Search PubMed⌕ Search

Biomedical subjects

C B Nemeroff

Publications and source records attributed to C B Nemeroff.

At least 19 recordsLinked to original sources
PubMed2001

Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine.

BACKGROUND: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS: In the present study, the potency and selectivity of escitalopram, R-fluoxetine, and all of the other currently available selective serotonin reuptake inhibitors were compared for binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand binding assays. RESULTS: Both escitalopram and R-fluoxetine were potent inhibitors of the serotonin transporter (K(i) = 1.1 and 1.4 nmol/L, respectively). Escitalopram was the most serotonin transporter-selective compound tested and was approximately 30-fold more potent than R-citalopram. CONCLUSIONS: As noted previously, paroxetine and sertraline possess moderate affinity (<50 nmol/L) for the human norepinephrine transporter and dopamine transporter, respectively. R-Fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity (K(i) = 64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R-fluoxetine are discussed.

Animals↗
PubMed2001

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates.

BACKGROUND: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. METHODS: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. RESULTS: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. CONCLUSIONS: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Age Factors↗
PubMed2001

The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies.

Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to subsequent stress as well as to the development of depression and anxiety. A number of preclinical studies suggest that early life stress induces long-lived hyper(re)activity of corticotropin-releasing factor (CRF) systems as well as alterations in other neurotransmitter systems, resulting in increased stress responsiveness. Many of the findings from these preclinical studies are comparable to findings in adult patients with mood and anxiety disorders. Emerging evidence from clinical studies suggests that exposure to early life stress is associated with neurobiological changes in children and adults, which may underlie the increased risk of psychopathology. Current research is focused on strategies to prevent or reverse the detrimental effects of early life stress on the CNS. The identification of the neurobiological substrates of early adverse experience is of paramount importance for the development of novel treatments for children, adolescents, and adults.

Adrenocorticotropic Hormone↗
PubMed2001

Paroxetine for the prevention of depression induced by high-dose interferon alfa.

BACKGROUND: Depression commonly complicates treatment with the cytokine interferon alfa-2b. Laboratory animals pretreated with antidepressants have less severe depression-like symptoms after the administration of a cytokine. We sought to determine whether a similar strategy would be effective in humans. METHODS: In a double-blind study of 40 patients with malignant melanoma who were eligible for high-dose interferon alfa therapy, we randomly assigned 20 patients to receive the antidepressant paroxetine and 20 to receive placebo. The treatment was begun 2 weeks before the initiation of interferon alfa and continued for the first 12 weeks of interferon alfa therapy. RESULTS: During the first 12 weeks of interferon alfa therapy, symptoms consistent with a diagnosis of major depression developed in 2 of 18 patients in the paroxetine group (11 percent) and 9 of 20 patients in the placebo group (45 percent) (relative risk, 0.24; 95 percent confidence interval, 0.08 to 0.93). Severe depression necessitated the discontinuation of interferon alfa before 12 weeks in 1 of the 20 patients in the paroxetine group (5 percent), as compared with 7 patients in the placebo group (35 percent) (relative risk, 0.14; 95 percent confidence interval, 0.05 to 0.85). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In patients with malignant melanoma, pretreatment with paroxetine appears to be an effective strategy for minimizing depression induced by interferon alfa.

Adult↗
PubMed2001

Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Acoustic Stimulation↗
PubMed2001

The effects of glutamate receptor agonists on neurotensin release using in vivo microdialysis.

In the present study, extracellular concentrations of neurotensin were measured from the striatum, nucleus accumbens and the medial prefrontal cortex in the awake, freely moving rat. Using a highly sensitive solid phase radioimmunoassay, basal concentrations of neurotensin were 2-5 pg/sample. In each region, glutamate receptor agonists, N-methyl-D-aspartate (NMDA) and kainic acid, increased neurotensin release 2-3-fold. Preincubation with the Na(+) channel blocker tetrodotoxin abolished the glutamate receptor agonist-induced increases except in the striatum following kainic acid infusion. These findings indicate that activation of glutamate receptors may indirectly stimulate neurotensin release.

Animals↗
PubMed2001

Effects of sodium valproate on corticotropin-releasing factor systems in rat brain.

We hypothesized that divalproex sodium, an anticonvulsant effective in the acute treatment of mania, may act upon neuropeptide systems that utilize corticotropin-releasing factor (CRF). Pharmacokinetic studies demonstrated that valproate has an apparent elimination half life of 17 minutes in rats after acute administration and that there is a nonlinear relationship between chronic dose and serum drug concentration. Acute valproate treatment neither altered plasma adrenocorticotropic hormone (ACTH) or corticosterone concentrations nor produced changes in CRF concentration in any of 10 brain regions examined. Subchronic treatment via SC-implanted osmotic minipumps (875 mg/kg/day x 7 days) resulted in decreased CRF concentrations in the median eminence and raphe nuclei. Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus. The benzodiazepine alprazolam, also a positive modulator of GABAergic function, similarly decreases CRF mRNA expression in the CeA. These results suggest that the mood stabilizing effects of valproic acid may be mediated in part by alterations in CRF neuronal activity.

Animals↗
PubMed2001

Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor.

Fluorine-18 labeled fluorobutyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d] pyrimidin-4-yl]ethylamine (FBPPA) and iodine-123 labeled butyl[2,5-dimethyl-7-(4-iodo-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]ethyl-amine (IBPPA) were synthesized in the development of a CRF receptor ligand. The methods of synthesis, in vitro binding assays, radiolabeling and in vivo tissue distribution in rats are described. Fluorine-18 labeled FBPPA was prepared with high specific activity (3 x 10(4) Ci/mmol) by nucleophilic displacement with an average radiochemical yield of 6% (EOB). Iodine-123 labeled IBPPA was prepared by electrophilic iododestannylation with good yield (60%) and high specific activity (3.3 x 10(3) Ci/mmol). The retention of FBPPA and IBPPA in the pituitary was good (1.16% i.d./g and 2.35% i.d./g respectively at 60 min). However, the accumulation of radioactivity in the brain for both radiotracers was very low at all time points of the study, which demonstrated the difficulties for these radiopharmaceuticals to penetrate the blood brain barrier (BBB).

Animals↗
PubMed2001

The evaluation and treatment of depression in primary care.

The evaluation and treatment of depressive disorders are vital functions for practicing primary care physicians. Depression is a prevalent, recurrent, highly treatable disorder that is debilitating and leads to significant psychosocial impairment. In view of the broadly available armamentarium of safe, newer medications, primary care physicians should be proficient in the treatment of these disorders. The following review will provide a synopsis of the current state of diagnosis, evaluation, and treatment of depression in the primary care setting. Appropriate treatment of depression can result in improvement in emotional, cognitive, and behavioral symptoms of depression and reduce psychosocial impairment, disability, and associated medical morbidity.

Adult↗
PubMed2001

An evaluation of risperidone drug interactions.

Risperidone, an atypical antipsychotic drug, is widely used in the treatment of psychoses associated with schizophrenia, Alzheimer's disease, and other psychiatric disorders. Polypharmacology is a necessary condition for the optimal treatment of many patients with comorbid psychiatric and medical illness. One concern raised by the widespread use of multiple concurrent pharmacotherapies is the potential for drug-drug interactions to adversely affect patient outcome. Accordingly, the biomedical literature was reviewed for reports of drug interactions involving risperidone, and the clinical significance of each report was evaluated. Additionally, the potential for risperidone to participate in drug interactions was evaluated by considering the drug's pharmacokinetic properties. Controlled studies and case reports indicate that risperidone has a low potential for metabolic drug interactions. Drugs that inhibit cytochrome P450 (CYP) 2D6 or induce or inhibit CYP3A4 may alter risperidone plasma concentrations, but the clinical significance of such interactions seems to be minimal. Adherence to a few guidelines for the design of dosage regimens should limit the effect of drug-drug interactions on patient status and contribute to optimal pharmacotherapy with risperidone.

Anticonvulsants↗
PubMed2001

The depressed suicidal patient. Assessment and treatment.

Depressive disorders are associated with significant psychosocial impairment and disability. Depression should be thoroughly evaluated, as should current and past suicidality and potential risk factors for suicide. Mortality by suicide characterizes the course of major affective disorders in approximately 15% of those suffering from these illnesses. Several neurobiological correlates of suicidality have been discovered. Treatment of depression with suicidality may involve hospitalization, pharmacotherapy, electroconvulsive therapy, and psychotherapy. Special populations include children and adolescents, the elderly, medically ill patients, patients with comorbid personality disorders, and patients with comorbid substance abuse disorders. Clinicians encountering patients with depressive disorders should be proficient in the assessment and treatment of depression with suicidality.

Adult↗
PubMed2001

Neurokinin(1) receptor antagonists as potential antidepressants.

Selective, nonpeptide antagonists for tachykinin receptors first became available ten years ago. Of the three known tachykinin receptors, drug development has focused most intensively on the substance P-preferring receptor, neurokinin(1) (NK(1)). Although originally studied as potential analgesic compounds, recent evidence suggests that NK(1) receptor antagonists may possess antidepressant and anxiolytic properties. If confirmed by further controlled clinical studies, this will represent a mechanism of action distinct from all existing antidepressant agents. As reviewed in this chapter, the existing preclinical and clinical literature is suggestive of, but not conclusive, concerning a role of substance P and NK(1) receptors in the pathophysiology of depression and/or anxiety disorders. The ongoing clinical trials with NK(1) receptor antagonists have served as an impetus for much needed, basic research in this field.

Animals↗
PubMed2001

Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse.

OBJECTIVE: Early adverse life events may predispose individuals to the development of mood and anxiety disorders in adulthood, perhaps by inducing persistent changes in corticotropin-releasing factor (CRF) neuronal systems. The present study sought to evaluate pituitary-adrenal responses to standard hypothalamic-pituitary-adrenal axis challenge tests in adult female survivors of childhood abuse with and without major depressive disorder. METHOD: Plasma ACTH and cortisol responses to the administration of 1 microg/kg ovine CRF and plasma cortisol responses to the administration of 250 microg ACTH(1-24) were measured in healthy women without early life stress (N=20), women with childhood abuse without major depressive disorder (N=20), women with childhood abuse and major depressive disorder (N=15), and women with major depression but no early life stress (N=11). RESULTS: Abused women without major depressive disorder exhibited greater than usual ACTH responses to CRF administration, whereas abused women with major depressive disorder and depressed women without early life stress demonstrated blunted ACTH responses. In the ACTH(1-24) stimulation test, abused women without major depressive disorder exhibited lower baseline and stimulated plasma cortisol concentrations. Abused women with comorbid depression more often suffered from posttraumatic stress disorder and reported more recent life stress than abused women without major depressive disorder. CONCLUSIONS: These findings suggest sensitization of the anterior pituitary and counterregulative adaptation of the adrenal cortex in abused women without major depressive disorder. On subsequent stress exposure, women with a history of childhood abuse may hypersecrete CRF, resulting in down-regulation of adenohypophyseal CRF receptors and symptoms of depression and anxiety.

Adrenocorticotropic Hormone↗
PubMed2001

Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression.

OBJECTIVE: This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult outpatients stabilized on a regimen of lithium. METHOD: In a double-blind, placebo-controlled study, 117 outpatients with DSM-III-R bipolar disorder, depressive phase, were randomly assigned to treatment with paroxetine (N=35), imipramine (N=39), or placebo (N=43) for 10 weeks. In addition to lithium monotherapy, patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms. Patients were stratified on the basis of trough serum lithium levels determined at the screening visit (high: >0.8 meq/liter; low: </=0.8 meq/liter). Primary efficacy was assessed by change from baseline in scores on the Hamilton Rating Scale for Depression and the Clinical Global Impression illness severity scale. RESULTS: Differences in overall efficacy among the three groups were not statistically significant. For patients with high serum lithium levels, antidepressant response at endpoint also did not significantly differ from placebo. However, both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels. Compared to imipramine, paroxetine resulted in a lower incidence of adverse events, most notably emergence of manic symptoms. CONCLUSIONS: Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels. However, antidepressant therapy may be beneficial for patients who cannot tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium.

Adult↗
PubMed2001

Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings.

OBJECTIVE: This study investigated whether cancer patients with and without major depression exhibit immune system abnormalities similar to those reported in medically healthy, depressed subjects without cancer. METHOD: The study subjects consisted of patients diagnosed with pancreatic, esophageal, or breast cancer. Other groups consisted of subjects with major depression (without cancer) and healthy comparison subjects. Subjects' diagnoses were made with the Structured Clinical Interview for DSM-III-R. Severity of depression was measured with the Hamilton Depression Rating Scale. Plasma concentrations of interleukin-6 (IL-6) and postdexamethasone cortisol were measured. RESULTS: Cancer patients with depression had markedly higher plasma concentrations of IL-6 than healthy comparison subjects and cancer patients without depression. Although significant correlations were found between Hamilton depression scale scores and plasma concentrations of postdexamethasone cortisol, no significant correlations were found between plasma IL-6 and postdexamethasone cortisol concentrations. CONCLUSIONS: Higher than normal plasma IL-6 concentrations were associated with a diagnosis of major depression in cancer patients. IL-6 may contribute to sickness behavior that has overlapping symptoms with major depression.

Adult↗
PubMed2001

Clinical pharmacokinetics of quetiapine: an atypical antipsychotic.

Quetiapine is a dibenzothiazepine derivative that has been evaluated for management of patients with the manifestations of psychotic disorders. In pharmacokinetic studies in humans, quetiapine was rapidly absorbed after oral administration, with median time to reach maximum observed plasma concentration ranging from 1 to 2 hours. The absolute bioavailability is unknown, but the relative bioavailability from orally administered tablets compared with a solution was nearly complete. Food has minimal effects on quetiapine absorption. The drug is approximately 83% bound to serum proteins. Single and multiple dose studies have demonstrated linear pharmacokinetics in the clinical dose range (up to 375mg twice daily). The drug is eliminated with a mean terminal half-life of approximately 7 hours. The primary route of elimination is through hepatic metabolism. In vitro studies show that quetiapine is predominantly metabolised by cytochrome P450 (CYP) 3A4. After administration of [14C]quetiapine, approximately 73% of the radioactivity was excreted in the urine and 21% in faeces. Quetiapine accounted for less than 1% of the excreted radioactivity. 11 metabolites formed through hepatic oxidation have been identified. Two were found to be pharmacologically active, but they circulate in plasma at 2 to 12% of the concentration of quetiapine and are unlikely to contribute substantially to the pharmacological effects of the drug. The pharmacokinetics of quetiapine do not appear to be altered by cigarette smoking. Oral clearance declines with age, and was reduced in 2 of 8 patients with hepatic dysfunction but not in patients with renal impairment. Quetiapine has no effect on the in vitro activity of CYP1A2, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations. The lack of effect of quetiapine on hepatic oxidation was confirmed in vivo by the lack of effect of quetiapine on antipyrine disposition. Quetiapine had no effect on serum lithium concentration. Phenytoin and thioridazine increase the clearance of quetiapine, and ketoconazole decreases clearance. No clinically significant effects of cimetidine, haloperidol, risperidone or imipramine on the pharmacokinetics of quetiapine were noted. Quetiapine dosage adjustment, therefore, may be necessary when coadministered with phenytoin, thioridazine or other potent CYP3A4 inducers or inhibitors. The relationship between the therapeutic effects and the plasma concentrations of quetiapine has been investigated in a multicentre clinical trial. There was no statistically significant association between trough plasma quetiapine concentration and clinical response as measured by traditional assessments of psychotic symptom severity. Subsequent clinical studies of the plasma concentration versus effect relationships for quetiapine may help to further define guidelines for dosage regimen design.

Adolescent↗