PET brain imaging with [11C](+)McN5652 shows increased serotonin transporter availability in major depression.

Background: Alterations in the brain serotonin (5-HT) system have been found in patients with depression. We used the selective 5-HT transporter site ligand [11C](+)McN5652 and positron emission tomography (PET) to examine the hypothesis that alterations in 5-HT transporter levels may be present in selected regions of the brain in depressed patients.

Methods: Four drug free depressed patients and four healthy control subjects were studied using [11C](+)McN5652 and PET.

Pindolol does not augment cortisol and prolactin responses to paroxetine in healthy subjects.

Objective: Animal studies have shown that pindolol augmentation of selective serotonin re-uptake inhibitors (SSRIs) may act through inhibition of 5-HT(1A) autoreceptors in the raphe. The combination of pindolol plus a SSRI produces increased synaptic 5-HT levels that are greater than those achieved with a SSRI alone. However, it is unclear whether this actually occurs in humans, and clinical studies of pindolol augmentation have produced inconsistent results.

Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression - low manic switch rate.

Objectives: Current guidelines for the initial treatment of bipolar type II (BP II) major depressive episode (MDE) recommend using either a mood stabilizer alone or a combination of a mood stabilizer plus a selective serotonin re-uptake inhibitor (SSRI). This recommendation is the result of concern over antidepressant-induced manic switch episodes. However, recent evidence suggests that the manic switch rate may be low in BP II MDE during SSRI therapy.

Antidepressant monotherapy for bipolar type II major depression.

Objectives: Bipolar type II (BP II) disorder is thought to be distinct from BP I disorder on genetic and biological grounds, and it is not merely a milder form of the illness. It affects 1.5-2.

Greater availability of brain dopamine transporters in major depression shown by [99m Tc]TRODAT-1 SPECT imaging.

Objective: Studies of laboratory animals have shown that administration of antidepressants of all pharmacological classes produces changes in dopamine transporter binding affinity. These observations suggest that dopamine transporter function may play a critical role in the pathophysiology of depression. The present study was an examination of the availability of brain dopamine transporter sites in patients with major depression and in healthy comparison subjects.

A single-site, double-blind, placebo-controlled, dose-ranging study of YKP10A--a putative, new antidepressant.

Background: YKP10A is a novel, new antidepressant that may affect dopamine neurotransmission. We present results from the first Phase II clinical trial of YKP10A antidepressant activity in patients with major depression.

Methods: This was a single-site, placebo-controlled, dose-ranging study.

Site variability in treatment outcome in antidepressant trials.

Objective: Site-specific differences in treatment outcome during multisite antidepressant drug trials may contribute to a negative or failed clinical trial. As part of a five-site, long-term, double-blind, placebo-controlled, relapse prevention trial with fluoxetine in major depression, the authors examined site-specific variability in outcome ratings.

Methods: Data from 390 patients with major depression who participated in a 64-week, placebo-controlled trial were retrospectively analyzed.

Fluoxetine and norfluoxetine plasma concentrations during relapse-prevention treatment.

Background: Virtually no attention has been given to the relationship between antidepressant plasma drug concentrations and relapse-prevention during maintenance therapy. The purpose of this study was to investigate the relationship between steady-state plasma drug concentrations and outcome during relapse-prevention therapy with fluoxetine.

Methods: The patients studied had responded to acute fluoxetine treatment for major depression (defined by DSM-III-R).

The MAO-B inhibitor deprenyl, but not the MAO-A inhibitor clorgyline, potentiates the neurotoxicity of p-chloroamphetamine.

The effect of co-administration of MAO inhibitors together with a low dose of the neurotoxic amphetamine p-chloroamphetamine (pCA) on neurotoxicity was examined. Neurotoxicity was assessed by measuring decreases in the binding of [3H]cyanoimipramine to serotonin uptake sites using quantitative autoradiography. By itself, a low dose of pCA (2 mg/kg) did not produce any alterations in radioligand binding, measured 7 days after drug administration.

Effect of repeated administration of antidepressants on serotonin uptake sites in limbic and neocortical structures of rat brain determined by quantitative autoradiography.

The binding of 3H-cyanoimipramine, a selective radioligand for the serotonin (5-HT) transporter, was measured by quantitative autoradiography on sections of rat brain to determine if 5-HT uptake sites are regulated by repeated administration of antidepressants. The drugs studied included selective inhibitors of the uptake of 5-HT (citalopram, sertraline) or norepinephrine (protriptyline). Also, effects of inhibitors of monoamine oxidase (MAO) that inhibit both type A and type B MAO (phenelzine), or just type B MAO (deprenyl), were investigated.

Effects of high-dose methamphetamine on monoamine uptake sites in rat brain measured by quantitative autoradiography.

The neurotoxicity of methamphetamine to monoaminergic neurons was examined. Neurotoxicity was assessed by quantitative autoradiography using radioligands specific for binding to norepinephrine, dopamine, and serotonin uptake sites. High-dose administration of methamphetamine led to decreases in binding to uptake sites for the three monoamines.

Lack of effect of high-dose cocaine on monoamine uptake sites in rat brain measured by quantitative autoradiography.

There have been a number of claims that high-dose administration of cocaine to rats leads to neurotoxic effects on dopamine neurons. In this study possible neurotoxic effects on monoamine neurons were examined by measuring the effects of cocaine (35 mg/kg daily for 10 days) on the binding of radioligands to uptake sites for dopamine, serotonin and norepinephrine using qualitative autoradiography. No effects of cocaine on any of the binding sites were observed and therefore, it is concluded that cocaine, unlike amphetamine derivatives which have similar pharmacologic properties, does not produce neurotoxic effects on monoamine neurons.

[3H]nisoxetine: a new radioligand for norepinephrine uptake sites in brain.

[3H]Nisoxetine binds with high affinity (Kd = 0.7 nM) and selectivity to a homogenous population of sites associated with the uptake of norepinephrine. Specific [3H]nisoxetine binding to rat cortical homogenates was saturable, sodium-dependent and averaged 90% of total binding at its Kd concentration.

N-substituted derivatives of 4-piperidinyl benzilate: affinities for brain muscarinic acetylcholine receptors.

N-Substituted derivatives of 4-piperidinyl benzilate were synthesized and their affinities for central muscarinic cholinergic receptors determined using an in vitro radioligand binding assay. 4-Piperidinyl benzilate exhibited a Ki value of 2.0 nM.

Effects of high-dose methamphetamine administration on serotonin uptake sites in rat brain measured using [3H]cyanoimipramine autoradiography.

Repeated administration of high doses of methamphetamine (15 mg/kg given for 5 doses over 24 h) resulted in long-term decreases in the binding of [3H]cyanoimipramine ([3H]CN-IMI) to serotonin uptake sites measured using quantitative autoradiography. Seven days after termination of drug administration decreases were seen in 23 of 28 regions examined. This is consistent with previous studies indicating that methamphetamine and related amphetamines are neurotoxic to serotonin neurons.

Evaluation of mono- and dibenzoyl esters of dopamine as potential pro-drugs for dopamine in the central nervous system.

In this study, two ester pro-drugs of dopamine (DA) were synthesized and evaluated. These derivatives were the monobenzoyl (MBDA) and dibenzoyl (DBDA) esters of DA. MBDA was 300-fold and DBDA was 20,000-fold more lipophilic than DA itself.

Quantitative autoradiography of serotonin uptake sites in rat brain using [3H]cyanoimipramine.

The binding of [3H]cyanoimipramine to serotonin uptake sites in rat brain slices was studied using quantitative autoradiography. Binding was of high affinity and was to a single class of binding site. This is in contrast to results previously obtained by others with [3H]imipramine where two binding sites were observed.

Insulin-induced hypoglycaemic response and release of growth hormone in depressed patients and healthy controls.

As part of the Collaborative Study of the Psychobiology of Depression, we have examined the pretreatment growth hormone response (delta GH) to insulin (0.1 U/kg) and the magnitude of the hypoglycaemic response in a large number of well-defined depressed patients (N = 132) and healthy controls (N = 80). After applying rigorous exclusion criteria, data were analysed from 93 patients and 66 controls for blood glucose response and from 56 patients and 52 controls for delta GH.

Structural derivatives of pindolol: relationship between in vivo and in vitro potencies for their interaction with central beta-adrenergic receptors.

Although (-)-125I-iodopindolol (IPIN) can be used to label beta-adrenergic receptors in the central nervous system (CNS) in vivo, use of this ligand for receptor imaging studies in humans may be limited due to its relatively poor penetration into the CNS. A series of derivatives related to pindolol was therefore studied in an effort to determine the factors that might influence the penetration and interaction of these compounds with central beta-adrenergic receptors in vivo. Evaluation of the ability of these derivatives to displace the binding of IPIN in the brain upon systemic administration provides an assessment of whether the derivatives penetrate and interact with central beta-adrenergic receptors in vivo.

Interaction of beta adrenergic agonists and antagonists with brain beta adrenergic receptors in vivo.

There is interest in knowing whether beta adrenergic antagonists or agonists, when administered systemically, can enter the brain to interact with central beta adrenergic receptors. To study this, the reduction in the radioactive content in the brain of rats after administration of (-)-[125I]iodopindolol (IPIN) by systemically administered beta agonists or antagonists was measured. Previous studies show that after the i.

Labeling in vivo of serotonin uptake sites in rat brain after administration of [3H]cyanoimipramine.

The properties of sites in rat brain labeled in vivo after administration of [3H]cyanoimipramine ([3H]CN-IMI) have been studied. The radioactivity in hypothalamus and cortex 20 min to 2 hr after [3H]CN-IMI administration was reduced in rats pretreated with chlorimipramine (10 mg/kg) 5 min before [3H]CN-IMI. No effect of chlorimipramine pretreatment was seen in the cerebellum; levels of radioactivity in this tissue were subtracted from total levels in hypothalamus and cortex to define specific binding.

Synthesis and beta-adrenergic receptor blocking potency of 1-(substituted amino)-3-(4-indolyloxy)propan-2-ols.

Although (-)-[125I]iodopindolol (IPIN) can be used to label beta-adrenergic receptors in the central nervous system in vivo, use of this ligand for receptor imaging studies in humans may be limited due to its relatively poor penetration into the brain. As a first step toward the development of radioligands for imaging studies, we report the synthesis and measurement of in vitro binding affinity to beta-receptors of a series of 1-(substituted amino)-3-(4-indolyloxy)-propan-2-ol derivatives. The synthesized compounds vary widely in their lipophilicity as measured by their distribution coefficients between phosphate buffer and octanol at pH 7.