Bipolar Disorder: Young LT

Yatham LN, Kennedy SH, O'Donovan C, Parikh S, MacQueen G, McIntyre R, Sharma V, Silverstone P, Alda M, Baruch P, Beaulieu S, Daigneault A, Milev R, Young LT, Ravindran A, Schaffer A, Connolly M, Gorman CP, Anonymous00076. · Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. · Bipolar Disord. · Pubmed #15952957 No free full text.

Abstract: Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence-based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first-line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood-stabilizing agents are first-line treatments for bipolar depression. First-line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar II disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring.

Young LT. · No affiliation provided · J Psychiatry Neurosci. · Pubmed #18982170 links to  free full text

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Young LT, Wang JF. · No affiliation provided · Can J Psychiatry. · Pubmed #18186174 No free full text.

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Young LT. · No affiliation provided · J Psychiatry Neurosci. · Pubmed #17476362 links to  free full text

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Andreazza AC, Kauer-Sant'anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, Yatham LN. · Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. · J Affect Disord. · Pubmed #18539338 No free full text.

Abstract: BACKGROUND: Oxidative stress is thought to mediate neuropathological processes of a number of neuropsychiatric disorders and recent data suggest that oxidative stress may be involved in the pathophysiology of bipolar disorder (BD). In the present investigation, we conducted a meta-analysis of studies that evaluated markers of oxidative stress in individuals with BD, as compared to healthy controls. METHODS: A Medline search was conducted to identify studies that measured peripheral markers of oxidative stress in bipolar disorder. Data were subjected to meta-analysis using a random effects model to examine the effect sizes of the pooled results. Bias assessment (Egger's test) and assessment of heterogeneity (I(2)) were also carried out. RESULTS: Thiobarbituric acidic reactive substances (TBARS) (p = 0.001) as well as NO activity (p = 0.02) were significantly increased in BD with a large effect size for TBARS and a moderate effect size for increase in NO. No significant effect sizes were observed for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase (all p>0.05). LIMITATIONS: Some caution is warranted in interpreting these results: (1) Egger's test was positive for SOD, suggesting that SOD results may have been influenced by a publication bias. (2) We analyzed the absolute values of each antioxidant enzyme separately and the literature suggests that an imbalance between the antioxidant enzymes is a better indication of the presence of oxidative stress. CONCLUSIONS: The present meta-analysis suggests that oxidative stress markers are increased in BD and that oxidative stress may play a role in the pathophysiology of BD.

Alda M, Grof P, Rouleau GA, Turecki G, Young LT. · Department of Psychiatry, Dalhousie University, 5909 Jubilee Road, Halifax, Nova Scotia, Canada B3H 2E2. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #15946781 No free full text.

Abstract: Attempts to map susceptibility genes for bipolar disorder have been complicated by genetic complexity of the illness and, above all by heterogeneity. This paper reviews the genetic research of bipolar disorder aiming to reduce the heterogeneity by focusing on definite responders to long-term lithium treatment. The available evidence strongly suggests that lithium-responsive bipolar disorder is the core bipolar phenotype, characterized by a more prominent role of genetic factors. Responders to lithium have typically a family history of bipolar disorder (often responsive to lithium). They differ from responders to other mood stabilizing drugs in their family histories as well as in other clinical characteristics. The molecular genetic investigations of bipolar disorder responsive to lithium indicate possibly several loci linked to and/or associated with the illness. A combination of research strategies employing multiple methods such as linkage, association, and gene-expression studies will be needed to clarify which of these represent true susceptibility loci.

Bauer M, Alda M, Priller J, Young LT, Anonymous00102. · Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Campus Charité-Mitte (CCM), Berlin, Germany. · Pharmacopsychiatry. · Pubmed #14677087 No free full text.

Abstract: Bipolar disorder is increasingly recognized as an illness that may progress to impairment in neurocognitive functioning and cell loss in cortical and limbic brain regions. Glutamatergic damage and/or damage due to high glucocorticoid levels that inhibit adult neurogenesis are likely contributing mechanisms. Drug treatments with possible neuroprotective effects are becoming increasingly important both clinically and as research tools. Mood stabilizing drugs and lithium in particular may act to prevent neuronal damage and tissue loss that may occur in the brain of patients with bipolar disorders. Lithium has been shown to exert neuroprotective effects in vitro and to stimulate neurogenesis in the hippocampus. Animal studies have demonstrated pharmacological effects of lithium suggestive of its role in neuroprotection, which range from reducing excitotoxicity through increased glutamate uptake, to regulation of a number of signal transduction intermediates such as myo-inositol, protein kinase C, phosphotidylinositol-3 kinase (PI-3K)/protein kinase B (Akt), ras-mitogen-activated protein kinase (MAPK), glycogen synthase kinase (GSK)-3alpha and -3beta and calcium. It remains to be established whether lithium treatment protects against possible cell damage in the same manner as it protects against recurrences of the illness. We propose to examine the effect of long-term lithium treatment on neurocognitive functioning of bipolar patients and the use of lithium in the treatment of chronic neuropsychiatric disorders.

Macdonald KJ, Young LT. · Mood Disorder Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada. · CNS Drugs. · Pubmed #12096935 No free full text.

Abstract: Antiepileptic drugs (AEDS) are used regularly in the treatment of patients with bipolar disorders. Carbamazepine and valproic acid (sodium valproate) are effective as antimanic treatments, and the success of these medications has prompted investigation of other AEDs as possible treatments in patients with mood disorders. Lamotrigine appears to be the most promising of the newer AEDs with respect to effects in mood disorders. Current evidence suggests efficacy of this drug both as monotherapy and as an adjunctive agent in bipolar depression, and studies are underway to clarify its efficacy in mood stabilisation and rapid cycling, as currently available data are equivocal. Use of gabapentin is not as well supported in the literature, although data from open trials using it as an adjunctive agent suggest that it may be helpful in patients with bipolar depression. There have been some open trials and case reports supporting the use of topiramate as an adjunctive agent for the treatment of mania; however, data from controlled trials are not yet available. Further controlled trials of lamotrigine, gabapentin or topiramate as monotherapy and adjunctive treatment are needed to clarify their potential roles in the treatment of patients with mood disorders.

Bown CD, Wang JF, Chen B, Young LT. · Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada. · Bipolar Disord. · Pubmed #12071512 No free full text.

Abstract: OBJECTIVES: This paper reviews results of our studies examining the regulation of endoplasmic reticulum (ER) stress proteins by valproate (VPA). and discusses the possible implications in bipolar disorder. METHODS: Our previous studies in the field are reviewed along with relevant literature. RESULTS: Using differential display PCR, we identified GRP78 as a VPA-regulated gene in rat cerebral cortex. We also showed that other members of the ER stress proteins family, GRP94 and calreticulin, are also upregulated by VPA. Immunohistochemistry identified that ER stress proteins are increased in frontal and parietal cortex, as well as regions of the hippocampus in rat brain following chronic treatment with VPA. CONCLUSIONS: Regulation of ER stress proteins by VPA may prove to be important to the mechanism of action of the drug. The neuroprotective role of these proteins may also prove to be involved in the pathophysiology of bipolar disorder.

Bezchlibnyk Y, Young LT. · Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario. · Can J Psychiatry. · Pubmed #11926075 No free full text.

Abstract: OBJECTIVE: This article presents an overview of signal transduction pathways and reviews the research undertaken to study these systems in clinically relevant samples from patients with bipolar disorder (BD). METHOD: We reviewed the published findings from studies of postmortem brain tissue and blood samples from patients with BD. RESULTS: Although the exact biochemical abnormalities have yet to be identified, the presented findings strongly suggest that BD may be due, at least in part, to abnormalities in signal transduction mechanisms. In particular, altered levels or function, or both, of G-protein alpha subunits and effector molecules such as protein kinase A (PKA) and protein kinase C (PKC) have consistently been associated with BD both in peripheral cells and in postmortem brain tissue, while more recent studies implicate disruption in novel second-messenger cascades, such as the ERK/MAPK pathway. CONCLUSIONS: Despite the difficulties inherent in biochemical studies of clinically relevant tissue samples, numerous investigations have illuminated the signal transduction mechanisms in patients with BD. These studies also suggest that BD may be due to the interaction of many abnormalities. In this context, novel techniques enabling the study of gene expression promise to assist in untangling these complex interactions, through visualizing the end result of these changes at the level of gene transcription.

Young LT. · Regional Mood Disorders Program, Department of Psychiatry, McMaster University, Hamilton, Ont. · J Psychiatry Neurosci. · Pubmed #11590965 links to  free full text

Abstract: Study of the norepinephrine pathway has elucidated the pathophysiology of depression and bipolar disorder. Various elements along this pathway, including adrenoreceptors, G proteins, cyclic adenosine monophosphate (AMP), cyclic AMP regulatory element binding protein and brain-derived neurotrophic factor, have been identified as potential targets for antidepressants and mood-stabilizing drugs. The results of a wide range of research in this area, along with the hypotheses now under investigation, are summarized in this paper.

Wang JF, Bown CD, Chen B, Young LT. · Department of Psychiatry and Behavioral Neuroscience, McMaster University, Hamilton, Ontario, Canada. · Int J Neuropsychopharmacol. · Pubmed #11343631 No free full text.

Abstract: An increasing body of evidence demonstrates that lithium and valproate have a regulatory effect on signal transduction pathways. Alteration of signalling molecules triggers changes in gene expression which are thought to contribute to the therapeutic effects of these drugs on bipolar disorder. Differential-display PCR was used to identify genes in rat cerebral cortex that are regulated by chronic treatment with lithium and valproate. One novel lithium-regulated gene was identified and was characterized and studied further with 5'-RACE-PCR and library screening. We also found that valproate regulated the expression of the 78-kDa glucose-regulated protein (GRP78). Chronic treatment with valproate has also been found to increase gene transcription, mRNA and protein levels of GRP78. These results suggest novel targets for lithium and valproate that may be relevant to their mechanism of action. The data further our understanding of the mechanism of the action of mood stabilizers, and help identify new targets for genetic studies and therapeutic strategies in bipolar disorder.

MacQueen GM, Young LT, Joffe RT. · Mood Disorders Program, McMaster University, Hamilton, Ontario, Canada. · Acta Psychiatr Scand. · Pubmed #11240572 No free full text.

Abstract: OBJECTIVE: The aim of this paper is to review outcome in patients with bipolar disorder as assessed by interepisode level of functioning, as until recently this dimension of outcome has been relatively under-emphasized. METHOD: Studies that examined psychosocial outcome in bipolar disorder were reviewed on the basis of rating measurements employed, length of follow-up, number of subjects followed and degree of impairment reported. Studies were included only if results from patients with bipolar and unipolar disorder were reported in such a way that the groups could be distinguished. RESULTS: When studies of psychosocial outcome in bipolar disorder are examined in aggregate, it appears that 30-60% of individuals with this disorder fail to regain full functioning in occupational and social domains. CONCLUSION: This review highlights the fact that inter-episode functional recovery is incomplete in some patients, suggesting that comprehensive rehabilitative assessment and intervention may be essential to reduce the morbidity associated with this disorder.

MacQueen GM, Young LT. · McMaster University, McMaster University Medical Center, Hamilton, Ontario, Canada. · Psychiatr Serv. · Pubmed #11239105 links to  free full text

Abstract: The authors provide an overview of the diagnosis, course, and treatment of bipolar II disorder, a distinct subtype that is often misdiagnosed as unipolar depression or bipolar I disorder. They discuss research suggesting that underdiagnosis of bipolar II disorder reflects a failure to identify subthreshold expression of mania (hypomania). The course of bipolar II disorder is different from that of bipolar I disorder or unipolar depression, with distinct differences in rates of recovery, clinical features, and number of episodes. The risk of suicide appears to be particularly elevated. High rates of comorbid disorders have been reported, including substance abuse or dependence, anxiety disorders, and personality disorders. Few definitive studies exist on which to base conclusions about the differential efficacy of various treatment strategies in bipolar II disorder and bipolar I disorder. Preliminary studies suggest that the newer anticonvulsants may be of benefit for patients with bipolar II disorder, while other data suggest that there may be a greater role for antidepressant medications.

Yatham LN, Kennedy SH, Schaffer A, Parikh SV, Beaulieu S, O'Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Young AH, Alda M, Milev R, Vieta E, Calabrese JR, Berk M, Ha K, Kapczinski F. · Department of Psychiatry, University of British Columbia,2255 Wesbrook Mall, Vancouver, BC V6T 2A1, , Canada. · Bipolar Disord. · Pubmed #19419382 No free full text.

Abstract: The Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder in 2005, with a 2007 update. This second update, in conjunction with the International Society for Bipolar Disorders (ISBD), reviews new evidence and is designed to be used in conjunction with the previous publications. The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate, and several atypical antipsychotics continue to be first-line treatments for acute mania. Tamoxifen is now suggested as a third-line augmentation option. The combination of olanzapine and carbamazepine is not recommended. For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. New data support the use of adjunctive modafinil as a second-line option, but also indicate that aripiprazole should not be used as monotherapy for bipolar depression. Lithium, lamotrigine, valproate, and olanzapine continue to be first-line options for maintenance treatment of bipolar disorder. New data support the use of quetiapine monotherapy and adjunctive therapy for the prevention of manic and depressive events, aripiprazole monotherapy for the prevention of manic events, and risperidone long-acting injection monotherapy and adjunctive therapy, and adjunctive ziprasidone for the prevention of mood events. Bipolar II disorder is frequently overlooked in treatment guidelines, but has an important clinical impact on patients' lives. This update provides an expanded look at bipolar II disorder.

Levinson AJ, Young LT, Fitzgerald PB, Daskalakis ZJ. · Mood and Anxiety Division, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada. · J Clin Psychopharmacol. · Pubmed #17873683 No free full text.

Abstract: OBJECTIVE: Neuroanatomic evidence suggests that patients with bipolar disorder (BD) have impaired cortical inhibition (CI). However, there is little in vivo neurophysiological evidence supporting the occurrence of such impairments in this disorder. Using 3 transcranial magnetic stimulation paradigms, known as short-interval CI (SICI), cortical silent period (SP), and interhemispheric inhibition (IHI), the authors measured inhibition in the motor cortex. METHOD: Fifteen patients with BD and 15 healthy subjects were enrolled. Short-interval CI involves stimulating with a subthreshold pulse a few milliseconds before a suprathreshold pulse, thereby inhibiting the size of the motor-evoked potential (MEP) produced by the suprathreshold pulse. In the SP paradigm, inhibition is reflected by the SP duration (ie, the duration of electromyographic activity cessation following a transcranial magnetic stimulation-induced MEP). Interhemispheric inhibition involves a subthreshold conditioning stimulus applied to the right motor cortex several milliseconds before a suprathreshold test stimulus is applied to the left motor cortex which inhibits the size of the MEP produced by the test stimulus by 50% to 75%. RESULTS: Patients with BD demonstrated deficits in all 3 paradigms: SICI (F1,28 = 5.55, P = 0.03; Cohen d = 0.86), SP (F1,28 = 5.24, P = 0.03; Cohen d = 0.84), and IHI (F1,28 = 3.41, P = 0.02; Cohen d = 0.77) compared with healthy volunteers with a large effect size. CONCLUSIONS: Our study supports the hypothesis that CI is decreased in BD. Further understanding of the neurophysiology of such deficiencies may help to elucidate future treatment options.

Joffe RT, MacQueen GM, Marriott M, Young LT. · Department of Psychiatry, UMDNJ-New Jersey Medical School, Newark, NJ 07101, USA. · Acta Psychiatr Scand. · Pubmed #15992391 No free full text.

Abstract: OBJECTIVE: To examine the risk of relapse into mania or depression with varying duration of antidepressant treatment in a cohort of 59 patients with bipolar disorder. METHOD: An open naturalistic evaluation using life charting methods of patients with 1 year follow-up, who responded to antidepressant treatment and who then less or more than 6 months of antidepressant treatment. RESULTS: Patients who received more than 6 months of antidepressant treatment were less likely to relapse into depression at follow-up of 1 year. There was no difference in relapse rates for mania in the different antidepressant treatment duration groups. Gender and bipolar subtype did not significantly affect relapse rates for depression or mania. CONCLUSION: Our data, taken with other studies, suggest that the duration of optimal antidepressant treatment in bipolar disorder must be further evaluated.

Patelis-Siotis I, Young LT, Robb JC, Marriott M, Bieling PJ, Cox LC, Joffe RT. · Hamilton Psychiatric Hospital, Mood Disorders Program, 100 West 5th St., Hamilton, Ontario L8N 3K7, Canada. · J Affect Disord. · Pubmed #11356238 No free full text.

Abstract: BACKGROUND: Bipolar disorder (BD) is a common disorder that results in significant psychosocial impairment, including diminished quality of life and functioning, despite aggressive pharmacotherapy. Psychosocial interventions that target functional factors could be beneficial for this population, and we hypothesized that the addition of group cognitive behavioral therapy (CBT) to maintenance pharmacotherapy would improve functioning and quality of life. METHODS: Patients diagnosed (by SCID) with bipolar disorder attending an outpatient clinic of a mood disorders program participated in the study. All patients were on maintenance mood stabilizers, and were required to have controlled symptoms before entering the study. Mood symptoms were assessed with the Hamilton Depression Rating scale and Young Mania scale at baseline and 14 weeks. Objective and subjective functioning was rated at the same interval using the Global Assessment of Functioning scale and the Medical Outcomes Survey SF-36. Treatment was provided via a specific manual based on CBT principles that could be applied to this population. RESULTS: Forty nine patients participated in this open trial, and 38 patients completed treatment. Objective and subjective indices of impairment showed improvement after 14 weeks. Both GAF and MOS scores increased significantly by the end of treatment. LIMITATIONS: This study was an open trial, and lack of control groups limits the interpretation of results. Because the study concerned effectiveness, the results do not clarify whether the improvement represents the normal course of illness or whether it is the result of the CBT intervention. CONCLUSIONS: The addition of group CBT to standard pharmacological treatment was acceptable to patients, and nearly 80% of patients complied with treatment. Despite the fact that mood symptoms were controlled at entry into the study, psychosocial functioning increased significantly at the end of treatment. Adjunctive CBT should be further investigated in this population.

Young LT, Joffe RT, Robb JC, MacQueen GM, Marriott M, Patelis-Siotis I. · Mood Disorders Program, Hamilton Psychiatric Hospital, Hamilton, Ont., Canada. · Am J Psychiatry. · Pubmed #10618026 links to  free full text

Abstract: OBJECTIVE: This study's purpose was to clarify the appropriate treatment of bipolar depression by comparing the addition of an antidepressant versus a second mood stabilizer for inpatients being treated with lithium carbonate or divalproex sodium. METHOD: Twenty-seven patients were randomly assigned to groups that received double-blind treatment with paroxetine or a second mood stabilizer (lithium carbonate or divalproex sodium) for 6 weeks. RESULTS: Both groups showed significant improvement in depressive symptoms during the 6-week trial. There were significantly more noncompleters in the group being treated with the two mood stabilizers than in the group being treated with a mood stabilizer and paroxetine. CONCLUSIONS: Both treatments appeared to be effective; however, the addition of an antidepressant may have greater clinical utility in the treatment of bipolar depression.

Wang JF, Shao L, Sun X, Young LT. · Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. · Bipolar Disord. · Pubmed #19624391 No free full text.

Abstract: BACKGROUND: Recent studies indicate the presence of mitochondrial dysfunction in brains of subjects with bipolar disorder (BD). Because the mitochondrial electron transport chain is a major source for production of reactive oxygen species that cause oxidative stress, we sought to determine in the present study if BD is associated with oxidative stress. METHODS: Postmortem anterior cingulate brain sections from subjects with BD, major depressive disorder (MDD), or schizophrenia, and from nonpsychiatric, non-neurologic comparison controls were generously provided by the Stanley Foundation Neuropathology Consortium. Oxidative stress was determined by analyzing 4-hydroxynonenal (4-HNE), a major product of lipid peroxidation. The level of 4-HNE was determined by measuring 4-HNE protein adducts using immunohistochemistry. RESULTS: We found that 4-HNE levels were significantly increased by 59% in BD subjects and by 47% in schizophrenia subjects, but not in MDD subjects, when compared with controls. Levels of 4-HNE were negatively correlated with pH in all 60 subjects. When pH was used as covariate, 4-HNE levels were still significantly increased in BD subjects when compared with controls. Further, 4-HNE levels were significantly correlated with pH values only in BD subjects, but not in MDD, schizophrenia, or control subjects. CONCLUSIONS: Oxidative damage in the brain may contribute in part to the pathological process in BD and schizophrenia. This finding also suggests antioxidative stress as a probable alternative approach to the pharmacological treatment of these psychiatric disorders.

Andreazza AC, Kapczinski F, Kauer-Sant'Anna M, Walz JC, Bond DJ, Gonçalves CA, Young LT, Yatham LN. · Department of Psychiatry, University of British Columbia, BC, Canada. · J Psychiatry Neurosci. · Pubmed #19568477 links to  free full text

Abstract: BACKGROUND: There has been an increasing interest in the role of oxidative stress in the pathophysiology of bipolar disorder. To explore this further, we evaluated the activity of glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST), as well as 3-nitrotyrosine levels and carbonyl content in patients in the early (within 3 years of illness onset) and late (a minimum of 10 years of illness) stages of bipolar disorder. METHODS: We matched 30 patients in the early stage and 30 patients in the late stage of bipolar disorder, diagnosed according to DSM-IV criteria, with 60 healthy controls (30 matched for each group of patients). We measured symptomatic status using the Hamilton Rating Scale for Depression and the Young Mania Rating Scale. RESULTS: We found a significant increase in 3-nitrotyrosine levels among patients in the early (p < 0.010) and late (p < 0.010) stages of bipolar disorder. The activity of GR and GST was increased only among patients in the late stage of illness. Glutathione peroxidase activity and carbonyl content did not differ among the groups. LIMITATIONS: Limitations of our study include its cross-sectional design, which did not allow us to examine direct causative mechanisms or the effects of progression of illness, and the potential environmental bias introduced by comparing patient groups recruited from different regions of the world. CONCLUSION: Our data indicate a possible tyrosine nitration-induced damage in patients with bipolar disorder that is present from the early stage of illness. Our data also indicate that patients in the late stage of illness demonstrate enhanced activity of GR and GST, which could suggest the involvement of a compensatory system in bipolar disorder.

Bakare A, Shao L, Cui J, Young LT, Wang JF. · Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. · Neurosci Lett. · Pubmed #19429109 No free full text.

Abstract: The anticonvulsant lamotrigine and atypical antipsychotic olanzapine, as therapeutic alternative mood stabilizing drugs to lithium and valproate, are well-tolerated maintenance treatments for bipolar disorder. Previous studies in our laboratory showed that both lithium and valproate increased expression of glutathione s-transferase (GST)-M1 subtype in primary cultured rat cerebral cortical cells. GST conjugates glutathione, the major antioxidant in brain, with a variety of oxidized products to form non-toxic and excretable products, and plays an important role in cellular protection against oxidative stress. The purpose of the present study is to determine whether lamotrigine and olanzapine also regulate GST-M1. Using immunoblotting analysis and spectrophotometric assay, we examined the effect of lamotrigine or olanzapine on GST-M1 protein levels and GST enzyme activity in primary cultured rat cerebral cortical cells. We found that chronic treatment with lamotrigine or olanzapine increased both GST-M1 protein levels and GST enzyme activity. These results suggest that GST-M1 may contribute a significant component to the treatment of bipolar disorder with mood stabilizing drugs.

Tseng M, Alda M, Xu L, Sun X, Wang JF, Grof P, Turecki G, Rouleau G, Young LT. · Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canda. · J Psychiatry Neurosci. · Pubmed #18787660 links to  free full text

Abstract: OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD. METHODS: Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein. RESULTS: BDNF levels were 36% lower in lymphoblasts from patients with BD (n = 12), compared with matched control participants (n = 13), and 55% lower when compared with their unaffected relatives (n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment. CONCLUSION: Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested.

Kauer-Sant'Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT, Yatham LN. · Mood Disorders Centre, Department of Psychiatry, University of British Columbia, Vancouver, Canada. · Int J Neuropsychopharmacol. · Pubmed #18771602 No free full text.

Abstract: Bipolar I disorder (BD) has a poorer longer-term outcome than previously thought, with persistent cognitive impairment and functional decline. The neurobiological underpinnings that might underlie these changes remain unknown. Changes in brain-derived neurotrophic factor (BDNF) levels and cytokines are potential candidates. The aim of this study was to examine both cytokine and BDNF levels and their relationship in BD patients in the early and late stages of the disorder. We measured serum BDNF, TNF-alpha, IL-6 and IL-10 levels in a total of 60 patients with BD I and we compared those in early stages of illness with those in late stages of illness and also compared both groups with 60 matched healthy controls. BDNF was decreased only in those patients in the late stage of bipolar disorder. Moreover, BDNF levels were negatively correlated with length of illness. In contrast, all interleukins and TNF-alpha were increased in the early stages of BD, compared to controls. While TNF-alpha and IL-6 continued to be significantly higher than controls at late stages of BD, IL-10 did not. When levels were compared between patients at early and late stages of illness, there was a significant decrease in BDNF and IL-6 in the later stage of BD compared to the early stage. Inversely, TNF-alpha showed a significant increase at the later stage. Failure of inflammatory defences in the late stage of the disorder may account for reduction in BDNF and continued elevations in cytokines; thus these may have the potential to serve as markers of illness progression in BD.

Mamdani F, Alda M, Grof P, Young LT, Rouleau G, Turecki G. · McGill Group for Suicide Studies-Depressive Disorders Group, Douglas Hospital, Research Centre, McGill University, Montreal, Quebec, Canada. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #18189280 No free full text.

Abstract: Bipolar disorder (BD) is a severe psychiatric disorder that affects 1% of the population. Recently, there have been many attempts to identify specific genes that are involved in BD; however, the task of finding susceptibility genes is not easy due to the complexity of the disorder. Since lithium (Li) has been used for over 40 years now as an effective prophylactic agent and response to Li treatment seems to be, at least in part, genetically determined, classification according to Li response is a manner through which more homogeneous populations can be obtained for investigation. It has previously been suggested that Li exerts an effect on signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP) pathway. We carried out an association study of BD with CREB1, CREB2 and CREB3 genes, located at ch 2q32.3-q34, 22q13.1 and 9pter-p22.1, respectively. A total of three promoter single nucleotide polymorphisms (SNP), 14 SNPs in the UTR, 6 exonic and 15 intronic SNPs were investigated for their frequency and haplotype distribution in a BD sample of 180 lithium responders and 69 nonresponders and 127 controls using a SNaPshot multiplex reaction from Applied Biosystems, a modified fluorescent single base pair extension procedure. Following correction for multiple testing, our results suggest that the CREB1-1H SNP (G/A change, P < 0.002) and the CREB1-7H SNP (T/C change, P < 0.002) may be associated with BD and/or lithium response.