In this study, we measured the plasma concentrations of perospirone and ID-15036 in the long-term stable schizophrenic patients with a single dose of perospirone at bedtime. The mean level of perospirone at 11-15 h after a last dosing was much lower (0.49 ng/ml) than that of ID-15036 (2.89 ng/ml). These results show that a long-term perospirone monotherapy with a single dose at bedtime is effective for the maintenance treatment of chronic schizophrenia and also suggest the possibility that intermittent D2 receptor blockade may be sufficient for effective relapse prevention.

A possible association between missense polymorphism of the breakpoint cluster region gene and lithium prophylaxis in bipolar disorder.

Lithium is one of the most commonly used drugs for the treatment of bipolar disorder. To prescribe lithium appropriately to patients, predictors of response to this drug were explored, and several genetic markers are considered to be good candidates. We previously reported a significant association between genetic variations in the breakpoint cluster region (BCR) gene and bipolar disorder. In this study, we examined a possible relationship between response to maintenance treatment of lithium and Asn796Ser single-nucleotide polymorphism in the BCR gene. Genotyping was performed in 161 bipolar patients who had been taking lithium for at least 1 year, and they were classified into responders for lithium mono-therapy and non-responders. We found that the allele frequency of Ser796 was significantly higher in non-responders than in responders. Further investigation is warranted to confirm our findings.

[Clinical relevance of antidepressant-induced activation syndrome: from a perspective of bipolar spectrum disorder].

Recent concerns have been raised regarding whether antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) might increase suicidal tendencies and intense debate-rages over the pros and cons of their use. Although systematic reviews and population-based studies have been conducted, a consensus on this association remains to be established. Subsequently, the concept of so-called 'activation syndrome' associated with antidepressants has been accepted without its adequate verification. In the present report, we present our experience of seven cases considered of having 'activation syndrome' brought on by antidepressants, and examine its clinical relevance to bipolar spectrum disorder (Ghaemi, et al., 2001) both symptomatologically and diagnostically. Five patients, diagnosed as having major depressive disorder according to the diagnostic manual (DSM-IV), met the criteria of bipolar spectrum disorder and suffered from activation syndrome following the administration of SSRIs, mainly paroxetine. Similarly, hypomania developed in all five cases with depression; the diagnostic criteria of a hypomanic episode were not met. In the remaining two patients, who were both diagnosed with bipolar disorder, one showed irritability and insomnia through imipramine use, and the another developed a hypomanic and/or a mixed state after the co-administration of fluvoxamine and trazodone. From the results of our examination, 'bipolarity', which is the pivotal factor of bipolar spectrum, might exist behind the phenomenon recognized as activation syndrome, and be revealed by antidepressant treatment, just like manic switching. Moreover, the various problems encountered in the current practice of treating mood disorders, including unipolar-bipolar dichotomy, manic switching by antidepressants, and narrow criteria for a mixed episode, were pointed out a new through this concept of activation syndrome. Actually, the understanding of activation syndrome clinically leads to the prevention of suicidal behavior and the careful use of antidepressants for bipolar (spectrum) disorder, but we must be prudent when applying this concept, since it has not yet been established.

Effects of cytochrome P450 (CYP) 3A4 inhibitors on the anxiolytic action of tandospirone in rat contextual conditioned fear.

The azapirone derivatives, including tandospirone and buspirone, are anxiolytics with 5-HT(1A) receptor agonistic action. Previous in vitro studies have suggested these azapirone derivatives are mainly metabolized by the cytochrome P450 (CYP) 3A4 isoform. The purpose of this study was to clarify the effects CYP3A4 inhibitors have on the anxiolytic action of tandospirone in a conditioned fear stress rat model. One day after fear conditioning, the orally administered tandospirone (30-100 mg/kg) significantly inhibited conditioned freezing in a dose-dependent manner. Co-administration of oral tandospirone and CYP3A4 inhibitors [ketoconazole (10 mg/kg, i.p.) and cimetidine (200 mg/kg, p.o.)] markedly inhibited conditioned freezing. Ketoconazole significantly increased the anxiolytic effect of buspirone similar to tandospirone. As with freezing behavior, the plasma concentrations of tandospirone and buspirone were increased by CYP3A4 inhibitors. This suggests the CYP3A4 isoform is involved in the metabolism of tandospirone, in vivo. Therefore, drugs with CYP3A4 inhibitory property may facilitate the anxiolytic effect of tandospirone when treating human anxiety disorders.

Effects of valproate on serotonin-induced intracellular calcium mobilization in human platelets.

OBJECTIVE: Valproate (VPA) is effectively used in the treatment of bipolar disorder, although the mechanism of action is unclear. In patients with bipolar disorder, 5-hydroxytryptamine (5-HT)-induced intraplatelet calcium (Ca) mobilization has been shown to be enhanced. METHODS: We examined the effect of VPA on 5-HT-induced Ca response in the platelets of normal subjects, in the presence of a calmodulin antagonist W-7 (N-[6-aminohexyl]-5-chloro-1-naphthalenesulfonamide), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or PKC inhibitors staurosporine and bisindolylmaleimide II. RESULTS: VPA inhibited the 5-HT-induced Ca response in a concentration-dependent manner. For calmodulin pathways, W-7 enhanced the 5-HT-stimulated Ca response, which was not affected by VPA. For PKC pathways, PMA reduced the Ca response, although both PKC inhibitors had no effect. PMA, staurosporine or bisindolylmaleimide II reversed the inhibitory effect of VPA on the Ca response, while W-7 did not modify it. CONCLUSION: These findings suggest the possibility that the mechanism of action of VPA may be partly related to PKC signalling.

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.

Involvement of a polymorphism in the 5-HT2A receptor gene in impulsive behavior.

RATIONALE AND OBJECTIVE: Impulsive behavior has been suggested to occur due to a dysfunction of serotonergic 5-HT neurotransmission. After evaluation by a self-reporting measure, a polymorphism in the promoter of the 5-HT2A receptor gene has been proposed to underlie the impulsive behavior; however, this hypothesis is not convincing. In this study, we examined whether this 5-HT2A receptor gene polymorphism is involved in impulsive aggression by evaluating a behavioral task (go/no-go task) in normal volunteers. MATERIALS AND METHODS: The polymorphism of the 5-HT2A receptor gene promoter was analyzed by polymerase chain reaction using lymphocytes from 71 volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a go/no-go task (a larger number of commission errors indicates greater difficulty in inhibiting the behavior). RESULTS: The subjects in the group with the A-1438A allele of the 5-HT2A receptor gene (A-1438A group) made more commission errors under the punishment-reward condition in a go/no-go task than those in the G-1438G group. CONCLUSIONS: These results suggest the possible involvement of the A-1438A polymorphism of the 5-HT2A receptor gene in impulsive behavior; this was evaluated using a behavioral task measure that can directly reveal the traits of human impulsive behavior.

Effect of carbamazepine on the single oral dose pharmacokinetics of perospirone and its active metabolite.

Perospirone is a serotonin 5-HT(2A) and dopamine D(2) receptor antagonist which originated in Japan. It has been shown that perospirone is metabolized to ID-15036 mainly by CYP3A4 based on an in vitro study. To investigate the metabolism of perospirone in humans, the authors measured the concentration of perospirone and ID-15036 after a single oral dose of perospirone (8 mg) in 10 healthy male subjects, before and during coadministration of carbamazepine, known as a potent inducer of CYP3A4. Before carbamazepine coadministration, the peak plasma concentrations+/-SD of perospirone and ID-15036 were 4.0+/-4.3 and 11.7+/-7.1 ng/ml, respectively. During carbamazepine coadministration, the concentration of perospirone was decreased below the detection limit, and that of ID-15036 was 6.0+/-1.7 ng/ml. The concentrations of perospirone and ID-15036 were influenced significantly by the treatment with carbamazepine, and this was probably attributable to the induction of CYP3A4. This study provided an in vivo evidence of involvement of CYP3A4 in the metabolism of perospirone.

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.

Effects of itraconazole and tandospirone on the pharmacokinetics of perospirone.

Perospirone is an atypical antipsychotic agent originated and clinically used in Japan. Based on an in vitro study, it is reported that perospirone is mainly metabolized to ID-15036 by cytochrome P450 (CYP) 3A4. In this study, the authors investigated the effects of itraconazole, which is a specific inhibitor of CYP3A4, or tandospirone, which is mainly metabolized by CYP3A4 and is expected to competitively inhibit the activity of this enzyme, on single oral dose pharmacokinetics of perospirone. After pretreatment with 200 mg daily of itraconazole or 10 mg daily of tandospirone for 5 days, 9 healthy male subjects received 8 mg of perospirone. Plasma concentrations of perospirone and ID-15036 up to 10 hours after perospirone dosing were measured by high-performance liquid chromatography (HPLC). The metabolism of perospirone was significantly inhibited by treatment with itraconazole but not by tandospirone. The present study suggests that CYP3A4 is significantly involved in metabolism of perospirone in humans.

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.

Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI.

There have been several researches on the role of personality in the pathophysiology of bipolar disorder. Recently, a polymorphism of XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Therefore, in this study, we examined the relationship between the XBP1 gene polymorphism and the personality traits assessed by two self-rating scales, a shortened version of Temperament and Character Inventory (TCI) and NEO-Five Factor Inventory (NEO-FFI) in healthy subjects. The present results suggested that the XBP1 gene polymorphism was associated with the NEO-FFI score of neuroticism in female subjects. However, no significant differences in the other personality scale scores of both assessments were observed among normal subjects with -116C/C, C/G and G/G genotypes. Further investigations are necessary to examine the relationship in patients with bipolar disorder, or use full version of various self-rating personality assessments.

Efficacy of carbamazepine against neuroleptic-induced akathisia in treatment with perospirone: case series.

Neuroleptic-induced akathisia is a distressing side effect of antipsychotics, and it is unmanageable in some cases. The authors report three cases of schizophrenia whose neuroleptic-induced akathisia did not respond to representative anti-akathisia drugs such as beta-adrenergic antagonists, anticholinergic agents, benzodiazepines and antihistaminergics, and they showed a marked improvement of it without worsening of psychotic symptoms during a combination treatment with carbamazepine and perospirone, a serotonin-dopamine antagonist developed in Japan. As the mechanism of current observation, we assumed that carbamazepine affected the pharmacokinetics of perospirone, and change in the proportion of perospirone and its major active metabolite (ID-15036). Further investigations including the monitoring pharmacokinetics of perospirone and ID-15036 under concomitant use of carbamazepine should be carried out to explain the mechanism of the current experience.

Lack of association between XBP1 genotype and calcium signaling in the platelets of healthy subjects.

Dysregulations of calcium (Ca) homeostasis may be involved in the pathophysiology of bipolar disorder. Enhanced Ca response to various agonists in peripheral blood cells is one of a few confirmed biological markers for bipolar disorder. Recently, a polymorphism of XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Thus, in this study, we examined the relationship between the XBP1 gene polymorphism and the Ca signaling in the platelets of healthy controls. The present results suggest no significant difference in the basal Ca level or 5-HT-induced Ca mobilization among normal subjects with -116C/C, C/G, and G/G genotypes. Further investigations are necessary to examine the relationship in the different peripheral blood cells and/or in larger samples from patients with bipolar disorder.