Takuya Masui

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.

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

Rationale and objectiveImpulsive 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 methodsThe 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).ResultsThe 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.ConclusionsThese 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.

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

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.

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.

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.

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.

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 Parkinsons 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.

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.

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.