Biomedical subjects

Greer M Murphy

Publications and source records attributed to Greer M Murphy.

18 recordsLinked to original sources

PubMed2006

Extended treatment with bupropion SR for cigarette smoking cessation.

The authors present results of a randomized clinical trial of the efficacy of extended treatment with bupropion SR in producing longer term cigarette smoking cessation. Adult smokers (N = 362) received open-label treatment (11 weeks) that combined relapse prevention training, bupropion SR, and nicotine patch followed by extended treatment (14 weeks) with bupropion SR or matching placebo. Abstinence percentages were relatively high (week 11: 52%; week 25: bupropion, 42%; placebo, 38%; week 52: bupropion, 33%; placebo, 34%), but bupropion SR did not surpass placebo. Gender and baseline craving level were identified as significant, independent moderators of treatment response. Men were more likely to abstain than women (week 11: 59% vs. 43%, p = .001; week 25: 48% vs. 31%, p = .001; week 52: 39% vs. 27%, p = .01). Because most smokers suffer relapse with any current cessation treatment, the comparatively high abstinence percentages achieved in this trial are of interest.

Adolescent↗

PubMed2006

Application of microarray technology in psychotropic drug trials.

Microarrays can be manufactured to detect hundreds of thousands of polymorphisms in DNA from patients in psychotropic drug trials. Some of these polymorphisms may be useful as pharmacogenetic predictors of treatment outcomes. We tested a microarray designed to detect common polymorphisms in the CYP2D6 gene that encodes debrisoquine hydroxylase (DH). DH is involved in the hepatic metabolism of many psychotropics. CYP2D6 genotypes predicted plasma steady state concentrations of nortriptyline, a classic DH substrate, in a sample of geriatric patients with major depression. However, in a sample of 246 geriatric patients treated with paroxetine or mirtazapine, both of which are metabolized in part by DH, CYP2D6 genotypes determined with microarrays did not predict discontinuations due to adverse events or severity of adverse events. For modern antidepressants such as paroxetine and mirtazapine, pharmacokinetic factors that are regulated by CYP2D6 such as plasma drug concentrations may be less important than pharmacodynamic factors in determining outcomes. Studies of single candidate genes such as CYP2D6 have only begun to utilize the potential of microarrays for pharmacogenetic prediction. Yet, there is controversy as to whether genome-wide studies designed to detect millions of genotypes with microarrays will lead to new pharmacogenetic discoveries, or whether a more focused, hypothesis-driven approach is better.

Clinical Trials as Topic↗

PubMed2006

The brain-derived neurotrophic factor Val66Met polymorphism and rate of decline in Alzheimer's disease.

It is largely unknown why some patients with Alzheimer's disease (AD) decline cognitively more rapidly than others. Genetic differences among patients could influence rate of decline. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in the survival neurons and in memory function. BDNF levels are reduced in the brain in AD. The Val66Met polymorphism in the BDNF gene modifies neuronal BDNF secretion, and affects hippocampal function and memory performance. We tested the hypothesis that the BDNF Val66Met polymorphism influences rate of cognitive decline in AD. In a sample of 149 AD patients followed for an average of 3.9 years, we found no effect of BDNF Val66Met genotype on rate of change in the Mini Mental State Examination. Results were similar when we excluded patients taking an acetylcholinesterase inhibitor, those placed in a nursing home during the study, or those with a neuropathological diagnosis that included AD plus an entity other than AD. We also found no evidence that the effects of the BDNF Val66Met genotype depend on APOE genotype, which itself had no effect on rate of cognitive change. These findings suggest that the functional BDNF Val66Met variant is not a major determinant of rate of cognitive decline in AD.

Aged↗

PubMed2005

Microglia overexpressing the macrophage colony-stimulating factor receptor are neuroprotective in a microglial-hippocampal organotypic coculture system.

Microglia with increased expression of the macrophage colony-stimulating factor receptor (M-CSFR; c-fms) are found surrounding plaques in Alzheimer's disease (AD) and in mouse models for AD and after ischemic or traumatic brain injury. Increased expression of M-CSFR causes microglia to adopt an activated state that results in proliferation, release of cytokines, and enhanced phagocytosis. To determine whether M-CSFR-induced microglial activation affects neuronal survival, we assembled a coculture system consisting of BV-2 microglia transfected to overexpress the M-CSFR and hippocampal organotypic slices treated with NMDA. Twenty-four hours after assembly of the coculture, microglia overexpressing M-CSFR proliferated at a higher rate than nontransfected control cells and exhibited enhanced migration toward NMDA-injured hippocampal cultures. Surprisingly, coculture with c-fms-transfected microglia resulted in a dramatic reduction in NMDA-induced neurotoxicity. Similar results were observed when cocultures were treated with the teratogen cyclophosphamide. Biolistic overexpression of M-CSFR on microglia endogenous to the organotypic culture also rescued neurons from excitotoxicity. Furthermore, c-fms-transfected microglia increased neuronal expression of macrophage colony-stimulating factor (M-CSF), the M-CSFR, and neurotrophin receptors in the NMDA-treated slices, as determined with laser capture microdissection. In the coculture system, direct contact between the exogenous microglia and the slice was necessary for neuroprotection. Finally, blocking expression of the M-CSF ligand by exogenous c-fms-transfected microglia with a hammerhead ribozyme compromised their neuroprotective properties. These results demonstrate a protective role for microglia overexpressing M-CSFR in our coculture system and suggest under certain circumstances, activated microglia can help rather than harm neurons subjected to excitotoxic and teratogen-induced injury.

Animals↗

PubMed2004

Biolistic expression of the macrophage colony stimulating factor receptor in organotypic cultures induces an inflammatory response.

The receptor for macrophage colony-stimulating factor (M-CSFR; c-fms) is expressed at increased levels by microglia in Alzheimer's disease (AD) and in mouse models for AD. Increased expression of M-CSFR on cultured microglia results in a strong proinflammatory response, but the relevance of this cell culture finding to intact brain is unknown. To determine the effects of increased microglial expression of M-CSFR in a complex organotypic environment, we developed a system for biolistic transfection of microglia in hippocampal slice cultures. The promoter for the Mac-1 integrin alpha subunit CD11b is active in cells of myeloid origin. In the brain, CD11b expression is restricted to microglia. Constructs consisting of the promoter for CD11b and a c-fms cDNA or an enhanced green fluorescent protein (EGFP) cDNA were introduced into monotypic cultures of microglia, neurons, and astrocytes. Strong CD11b promoter activity was observed in microglia, whereas little activity was observed in other cell types. Biolistic transfection of organotypic hippocampal cultures with the CD11b/c-fms construct resulted in expression of the c-fms mRNA and protein that was localized to microglia. Furthermore, biolistic overexpression of M-CSFR on microglia resulted in significantly increased production by the hippocampal cultures of the proinflammatory cytokines interleukin (IL)-1alpha macrophage inflammatory protein (MIP-1alpha), and trends toward increased production of IL-6 and M-CSF. These findings demonstrate that microglial overexpression of M-CSFR in an organotypic environment induces an inflammatory response, and suggest that increased microglial expression of M-CSFR could contribute to the inflammatory response observed in AD brain.

Animals↗

PubMed2004

Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression.

BACKGROUND: The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors. OBJECTIVE: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122). MAIN OUTCOME MEASURES: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes. RESULTS: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses. CONCLUSIONS: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.

Adrenergic alpha-Antagonists↗

PubMed2004

Pharmacogenetics of psychotropic drug response.

OBJECTIVE: Molecular genetic approaches provide a novel method of dissecting the heterogeneity of psychotropic drug response. These pharmacogenetic strategies offer the prospect of identifying biological predictors of psychotropic drug response and could provide the means of determining the molecular substrates of drug efficacy and drug-induced adverse events. METHOD: The authors discuss methods issues in executing pharmacogenetic studies, review the first generation of pharmacogenetic studies of psychotropic drug response, and consider future directions for this rapidly evolving field. RESULTS: Pharmacogenetics has been most commonly used in studies of antipsychotic drug efficacy, antidepressant drug response, and drug-induced adverse effects. Data from antipsychotic drug studies indicate that polymorphisms within the serotonin 2A and dopamine receptor 2 genes may influence drug efficacy in schizophrenia. Moreover, a growing body of data suggests a relationship between the serotonin transporter gene and clinical effects of the selective serotonin reuptake inhibitors used to treat depression. A significant relationship between genetic variation in the cytochrome P450 system and drug-induced adverse effects may exist for certain medications. Finally, a number of independent studies point to a significant effect of a dopamine D(3) receptor polymorphism on susceptibility to tardive dyskinesia. CONCLUSIONS: Initial research into the pharmacogenetics of psychotropic drug response suggests that specific genes may influence phenotypes associated with psychotropic drug administration. These results remain preliminary and will require further replication and validation. New developments in molecular biology, human genomic information, statistical methods, and bioinformatics are ongoing and could pave the way for the next generation of pharmacogenetic studies in psychiatry.

Antidepressive Agents↗

PubMed2003

The apolipoprotein E epsilon4 allele and antidepressant efficacy in cognitively intact elderly depressed patients.

BACKGROUND: Patients vary in response to antidepressant medications. Apolipoprotein E (APOE) genotype affects vulnerability to stress and risk for cognitive impairment. We sought to determine if the APOE epsilon4 allele influences response in geriatric depression to mirtazapine and paroxetine, two frequently prescribed antidepressants. We hypothesized that epsilon4 carriers would show impaired antidepressant response. METHODS: The study was a double-blind, randomized, 8-week trial with a 16-week extension phase involving 246 cognitively intact patients aged 65 years or older with major depression. Patients were treated with mirtazapine 15-45 mg (n = 124) or paroxetine 20-40 mg (n = 122). The outcome measures were the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Clinical Global Impression Scale. APOE genotype was determined by restriction isotyping. RESULTS: Patients carrying the epsilon4 allele showed a rapid onset of mirtazapine action, whereas paroxetine-treated patients with the epsilon4 allele were slow to respond. This difference could not be attributed to dosage, compliance, severity of adverse events, ethnicity, baseline depression or cognition, gender, or age. CONCLUSIONS: The APOE epsilon4 allele may affect antidepressant treatment outcome, but the effect depends on the medication. Further studies should determine if this result applies to other samples and medications.

Aged↗

PubMed2003

Macrophage colony stimulating factor promotes phagocytosis by murine microglia.

Macrophage colony stimulating factor (M-CSF) and its receptor are upregulated in the brain in Alzheimer's disease. M-CSF induces activation and proliferation of microglial cells and expression of proinflammatory cytokines. Amyloid beta (Abeta) immunization experiments suggest that microglia have the capacity to aggressively clear Abeta from the brain under certain circumstances. We examined the role of M-CSF in phagocytosis of fluorescent microspheres and Abeta by cultured microglia. M-CSF treatment increased microglial cell phagocytosis of both microspheres and of Abeta. Antibody neutralization of M-CSF inhibited Abeta uptake induced by overexpression of the M-CSF receptor on microglia. These results suggest that M-CSF could be important in promoting microglial clearance of abnormal protein aggregates such as Abeta.

Amyloid beta-Peptides↗

PubMed2003

Microglial overexpression of the M-CSF receptor augments phagocytosis of opsonized Abeta.

The role of microglia in Alzheimer's disease (AD) has come under intense scrutiny recently because microglia may clear amyloid beta (Abeta) by phagocytosis after immunization of transgenic mice. Increased expression of the macrophage colony-stimulating factor receptor (M-CSFR) is an important feature of microglia in AD and transgenic mouse models for AD. Increased expression of M-CSFR on mouse and human microglia accelerates phagocytosis of aggregated Abeta in part through macrophage scavenger receptors. We now show that Abeta phagocytosis by microglia overexpressing M-CSFR is further enhanced by antibody opsonization of Abeta. M-CSFR overexpression increased microglial phagocytosis of opsonized aggregated Abeta in culture medium, and accelerated ingestion of native Abeta from AD brain sections. M-CSFR overexpression also increased microglial expression of Fcgamma receptors, and blocking Fcgamma receptors attenuated the enhanced Abeta uptake observed after M-CSFR overexpression and antibody opsonization. Microglia in AD and in AD mouse models with increased expression of M-CSFR are likely to rapidly ingest opsonized Abeta after immunization, making high intracerebral antibody titers unnecessary.

Aged↗

PubMed2003

Pharmacogenetics of antidepressant medication intolerance.

OBJECTIVE: The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect). METHOD: An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood. RESULTS: Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication. CONCLUSIONS: Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.

Aged↗

PubMed2002

Analysis of neuronal gene expression with laser capture microdissection.

The brain is a heterogeneous tissue in which the numbers of neurons, glia, and other cell types vary among anatomic regions. Gene expression studies performed on brain homogenates yield results reflecting mRNA abundance in a mixture of cell types. Therefore, a method for quantifying gene expression in individual cell populations would be useful. Laser capture microdissection (LCM) is a new technique for obtaining pure populations of cells from heterogeneous tissues. Most studies thus far have used LCM to detect DNA sequences. We developed a method to quantify gene expression in hippocampal neurons from mouse brain using LCM and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). This method was optimized to permit histochemical or immunocytochemical visualization of nerve cells during LCM while minimizing RNA degradation. As an example, gene expression was quantified in hippocampal neurons from the Tg2576 mouse model for Alzheimer's disease.

Acridine Orange↗

PubMed2002

Accelerated phagocytosis of amyloid-beta by mouse and human microglia overexpressing the macrophage colony-stimulating factor receptor.

Microglia surrounding A beta plaques in Alzheimer's disease and in the APPV717F transgenic mouse model of Alzheimer's disease have enhanced immunoreactivity for the macrophage colony-stimulating factor receptor (M-CSFR), encoded by the proto-oncogene c-fms. Increased expression of M-CSFR on cultured microglia results in proliferation and release of pro-inflammatory cytokines and expression of inducible nitric-oxide synthase. We transfected mouse BV-2 and human SV-A3 microglia to overexpress M-CSFR and examined microglial phagocytosis of fluorescein-conjugated A beta. Flow cytometry and laser confocal microscopy showed accelerated phagocytosis of A beta in mouse and human microglia because of M-CSFR overexpression that was time- and concentration-dependent. In contrast, microglial uptake of 1-microm diameter polystyrene microspheres was not enhanced by M-CSFR overexpression. Microglial uptake of A beta was blocked by cytochalasin D, which inhibits phagocytosis. M-CSFR overexpression increased the mRNA for macrophage scavenger receptor A, and fucoidan blocking of macrophage scavenger receptors inhibited uptake of A beta. M-CSFR antibody blocking experiments demonstrated that increased A beta uptake depended on the interaction of the M-CSFR with its ligand. These results suggest that overexpression of M-CSFR in APPV717F mice may prime microglia for phagocytosis of A beta after immunization.

Amyloid beta-Peptides↗

PubMed2002

Macrophage colony stimulating factor prevents NMDA-induced neuronal death in hippocampal organotypic cultures.

Macrophage colony stimulating factor (M-CSF) and its receptor are up-regulated in the brain in Alzheimer's disease (AD), in transgenic mouse models for AD, and experimental models for traumatic and ischemic brain injury. M-CSF induces activation and proliferation of microglial cells and expression of proinflammatory cytokines. We examined the role of M-CSF in excitotoxic neuronal cell death in organotypic hippocampal cultures. NMDA treatment induced neuronal apoptosis and caspase-3 activation in organotypic hippocampal cultures, whereas treatment with M-CSF protected hippocampal neurons from NMDA-induced apoptosis. Caspase-3 activation was inhibited by M-CSF treatment to the same degree as with the caspase inhibitor Z-VAD-FMK. These results suggest that M-CSF has neuroprotective properties through inhibition of caspase-3 that could promote neuronal survival after excitotoxic insult. The role of M-CSF in neurological disease should be reevaluated as a microglial activator with potentially neuroprotective effects.

Amino Acid Chloromethyl Ketones↗

PubMed2002

Single nucleotide polymorphisms and their characterization with oligonucleotide microarrays.

Small variations in human DNA sequences influence our predisposition to disease and our response to medications. Many psychiatric diseases appear to be polygenic. Because our molecular understanding of the genetic etiology of neuropsychiatric disorders is very limited, the discovery and characterization of these variations is crucial in identifying disease genes. Furthermore, this knowledge may enable the customized selection of drug treatments based on an individual's genotype so as to maximize efficacy yet avoid adverse side effects. Examples of findings using conventional methods for determining genotypes, as well as new and future technologies for the characterization of single nucleotide polymorphisms, will be discussed, with a focus on psychiatric diseases and medications.

Base Sequence↗

PubMed2002

Cardiac gene expression profile and lipid accumulation in response to starvation.

Starvation induces many biochemical and histological changes in the heart; however, the molecular events underlying these changes have not been fully elucidated. To explore the molecular response of the heart to starvation, microarray analysis was performed together with biochemical and histological investigations. Serum free fatty acids increased twofold in both 16- and 48-h-fasted mice, and cardiac triglyceride content increased threefold and sixfold in 16- and 48-h-fasted mice, respectively. Electron microscopy showed numerous lipid droplets in hearts of 48-h-fasted mice, whereas fewer numbers of droplets were seen in hearts from 16-h-fasted mice. Expression of 11,000 cardiac genes was screened by microarrays. More than 50 and 150 known genes were detected by differential expression analysis after 16- and 48-h-fasts, respectively. Genes for fatty acid oxidation and gluconeogenesis were increased, and genes for glycolysis were decreased. Many other genes for metabolism, signaling/cell cycle, cytoskeleton, and tissue antigens were affected by fasting. These data provide a broad perspective of the molecular events occurring physiologically in the heart in response to starvation.

Animals↗

PubMedDate not supplied

Proinflammatory effects of M-CSF and A beta in hippocampal organotypic cultures.

Macrophage colony stimulating factor (M-CSF) is a microglial activator expressed at increased levels in the brain in Alzheimer's disease. In monotypic microglial cultures, M-CSF strongly augments amyloid beta (Abeta) induced microglial production of proinflammatory cytokines and nitric oxide. However, this augmentation could be due to strong autocrine and paracrine effects in monotypic cultures. We used hippocampal organotypic cultures to test M-CSF/Abeta augmentation in a system modeling intact brain. Combined M-CSF/Abeta treatment increased interleukin-1 (IL-1) and macrophage inflammatory protein 1-alpha expression by microglia, whereas inducible nitric oxide synthase (iNOS) expression was localized primarily to astroglia. Induction of cytokines and iNOS was also observed after lipopolysaccharide treatment of organotypic hippocampal cultures, but iNOS expression was localized mainly to microglia rather than astrocytes. Treatment with M-CSF/Abeta did not result in neuronal death. These results demonstrate that combined M-CSF/Abeta treatment results in a strong inflammatory response in the organotypic environment without inducing neurotoxicity.

Adjuvants, Immunologic↗

PubMedDate not supplied

Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients.

OBJECTIVE: Authors studied the efficacy and tolerability of mirtazapine and paroxetine in elderly patients with major depression during an acute phase (8 weeks) and an extension phase (16 weeks). METHODS: Patients with major depression and without dementia, at least 65 years old, were eligible; they were randomized to mirtazapine or paroxetine once daily, with doses increasing over 42 days. Efficacy was assessed with the Ham-D and Clinical Global Impressions Scale, and tolerability was assessed from adverse events. RESULTS: Of 255 patients randomized, 126 on mirtazapine and 120 on paroxetine were included in the efficacy analysis. Differences favoring mirtazapine were observed for the mean change from baseline in Ham-D-17 score. Other significant differences were in the proportion of patients classified as responders (50% decrease from baseline Ham-D-17 scores) at Day 14 and in remission (Ham-D-17 score of 7 or less) at Day 42. The median time to response was 26 days in the mirtazapine group and 40 days in the paroxetine group. The mirtazapine group also showed more reduction in Ham-D Factor I (Anxiety/Somatization) and Factor VI (Sleep Disturbance) scores. Efficacy of both drugs was maintained during the extension phase. Patients on paroxetine were more likely to discontinue therapy in the acute phase because of adverse events. CONCLUSION: During the first weeks of treatment, antidepressant effects were more pronounced in the mirtazapine group, suggesting that mirtazapine has an earlier onset of action. Mirtazapine also demonstrated a better tolerability profile and represents a valuable option for the treatment of depression in elderly patients.

Aged↗