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Biomedical subjects

L Trevor Young

Publications and source records attributed to L Trevor Young.

At least 19 recordsLinked to original sources
PubMed2025

Psychiatric Polygenic Risk Scores and Week-by-Week Symptomatic Status in Youth with Bipolar Disorder: An Exploratory Study.

Introduction: Prior studies have demonstrated that, in both adults and youth, bipolar disorder (BD) is a polygenic illness. However, no studies have examined polygenic risk scores (PRSs) in relation to the longitudinal course of mood symptoms in youth with BD. Methods: This study included 246 youth of European ancestry with BD (7-20 years old at intake) from the Course and Outcome of Bipolar Youth study and Centre for Youth Bipolar Disorder. Mood symptom severity was assessed at intake and, for 168 participants, prospectively for a median of 8.7 years. PRSs for BD, schizophrenia (SCZ), major depressive disorder (MDD), and attention-deficit/hyperactivity disorder (ADHD) were constructed using genome-wide summary statistics from independent adult cohorts. Results: Higher BD-PRS was significantly associated with lower most severe lifetime depression score at intake (β = -0.14, p = 0.03). Higher SCZ-PRS and MDD-PRS were associated with significantly less time spent in euthymia (SCZ-PRS: β = -0.21, p = 0.02; MDD-PRS: β = -0.22, p = 0.01) and more time with any subsyndromal mood symptoms (i.e., any mania, mixed, or depression symptoms; SCZ-PRS: β = 0.15, p = 0.04; MDD-PRS: β = 0.17, p = 0.01) during follow-up. PRSs for BD and ADHD were not significantly associated with any longitudinal mood variable. Conclusions: This exploratory analysis was the first to examine psychiatric PRSs in relation to the prospective course of mood symptoms among youth with BD. Results from the current study can serve to guide future youth BD studies with larger sample sizes on this topic.

Humans↗
PubMed2006

Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia.

Impairment of neuroplasticity is considered to play a role in the pathogenesis of psychiatric disorders. To further characterize the impairment of neuroplasticity in psychiatric disorders, expression of the neuronal plasticity marker 43 kDa growth-associated protein (GAP-43) was detected in postmortem hippocampal sub-regions from psychiatric patients including major depressive disorder, bipolar disorder and schizophrenia subjects, and matched control subjects. We found that GAP-43 protein levels in the hippocampal hilar region were significantly lower in bipolar disorder and schizophrenia subjects than in control subjects. We also found that GAP-43 protein levels in the inner molecular layer of the dentate gyrus and the stratum radiatum of CA2 region were reduced in a trend in bipolar disorder and schizophrenia subjects when compared with control subjects. These results suggest that impairment of neuroplasticity may occur in the hippocampus of bipolar disorder and schizophrenia patients.

Analysis of Variance↗
PubMed2006

Insulin-like growth factor binding protein-2 expression is decreased by lithium.

Lithium has been shown to possess cytoprotective properties in both cellular and animal models. Moreover, previous studies indicate that lithium treatment alters the expression of insulin-like growth factor binding protein-1 (IGFBP-1), a critical modulator of insulin-like growth factor bioactivity. Given the critical roles played by insulin-like growth factors in cellular mitogenesis, differentiation, and cell death, and that IGFBP-2 is the major brain resident IGFBP, we assessed IGFBP-2 expression in primary cortical neuroncultures subsequent to lithium treatment. We report that 7 days of lithium treatment at therapeutically relevant doses attenuates the expression of IGFBP-2 mRNA and protein in a dose and time-dependent manner. Therefore, these results suggest a possible role for the insulin-like growth factor system in lithium's mechanism of action.

Analysis of Variance↗
PubMed2006

Chronic restraint stress decreases the expression of glutathione S-transferase pi2 in the mouse hippocampus.

Chronic restraint stress in mice affects hippocampal structure and function. Mice were subjected to daily restraint for 3 weeks, and gene expression in hippocampus was compared to controls using large-scale cDNA microarrays. We found that 444 genes were differentially expressed, and further analysis of 6 genes by real-time reverse transcription PCR confirmed that 3 of them were downregulated by stress. These 3 genes, growth factor receptor-bound protein 2 (Grb2), phosphatidylinositol-4-phosphate 5-kinase, type 1 beta (Pip5k1b), and glutathione S-transferase, pi2 (Gstp2), were also analyzed by in situ hybridization. The downregulation of Gstp2 may induce an increase of oxidative damage in the pyramidal cells of the CA1 and CA3 regions and granular layer of the dentate gyrus, leading to structural and functional damage. Those regions are affected by stress, and our results could help understand further the mechanisms involved in the occurrence of stress-related disorders.

Animals↗
PubMed2006

Risk and resilience markers in bipolar disorder: brain responses to emotional challenge in bipolar patients and their healthy siblings.

OBJECTIVE: The authors previously identified depression-specific differences in brain responses to an emotional challenge in patients with bipolar and unipolar mood disorder. In this study, potential markers of bipolar risk and resilience were examined in a new cohort of lithium-responsive bipolar patients and their healthy siblings. METHOD: Changes in regional cerebral blood flow (rCBF) were measured with [(15)O]water positron emission tomography after induction of transient sadness in nine euthymic lithium responders and nine healthy siblings. The patterns of change in these groups were compared, and then they were contrasted with previous findings on bipolar responders to valproate. RESULTS: Common to all three groups with induced sadness were rCBF increases in the dorsal/rostral anterior cingulate and anterior insula and decreases in the orbitofrontal and inferior temporal cortices. Distinguishing the groups were decreases in the medial frontal cortex in the patients but an increase in this region in the siblings. DISCUSSION: Common changes with emotional challenge were identified in bipolar patients and their healthy siblings. These were not seen previously in healthy subjects without a family history of mood disorder, suggesting a potential marker of bipolar risk. The siblings' unique increases in the medial frontal cortex appear to identify a compensatory response in this at-risk group, as this pattern was not seen previously in healthy subjects without depression risk factors. This differential change pattern in patients and their siblings highlights the role of the anterior cingulate and medial frontal regions in mediating resiliency and vulnerability in bipolar disorder families.

Adult↗
PubMed2006

Downregulation in components of the mitochondrial electron transport chain in the postmortem frontal cortex of subjects with bipolar disorder.

OBJECTIVE: Many studies indicate a genetic predisposition to bipolar disorder (BD) and suggest that a number of abnormal genes are involved in its development. In this study, we used DNA microarray technology to analyze gene-expression profiles in the postmortem frontal cortex of subjects with BD. METHODS: Microarray hybridization was performed using human 19K microarray with universal human reference RNA in each hybridization. The reference cDNA was labelled with Cy3 and experimental cDNA, with Cy5. Glass array slides were cohybridized with equal amounts of mixed reference and experimental cDNA. Selected gene targets were further verified using real-time polymerase chain reaction (PCR). RESULTS: We found that 831 genes were differentially expressed in subjects with BD, including a number of genes in the mitochondrial electron transport chain (ETC), phosphatidylinositol-signalling system and glycolysis/ gluconeogenesis. Eight genes coding for the components of the mitochondrial ETC were identified along with 15 others related to mitochondrial function. Downregulation of NADH-ubiquinone oxidoreductase 20-kd subunit (ETC complex I), cytochrome c oxidase polypeptide Vic (ETC complex IV) and ATP synthase lipid-binding protein (ETC complex V) were further verified by real-time PCR. We also found that the expression of the NADH-ubiquinone oxidoreductase 20-kd subunit was increased in subjects with BD who were receiving mood-stabilizing treatment with lithium at the time of death, when compared with subjects with BD who were not being treated with lithium. CONCLUSIONS: Because the mitochondrial ETC is a major source for the generation of reactive oxygen species, these findings suggest that oxidative damage may play an important role in the pathophysiology of BD and that neuroprotection against this damage may be involved in the effect of lithium treatment.

Adult↗
PubMed2005

Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells.

The mood stabilizing drug lithium is a highly effective treatment for bipolar disorder. Previous studies in our laboratory found that chronic treatment with the mood stabilizing drug valproate in rat brain increased the expression of endoplasmic reticulum (ER) stress proteins GRP78, GRP94 and calreticulin. We report here that in primary cultured rat cerebral cortical cells, expression of GRP78, GRP94 and calreticulin are increased not only by valproate, but also by lithium after chronic treatment for 1 week at therapeutically relevant concentrations. However, two other mood stabilizing drugs carbamazepine and lamotrigine had no effect on expression of GRP78, GRP94 or calreticulin. Chronic treatment with lithium for 1 week increased both mRNA and protein levels of ER stress proteins. In contrast to a classic GRP78 inducer thapsigargin, an inhibitor of the ER Ca2+ -ATPase, chronic treatment with lithium or valproate for 1 week modestly increased GRP78 expression in neuronal cells, had no effect on basal intracellular free Ca2+ concentration and does not induce cell death. These results indicate that lithium and valproate may increase expression of GRP78, GRP94 and calreticulin in primary cultured rat cerebral cortical cells without causing cell damage. These results also suggest that the mechanism of GRP78 increase induced by lithium and valproate may be different from that of thapsigargin.

Animals↗
PubMed2005

Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells.

BACKGROUND: Recent studies indicate that chronic treatment with the mood-stabilizing drugs lithium and valproate produces a neuroprotective effect against excitotoxicity. In this study, we aimed to determine whether inhibiting oxidative damage plays a role in a neuroprotective effect of lithium and valproate against excitotoxicity. METHODS: Intracellular free calcium concentration was measured with the fluorescent calcium ion indicator fluo-3. Malondialdehyde, an end product derived from peroxidation of polyunsaturated fatty acid, and protein carbonyls were used to assess oxidative damage to lipid and protein. Excitotoxicity was assayed by measuring cell viability with the MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide] method and by measuring deoxyribonucleic acid (DNA) fragmentation with TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining. RESULTS: We found that chronic treatment with lithium and valproate at their therapeutically relevant concentrations significantly inhibited the glutamate-induced increase of intracellular free calcium concentration, lipid peroxidation, protein oxidation, DNA fragmentation, and cell death in primary cultured rat cerebral cortical cells. This treatment had no effect on basal intracellular free calcium concentration, lipid peroxidation, protein oxidation, DNA fragmentation, and cell death. CONCLUSIONS: Our results suggest that chronic treatment with lithium and valproate inhibits oxidative damage to lipid and protein and in turn produces a neuroprotective effect against excitotoxicity.

Animals↗
PubMed2005

Investigating responders to lithium prophylaxis as a strategy for mapping susceptibility genes for bipolar disorder.

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.

Antimanic Agents↗
PubMed2005

Pharmacotherapy of bipolar mixed states.

OBJECTIVE: Mixed episodes comprise up to 40% of acute bipolar admissions. They are difficult-to-treat, complex clinical pictures. This review provides an overview of the available literature on the pharmacotherapy of manic-depressive mixed states and suggests treatment options. METHOD: Literature was identified by searches in Medline, Embase and the Cochrane Controlled Trials Register. Studies were considered relevant if they contained the keywords mixed mania, mixed state(s), mixed episode(s), treatment, therapy, study or trial. RESULTS: Overall, there were very few double-blind, placebo-controlled studies specifically designed to treat manic-depressive mixed states. Rather, patients with mixed states comprised a sub-group of the examined patient cohorts. Nevertheless, the data show that acute mixed states do not respond favourably to lithium. Instead, valproate and olanzapine are drugs of first choice. Carbamazepine may play a role in the prevention of mixed states. Antidepressants should be avoided, because they may worsen intraepisodic mood lability. Lamotrigine may be useful in treating mixed states with predominantly depressive symptoms. CONCLUSIONS: More treatment studies specifically designed to treat the complex clinical picture of mixed states are clearly needed. Current treatment recommendations for clinical practice based on the available literature can only target select aspects of these episodes.

Anticonvulsants↗
PubMed2005

Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies.

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.

Adolescent↗
PubMed2004

Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment.

BACKGROUND: Signal transduction abnormalities have been identified in patients with bipolar (BD) and major depressive (MDD) disorders and are targets for lithium and antidepressant drugs. A key downstream target for signal transduction pathways is the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Therefore, we measured the levels of phosphorylated CREB (pCREB) in the amygdala, a region critical to emotional processing and important in the pathophysiology of both BD and MDD. METHODS: Human postmortem amygdala sections were generously provided by the Stanley Foundation Neuropathology Consortium. Samples consisted of subjects with MDD, BD, schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects (n = 15 per group). Levels of pCREB were measured by immunohistochemistry, relative to total cell number. RESULTS: There were no differences between diagnostic groups--control subjects and subjects with BD, MDD, or SCZ--but increased numbers of pCREB stained cells were found in several amygdalar nuclei in subjects who had died by suicide. In contrast, patients treated with lithium at the time of death had significantly lower pCREB levels in the same region. CONCLUSIONS: These results suggest that CREB activity may be an important factor in the neurobiology of suicide and the well-documented antisuicidal effect of lithium.

Adult↗
PubMed2004

Stress-induced structural remodeling in hippocampus: prevention by lithium treatment.

Chronic restraint stress, psychosocial stress, as well as systemic or oral administration of the stress-hormone corticosterone induces a morphological reorganization in the rat hippocampus, in which adrenal steroids and excitatory amino acids mediate a reversible remodeling of apical dendrites on CA3 pyramidal cell neurons of the hippocampus. This stress-induced neuronal remodeling is accompanied also by behavioral changes, some of which can be prevented with selective antidepressant and anticonvulsive drug treatments. Lithium is an effective treatment for mood disorders and has neuroprotective effects, which may contribute to its therapeutic properties. Thus, we wanted to determine whether lithium treatment could prevent the effects of chronic stress on CA3 pyramidal cell neuroarchitecture and the associated molecular and behavioral measures. Chronic lithium treatment prevented the stress-induced decrease in dendritic length, as well as the stress-induced increase in glial glutamate transporter 1 (GLT-1) mRNA expression and the phosphorylation of cAMP-response element binding in the hippocampus. Lithium treatment, however, did not prevent stress effects on behavior in the open field or the plus-maze. These data demonstrate that chronic treatment with lithium can protect the hippocampus from potentially deleterious effects of chronic stress on glutamatergic activation, which may be relevant to its therapeutic efficacy in the treatment of major depressive disorder and bipolar disorder.

Animals↗
PubMed2004

Identification of lithium-regulated genes in cultured lymphoblasts of lithium responsive subjects with bipolar disorder.

Lithium, a common drug for the treatment of bipolar disorder (BD), requires chronic administration to prevent recurrences of the illness. The necessity for long-term treatment suggests that changes in genes expression are involved in the mechanism of its action. We studied effects of lithium on gene expression in lymphoblasts from BD patients, all excellent responders to lithium prophylaxis. Gene expression was analyzed using cDNA arrays that included a total of 2400 cDNAs. We found that chronic lithium treatment at a therapeutically relevant concentration decreased the expression of seven genes in lymphoblasts from lithium responders. Five of these candidate lithium-regulated genes, including alpha1B-adrenoceptor (alpha1B-AR), acetylcholine receptor protein alpha chain precursor (ACHR), cAMP-dependent 3',5'-cyclic phosphodiesterase 4D (PDE4D), substance-P receptor (SPR), and ras-related protein RAB7, were verified by Northern blotting analysis in lithium responders. None of these genes were regulated by lithium in healthy control subjects. When we compared the expression of these five genes between bipolar subjects and healthy control subjects at baseline, prior to lithium administration, we found that alpha1B-AR gene expression was higher in bipolar subjects than in healthy control subjects. Our findings indicate that alpha1B-AR may play an important role in the mechanism of action of lithium treatment.

Adult↗
PubMed2004

A prospective, longitudinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders.

BACKGROUND: There is a recent appreciation that patients with bipolar disorder spend a substantial period of time with minor or subsyndromal mood symptoms both manic and depressive. This study examined time spent in minor and subsyndromal mood states as well as with mania and depression in a cohort of well characterized bipolar I and II patients who were followed prospectively for an average of three years. METHOD: Detailed life-charting data were obtained from 138 patients with bipolar disorder. Mood states were characterized as euthymic, subsyndromal, minor or major affective episodes based on rigorously defined criteria. The amount of time spent in these mood states during follow-up was examined. RESULTS: Patients in the total sample and within each bipolar subtype spent approximately half of their time euthymic. The remainder of the time was spent in varying severity of mood states. However, the majority of time was spent with minor and subsyndromal symptoms, both manic and depressive. Bipolar I patients differ from bipolar II in that significantly more time was spent with subsyndromal, minor and manic symptoms. There was no difference in time spent with depressive symptoms between the two groups. CONCLUSIONS: Patients with bipolar disorder spend a substantial proportion of time with depressive or manic symptoms with the preponderance being minor or subsyndromal. Awareness of subthreshold symptoms in bipolar disorders and treatment of such symptoms may be improved by establishing guidelines that specifically outline appropriate strategies for reducing the duration of subsyndromal symptoms in bipolar disorder.

Adult↗
PubMed2004

Glutathione S-transferase is a novel target for mood stabilizing drugs in primary cultured neurons.

Oligonucleotide microarray technology was used to analyze gene expression profiles after chronic treatment with the mood stabilizing drug valproate at a therapeutically relevant concentration in primary cultured rat cerebral cortical cells. We discovered that valproate regulates expression of 28 genes, including three isoenzymes (M1, A3 and A4) of glutathione S-transferase (GST), an important protective factor against oxidative stress. Because previous studies in our laboratory found that chronic valproate treatment protected cultured neurons against oxidative stress, further experiments on the regulation of GST were performed. Regulation of GST M1, GST A3 and GST A4 was verified using northern blotting hybridization. Chronic valproate treatment increased mRNA levels of M1 and A4, but decreased the A3 mRNA level dose-dependently, indicating further complexities in the regulation of GST by valproate. The level of GST M1 protein and GST activity were also increased by chronic valproate treatment. In addition, chronic treatment with lithium, another commonly prescribed mood stabilizer, also increased levels of GST M1 mRNA and protein. The present findings suggest that regulation of GST M1, and possibly GST A4, may mediate the anti-oxidative effects of valproate treatment, and regulation of GST may be involved in the mood stabilizing effect of valproate and lithium.

Animals↗
PubMed2004

A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder.

BACKGROUND: Cognitive dysfunction is evident in some euthymic patients with established bipolar disorder (BD), including deficits in visual backward masking (VBM) tasks which map to a specific neural pathway. A high-risk paradigm would clarify the temporal relation of cognitive dysfunction to clinical course. METHOD: We compared euthymic offspring (age range: 18-32 years) of lithium-responsive bipolar parents with and without a previous lifetime history of psychiatric illness to healthy comparison subjects with a negative family history, on a VBM task that requires target location. RESULTS: High-risk offspring with no lifetime psychiatric history performed the VBM task at levels of healthy controls. High-risk offspring with a previous history of a mood disorder, in complete remission, made significantly more errors at short target-mask intervals than control or never ill offspring. These higher error rates were not a consequence of faster response times. CONCLUSIONS: There is preliminary evidence of specific cognitive dysfunction early in the course of illness in affected offspring of parents with lithium responsive BD. VBM is ideal for future longitudinal studies addressing whether cognitive dysfunction in BD is a trait marker or a consequence of illness manifestation.

Adolescent↗