Biomedical subjects

L T Young

Publications and source records attributed to L T Young.

At least 19 recordsLinked to original sources

PubMed2006

Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate.

Mood stabilizing drugs lithium and valproate are the most commonly used treatments for bipolar disorder. Previous studies in our laboratory indicate that chronic treatment with lithium and valproate inhibits oxidative damage in primary cultured rat cerebral cortical cells. Glutathione, as the major antioxidant in the brain, plays a key role in defending against oxidative damage. The purpose of this study was to determine the role of glutathione in the neuroprotective effects of lithium and valproate against oxidative damage. We found that chronic treatment with lithium and valproate inhibited reactive oxygen metabolite H(2)O(2)-induced cell death in primary cultured rat cerebral cortical cells, while buthionine sulfoximine, an inhibitor of glutathione rate-limiting synthesis enzyme glutamate-cysteine ligase, reduced the neuroprotective effect of lithium and valproate against H(2)O(2)-induced cell death. Further, we found that chronic treatment with lithium and valproate increased glutathione levels in primary cultured rat cerebral cortical cells and that the effects of lithium and valproate on glutathione levels were dose-dependent in human neuroblastoma SH-SY5Y cells. Chronic treatment with lithium and valproate also increased the expression of glutamate-cysteine ligase in both rat cerebral cortical cells and SH-SY5Y cells. In addition, chronic treatment with other mood stabilizing drugs lamotrigine and carbamazepine, but not antidepressants desipramine and fluoxetine, increased both glutathione levels and the expression of glutamate-cysteine ligase in SH-SY5Y cells. These results suggest that glutathione plays an important role in the neuroprotective effects of lithium and valproate, and that glutathione may be a common target for mood stabilizing drugs.

Animals↗

PubMed2006

Effects of restraint stress on the expression of proteins involved in synaptic vesicle exocytosis in the hippocampus.

Chronic restraint stress has been associated with induction of morphological changes in the hippocampus. Postsynaptically, these changes include decreased length and branching of apical dendrites from CA3 pyramidal neurons, while presynaptically, depletion and clustering of synaptic vesicles have been observed. However, the molecular correlates of these changes remain poorly defined; while some studies have identified changes in the levels of some presynaptic proteins, none have assessed the coordinate expression of components of the membrane fusion complex, including synaptobrevin, syntaxin, and synaptosomal-associated protein 25 kDa, and their major regulatory molecules synaptotagmin, synaptophysin, and synapsin. Therefore, we undertook to assess the immunoreactivity of these proteins in hippocampal slices obtained from rats subjected to either acute (one 6 h session) or chronic (21 days at 6 h per day) of restraint stress. Specifically, we observed a significant increase in synaptobrevin immunoreactivity in the inner molecular layer of the dentate gyrus (54.2%; P=0.005), the stratum radiatum in the CA1 subfield (55.5%; P=0.007), and a region including the stratum lucidum and the proximal portion of the stratum radiatum in the CA3 subfield (52.7%; P=0.002); we also observed a trend toward increased synaptophysin levels in the stratum lucidum/radiatum of the CA3 subfield (8.0%; P=0.051) following chronic, but not acute, restraint stress. In that synaptobrevin has been associated with replenishment of the "readily-releasable" pool of synaptic vesicles and the efficiency of neurotransmitter release, the present results suggest that stress-induced changes in synaptobrevin may at least in part underlie the previously observed changes in synaptic and neuronal morphology.

Analysis of Variance↗

PubMed2005

One-year outcome with antidepressant--treatment of bipolar depression.

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.

Adult↗

PubMed2004

Differential display polymerase chain reaction reveals increased expression of striatal rat glia-derived nexin following chronic clozapine treatment.

Clozapine is considered a prototype of the 'so-called' atypical antipsychotic drug class. It has affinity for a broad range of receptors and, in comparison to typical antipsychotic drugs, produces less extrapyramidal side effects. However, its mechanism of action remains unclear. Differential display polymerase chain reaction (ddPCR) was implemented in this study to contribute to the current understanding of this mechanism at the genetic level and to identify novel genes regulated by clozapine. This technique generated approximately 2400 gene sequences that were analyzed for differential gene expression following protracted clozapine treatment. One of these sequences, originally termed Clozapine Regulated Gene (CRG), was shown to be significantly upregulated following the treatment. Northern hybridization confirmation of this finding revealed that chronic clozapine administration caused a five-fold increase in CRG mRNA. Elongation of the 5'- and 3'-ends of CRG indicated that the fragment was in fact rat glia-derived nexin mRNA. Western blotting demonstrated that levels of the mRNA's associated protein also increased comparably (three-fold) following chronic treatment with the antipsychotic drug. This study presents a possible neuroprotective role of nexin in clozapine treatment, particularly in the prevention of neuronal proteolytic degradation, since nexin has been shown to be a protease inhibitor.

Amino Acid Sequence↗

PubMed2003

Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells.

Valproate is often prescribed as a long-term therapeutic mood stabilizing agent for individuals with bipolar disorder. Although research suggests that this drug may produce a neuroprotective effect, its neuroprotective mechanism is not yet clear. The purpose of this study was to determine if valproate provides a neuroprotective effect against damage caused by oxidative stress in primary cultured rat cerebral cortical cells. We found that chronic treatment with valproate at therapeutically relevant concentrations for 7 days inhibited lipid peroxidation and protein oxidation induced by treatment with 0.25 mM oxidant FeCl(3) for 90 min, indicating that valproate inhibits oxidative damage to lipid and protein. Our results suggest that chronic treatment with valproate may protect neuronal cells from damage caused by oxidative stress and that neuroprotection from oxidative damages may be involved in the mechanism of action of valproate. Supporting this possibility are recent findings that chronic treatment with valproate increased the expression of endoplasmic reticulum stress protein GRP78 and antiapoptotic factor bcl-2 in rat cerebral cortex. Since GRP78 binds Ca(2+) and folds damaged protein, bcl-2 stabilizes mitochondrial transmembrane potential and inhibits cytochrome C release, and both GRP78 and bcl-2 have been shown to inhibit oxyradical accumulation, together these findings indicate that valproate may target one or more of these processes in order to produce neuroprotective effects.

Animals↗

PubMed2003

Attenuation of N-methyl-D-aspartate-mediated cytoplasmic vacuolization in primary rat hippocampal neurons by mood stabilizers.

Recent post-mortem and brain imaging studies suggest that decreased neuronal and glial densities may account for cell loss in vulnerable brain regions such as the hippocampus and the frontal cortex in patients with bipolar disorder. Investigations into the mechanisms of action of mood stabilizers suggest that these drugs may regulate the expression of neuroprotective genes and protect against excitotoxicity. In this study, we characterized the ultrastructural appearance of rat hippocampal neurons pretreated with mood stabilizers and then exposed to the glutamate receptor agonist N-methyl-D-aspartate. Using transmission electron microscopy we found that rat hippocampal neurons exposed to 0.5 mM N-methyl-D-aspartate for 10 min produced more cytoplasmic vacuolization than in control neurons. Chronic treatment with mood stabilizers, lithium, valproate or carbamazepine for 7 days at therapeutically relevant concentrations fully attenuated N-methyl-D-aspartate-mediated cytoplasmic vacuolization. These results suggest that inhibition of neurotoxicity may be involved in the action of mood stabilizers.

Animals↗

PubMed2003

Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders.

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.

Alzheimer Disease↗

PubMed2002

Recollection memory deficits in patients with major depressive disorder predicted by past depressions but not current mood state or treatment status.

BACKGROUND: Neuropsychological studies have suggested that memory systems reliant on medial temporal lobe structures are impaired in patients with depression. There is less data regarding whether this impairment is specific to recollection memory systems, and whether clinical features predict impairment. This study sought to address these issues. METHOD: A computerized process-dissociation memory task was utilized to dissociate recollection and habit memory in 40 patients with past or current major depression and 40 age, sex and IQ matched non-psychiatric control subjects. The Cognitive Failures Questionnaire was used to assess patients' perceptions of day-to-day memory failures. RESULTS: Patients had impaired recollection memory (t = 4.7, P < 0.001), but no impairment in habit memory when compared to controls. Recollection memory performance was not predicted by indices of current mood state, but was predicted by self-assessments of impairment (beta = -0.33; P = 0.008) and past number of depressions (beta = -0.41; P = 0.001). There was no evidence that standard therapy with antidepressant medication either improved or worsened memory performance. CONCLUSIONS: The results confirm that patients with multiple past depressions have reduced function on recollection memory tasks, but not on habit memory performance. The memory deficits were independent of current mood state but related to past course of illness and significant enough that patients detected impairment in day-to-day memory function.

Adult↗

PubMed2002

Induction of mania and cycle acceleration in bipolar disorder: effect of different classes of antidepressant.

OBJECTIVE: To assess the effect of different antidepressants on induction of mania and cycle acceleration, commonly accepted unwanted effects of antidepressant treatment for acute bipolar depression. There is, however, the suggestion that certain classes of antidepressants may be less likely than others to cause these unwanted effects. METHOD: We conducted a prospective, open, naturalistic, life charting study to assess the occurrence of onset of mania and cycle acceleration attributable to two antidepressant classes: selective serotonin reuptake inhibitors (SSRIs) and bupropion. RESULTS: No difference was found between the two drug classes for either antidepressant-induced mania or cycle acceleration. Antidepressant-induced mania was much more likely to occur in bipolar I rather than bipolar II patients. The overall occurrence of induction of mania and cycle acceleration was low across antidepressant classes. CONCLUSION: These findings suggest that there is probably no difference in the risk of antidepressant-induced mania or cycle acceleration across commonly used classes of antidepressants for the treatment of bipolar depression.

Adolescent↗

PubMed2001

Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.

BACKGROUND: The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain. METHODS: Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. RESULTS: Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. CONCLUSIONS: These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.

Adult↗

PubMed2001

Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium.

There is an established relationship between the monoaminergic neurotransmitter system and mood disorders. In an attempt to define further the pathophysiology of mood disorders, research is focussing on intracellular second messenger systems, including cyclic adenosine 3',5'-monophosphate (cAMP) and the polyphosphoinositol generated second messengers. The availability of tissue from the Stanley Foundation Neuropathology Consortium has offered us the opportunity to make a number of observations with respect to these second messenger systems in tissue from patients with major depressive disorder and bipolar affective disorder. There is evidence that antidepressants stimulate components of the cAMP pathway in patients with depression while mood stabilizers blunt the same pathway in patients with bipolar disorder. Furthermore, downstream targets of this pathway appear to be altered in patients with mood disorders. The relations between changes in second messenger systems, gene transcription, and clinical effects of current therapeutic regimens has implications for development of novel treatments of mood disorders.

Adenylyl Cyclases↗

PubMed2001

Is lithium response related to G(s)alpha levels in transformed lymphoblasts from subjects with bipolar disorder?

BACKGROUND: A series of studies from independent laboratories have found increased levels of G(s)alpha in bipolar disorder in postmortem brain and peripheral blood cells. Long-term lithium administration blunts G-protein coupled cAMP signaling and may regulate G(s)alpha levels. METHODS: We measured G(s)alpha in transformed lymphoblasts obtained from subjects with bipolar disorder and compared the findings with 23 age- and sex-matched controls. To reduce patient heterogeneity, we included only patients with an excellent response to lithium prophylaxis. RESULTS: We found no differences in G(s)alpha protein levels measured with immunoblotting. G(s)alpha levels did not correlate with age, age of onset or duration of lithium therapy. LIMITATIONS: This study made use of transformed lymphoblasts, which may not fully represent changes that occur in regionalized brain tissue. Furthermore, the transformed lymphoblasts used in this study were acquired from a select group of bipolar disorder subjects that responded to lithium treatment. Lastly, consideration has to be given to the small sample size of the study. CONCLUSIONS: These results are consistent with recent observations suggesting that mood state and treatment effects may account at least in part for increased G(s)alpha levels in bipolar disorder. CLINICAL RELEVANCE: This study suggests a need to further characterize biological phenotypes in subjects with mood disorders to enhance genetic studies.

Adult↗

PubMed2001

Is antidepressant-benzodiazepine combination therapy clinically more useful? A meta-analytic study.

BACKGROUND: Anxiety frequently coexists with depression, and benzodiazepines are often prescribed together with antidepressants. However, benzodiazepines themselves have little or no antidepressive effects and we lack firm evidence for or against this combination therapy. We therefore conducted a meta-analysis of relevant randomized controlled trials to date. METHODS: All randomized controlled trials that compared antidepressant-benzodiazepine treatment with antidepressant alone for adult patients with major depression were sought by electronic searches of Medline and several other databases (January 1972 to December 1998), combined with hand searching, reference searching and SciSearch. Two reviewers independently assessed the eligibility and quality of the studies. Relative risks were estimated with random effects model. RESULTS: Aggregating nine studies with a total of 679 patients, the combination therapy group was 37% (95%CI: 19-51%) less likely to drop out than the antidepressant alone group. The intention-to-treat analysis showed that the former were 63% (18-127%) to 38% (15-66%) more likely to show response (defined as 50% or greater reduction in the depression scale from baseline) up to 4 weeks. LIMITATIONS: None of the included RCTs followed the patients beyond 8 weeks. CONCLUSIONS: The potential benefits of adding a benzodiazepine to an antidepressant must be balanced judiciously against possible harm, including development of dependence and accident proneness, on the one hand, and against continued suffering following no response and drop-out, on the other.

Adult↗

PubMed2001

Group cognitive behavioral therapy for bipolar disorder: a feasibility and effectiveness study.

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.

Adult↗

PubMed2001

Backward masking task performance in stable, euthymic out-patients with bipolar disorder.

BACKGROUND: Several studies have suggested that visual backward masking (VBM) impairment is present in patients with bipolar disorder, but the clinical features, such as current symptoms, treatment status and past burden of illness that may contribute to the impairment have not been well described. This study examined well-characterized euthymic patients on two VBM tasks to ascertain the extent of VBM impairment in this group and the clinical correlates of this impairment. METHOD: Twenty-eight euthymic patients with a DSM-IV diagnosis of bipolar disorder were matched by age, sex and IQ with 28 non-psychiatric control subjects. Both groups completed two VBM tasks; one required subjects to locate the target stimulus, one required identification of the target stimulus. Reaction times and error rates across a range of target-mask inter-stimulus intervals were assessed. RESULTS: Patients were significantly slower and had more errors on both VBM tasks. There was a significant relation between reaction times on the identification task and past burden of illness, particularly past number of depressions. There was no discernible impact of treatment status on reaction time or performance, including no difference in lithium-treated versus not treated subjects. CONCLUSIONS: These results are consistent with previous reports of neuropsychological deficits in euthymic bipolar disorder patients. The potential benefit to employing tasks such as VBM is that it may provide a method for relating clinical variables such as illness burden with known neural pathways in order to elucidate better the pathophysiology leading to impaired cognitive performance in patients with bipolar disorder.

Adult↗

PubMed2001

Identification of mood stabilizer-regulated genes by differential-display PCR.

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.

Animals↗

PubMed2001

A review of psychosocial outcome in patients with bipolar disorder.

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.

Adaptation, Psychological↗

PubMed2001

Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression.

Evidence suggests that brain-derived neurotrophic factor (BDNF) may be important in the pathophysiology of depression, in addition to its role as a neurotrophic factor for sensory neurons. The authors conducted a series of experiments examining the behavioral profile of BDNF heterozygous knockout and wild-type mice. The heterozygous and wild-type mice did not differ on measures of activity, exploration, or hedonic sensitivity, or in the forced swim test. When assessed in the learned helplessness paradigm, heterozygous mice were slower to escape after training than were wild-type mice (p = .02). This effect may be accounted for by the fact that these mice demonstrate a reduced sensitivity to centrally mediated pain, apparent on the hot plate and Formalin injection tests of nociception. Overall, heterozygous mice were not more likely to display anxious or depressive-like behaviors and, consequently, may not constitute a murine model of genetic vulnerability to mood and anxiety disorders.

Affect↗