Desipramine and 2-hydroxydesipramine plasma levels in endogenous depressed patients. Lack of correlation with therapeutic response.

Studies of the relationship between plasma concentrations of desipramine hydrochloride and clinical response have shown contradictory results, and only one prior study examined 2-hydroxydesipramine and its relationship to treatment. We therefore performed a study in a large, carefully diagnosed group of depressed patients taking fixed maintenance doses of desipramine to elucidate a potential relationship between clinical response and plasma concentrations of desipramine and 2-hydroxydesipramine. There was no significant correlation between clinical response and steady-state plasma levels of desipramine, 2-hydroxydesipramine, or the sum of desipramine plus 2-hydroxydesipramine. Although some commercial laboratories suggest a specific therapeutic plasma level "range" for desipramine, our data provide no support for such a range, nor for the routine measurement of plasma desipramine and 2-hydroxydesipramine concentrations in depressed patients.

Multiple hormonal responses to protirelin (TRH) in depressed patients.

The effects of protirelin (thyrotropin-releasing hormone [TRH]) administration on the release of five pituitary hormones (thyrotropin [TSH], prolactin [Prol], growth hormone, luteinizing hormone, and follicle-stimulating hormone [FSH]) were examined in 45 patients with major depressive disorder and 32 healthy volunteers. Although mean pituitary responses to protirelin in depressed patients and controls appeared to be comparable, depressed patients had higher SDs in all cases. Twelve patients (26.7%) but no controls had two or more abnormal hormonal responses to protirelin administration. The use of several nonparametric analyses revealed significant differences in patterns of hormonal response between depressed patients and controls for TSH, Prol, and FSH. These findings support the hypothesis that increased variability of neuroendocrine responsiveness represents a fundamental aspect of physiologic function in patients with endogenous depression.

A.E. Bennett Award Paper. A kinetic analysis of 5-hydroxyindoleacetic acid excretion from rat brain and csf.

Studies of neurotransmitter kinetics based on intraventricular injections of radio-labeled metabolites have been limited by several problems, including the inability of most investigators to recover more than 45% of the infected isotope from brain homogenates within several minutes after the injection...

Prediction of steady-state imipramine and desmethylimipramine plasma concentrations from single-dose data.

Tricyclic antidepressant plasma levels were measured in patients and healthy subjects after a single dise of desmethylimipramine (DMI) or imipramine (IMI) and after chronic dosing to steady states. Tricyclic plasma levels measured 24 hr after the single oral dose correlated with steady-state plasma levels. In patients receiving DMI there was a correlation (r = 0.97, n = 10) between 24-hr and steady-state DMI levels, while in normal subjects receiving IMI the correlation was r = 0.92 (n = 20) between 24-hr and steady-state total tricyclic levels (IMI plus its metabolite, DMI). These results suggest the possibility that after a test dose of tricyclic antidepressant, a patient may be put on a "therapeutic" dosage regimen without delay.

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. In addition, the atypical antidepressant mianserin, which has antagonist properties at both alpha 2 adrenoceptors and 5-HT2 receptors, was studied. A total of 19 limbic areas and 4 regions of the parietal cortex were quantitated. The binding of 3H-cyanoimipramine was increased (14% to 31%) by phenelzine and deprenyl in a total of 3 brain areas and decreased (15% to 21%) by sertraline in 4 brain areas. Citalopram, protriptyline, and mianserin produced no statistically significant effect in any brain region examined. The results indicate that different types of antidepressants do not exert consistent or substantial regulatory effect on the density of uptake sites for 5-HT in the limbic system or parietal cortex.

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 7.4. The affinity of these compounds for beta-receptors, as measured by their inhibition of binding of IPIN to rat cortical and cerebellar membranes in vitro, ranges from 2- to 100-fold less potent than pindolol; the most potent compounds have Ki values of 2-5 nM. The radiolabeled analogues of some of these compounds may prove useful for receptor imaging studies.

Reliability of commercially available tricyclic antidepressant levels.

Recent studies show that there may be a relationship between plasma levels of tricyclic antidepressants and clinical response. A number of commercial laboratories have introduced methods for measuring these drugs in plasma for clinical practice, and each recommends a particular method by which plasma samples should be drawn, processed, and stored. In this pilot study we compare results from 4 laboratories, using identical plasma samples containing amitriptyline and nortriptyline, in order to assess interlaboratory reliability. While there is generally good agreement between our results and those of the commercial facilities, some large interlaboratory discrepancies are evident. Caution is advised when utilizing plasma tricyclic levels to monitor patient progress, and we suggest using a laboratory which is well established in this area.

High dose desipramine, plasma drug levels and clinical response.

The concentration of tricyclic antidepressants in plasma may be a more important factor than the oral dose in determining whether or not a patient will respond to treatment. Knowledge of the drug dose-response curve and its levels in blood may enable the physician to convert a patient from a "nonresponder" into a "responder."

Prediction of steady-state plasma levels of amitriptyline and nortriptyline from a single dose 24 hr. level in depressed patients.

Amitriptyline and nortriptyline plasma levels were measured in depressed outpatients 24 hours after a single dose of amitriptyline and following chronic dosing to steady state. Plasma levels of amitriptyline and nortriptyline measured after the single dose correlated highly with steady state plasma levels. Full use as a test to rapidly place patients on a "therapeutic" dosage of drug will need to await a clear delineation of the relationship between blood levels and clinical response for amitriptyline.

Cimetidine-induced alterations in desipramine plasma concentrations.

Concurrent administration of cimetidine for 4 days to eight patients taking maintenance doses of desipramine led to significant elevations of desipramine (P less than 0.001) and its hydroxylated metabolite 2-hydroxydesipramine (P less than 0.001). The mean increase in desipramine plasma levels was 51% and that for 2-hydroxydesipramine was 46%. The present results suggest that tricyclic antidepressant plasma level monitoring might be indicated for certain patients taking concurrent cimetidine and desipramine.

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.

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. However, co-administration of the MAO-B selective inhibitor deprenyl (1 mg/kg) or the non-selective inhibitor pargyline (50 mg/kg) produced significant decreases in radioligand binding. Measurements of the effects of these drugs on body temperature ruled out the possibility that deprenyl and pargyline were increasing neurotoxicity by producing a drug-induced hyperthermia. In contrast to the effects of deprenyl and pargyline, co-administration of the MAO-A selective inhibitor clorgyline (1 mg/kg) did not alter binding. By themselves none of the MAO inhibitors produced neurotoxic effects. There are a number of possible explanations for these results. Administration of deprenyl or pargyline, together with pCA, itself a MAO-A inhibitor, will lead to inhibition of both MAO-A and MAO-B activities. This will likely lead to an enhanced release of dopamine and serotonin compared with the release following administration of pCA alone or pCA together with clorgyline. Elevation of the extracellular levels of either or both of these monoamines could lead to enhanced neurotoxicity. Whatever the mechanism involved, our results show that the co-administration of a type-B MAOI enhances the neurotoxic effects of pCA on serotonin neurons.

Effect of age on the rate of recovery of beta-adrenergic receptors in rat brain following desmethylimipramine-induced subsensitivity.

Brain tissues from aged rats have an impaired ability to increase beta-adrenergic receptors in response to reduced noradrenergic input, but can down-regulate these receptors in response to repeated administration of desmethylimipramine (DMI). In this study we compared the ability of brain tissues from young (3-month) and aged (20- to 26-month) rats to restore their density of beta-adrenergic receptors following desmethylimipramine (DMI)-induced receptor subsensitivity. Either DMI or saline was administered i.p. twice daily for 7 days to groups of young and aged rats. At various times after drug administration [3H]dihydroalprenolol (DHA) binding was determined in homogenates of pineal gland and cerebral cortex. Four hours after the last dose of DMI there was a decrease in DHA binding in both brain areas of young and aged rats. In young rats DHA binding in these tissues returned to control levels by 2 days after DMI administration. In contrast, in aged rats it took 8 and 16 days for DHA binding to recover in cerebrum and pineal, respectively. The concentration and half-life for the disappearance of DMI from serum and cerebrum were significantly greater in aged rats than in young rats, but the differences do not entirely explain the delayed recovery of beta-receptors in the aged rats. The results suggest that beta-adrenergic receptors of brain tissues from aged rats cannot recover from beta-receptor subsensitivity as readily as those from young rats. If this recovery process requires the synthesis of new receptors, then this synthetic mechanism may be impaired with age.(ABSTRACT TRUNCATED AT 250 WORDS)

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. The sites labeled by [3H]cyanoimipramine had properties consistent with this ligand labeling serotonin uptake sites, as: (1) binding is displaced by drugs which are potent inhibitors of serotonin uptake but not by drugs which are weak inhibitors of uptake; (2) binding is dependent on the presence of sodium ions as is the uptake of serotonin; (3) binding is almost completely eliminated in the brains of rats lesioned by the serotonin neurotoxin 5,7-dihydroxytryptamine; (4) the distribution of binding sites throughout the rat brain is highly correlated with that found previously for [3H]indalpine, a potent serotonin uptake inhibitor, and for [3H]imipramine. The properties of binding of [3H]cyanoimipramine make it an ideal ligand for the quantitative autoradiography of serotonin uptake sites.

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. Significant decreases were still present in many brain areas on the same dosage schedule 30 days after drug administration. However, the number of areas affected was considerably less, consistent with some regrowth of serotonin neurons. At a lower dosage (7.5 mg/kg on the same schedule) no effects on [3H]CN-IMI binding were seen. The results of this study provide support for the serotonergic neurotoxicity of repeated methamphetamine administration in rats. They also show that the neurotoxicity is highly regional and dose dependent.

The effect of antidepressant drugs on regional cerebral glucose utilization in the rat.

The 2-deoxyglucose (2-DG) technique is a potentially powerful method for assessing the effect of centrally acting drugs on local neuronal function in the brain. Since little is established on the effect of antidepressant drugs on local functional activity throughout the brain, we have employed this technique to study the effects of desmethylimipramine (DMI), a tricyclic antidepressant, and assessing the effect of centrally acting drugs on local neuronal function in the brain. Since little is established on the effect of antidepressant drugs on local functional activity throughout the brain, we have employed this technique to study the effects of desmethylimipramine (DMI), a tricyclic antidepressant, and assessing the effect of centrally acting drugs on local neuronal function in the brain. Since little is established on the effect of antidepressant drugs on local functional activity throughout the brain, we have employed this technique to study the effects of desmethylimipramine (DMI), a tricyclic antidepressant, and phenelzine, a monoamine oxidase inhibitor used clinically as an antidepressant, on local glucose utilization. The drugs were administered either as an acute dose, or repeatedly for 7 days, or chronically for 28 days. The local metabolic rate of glucose was determined in 30 regions of rat brain. Acute DMI increased glucose utilization in 11 regions whereas, in contrast, chronic DMI decreased glucose utilization in 7 regions of rat brain. Many of the areas affected are those of the telencephalon and diencephalon that receive prominent noradrenergic innervation. This is consistent with the notion that acute DMI treatment leads to enhanced and chronic DMI treatment leads to reduced noradrenergic functioning in the CNS. In contrast to these effects with DMI, phenelzine had little effects on glucose utilization either after acute or chronic dosing.

[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. Pretreatment with the neurotoxin DSP-4 resulted in 95% decrease in binding. [3H]Nisoxetine exhibits superior properties to radioligands previously used and appears to be the radioligand of choice for studies involving uptake sites for norepinephrine.

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. The half-lives of hydrolysis for MBDA and DBDA at physiologic pH and temperature were 15 and 420 min respectively. These compounds were radiolabelled and their uptake into brain measured. 14C-DBDA penetrated the brain rapidly; 0.28% of the dose injected was taken up per gram of brain tissue at 5 min. However DBDA did not produce measurable increases in DA levels in the brain. 14C-MBDA was found not to penetrate the brain. However, when MBDA was administered intracerebroventricularly (i.c.v.) to rats, it caused DOPAC levels to increase significantly both in the striatum and in the rest of the brain. The increase in the amount of DOPAC measured in the striatum was 3 to 10-fold greater than that seen in the rest of the brain. In rats that were pretreated with the MAO inhibitor, pargyline, MBDA given i.c.v. caused increases in DA levels in both the striatum and in the rest of the brain. The increased DA levels in striatum were considerably greater than those seen in the rest of the brain. From these results, it is inferred that MBDA is being hydrolyzed in vivo in the brain to form DA which is then taken up into dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

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. Multiple regression analyses showed that the most important factor which influences the ability of the pindolol derivatives to penetrate into the brain and interact with beta-adrenergic receptors in vivo is the affinity of the derivatives for binding to beta-adrenergic receptors in vitro. Both lipophilicity and the molecular weights of the derivatives are important secondary factors which influence their in vivo potency.

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. N-Substitution with a methyl or an ethyl group increased the affinity to 0.2 nM, whereas substitution with a n-propyl or isopropyl group decreased the binding affinity over 100 fold. Compounds with aralkyl substitutions at the nitrogen atom of piperidinyl benzilate were also synthesized and evaluated. The Ki values (nM) obtained for these compounds were: benzyl, 0.2; p-nitrobenzyl, 13.0; p-fluorobenzyl, 3.0; phenethyl, 8.0; p-nitrophenethyl, 15.0. These data suggest that a binding region near the piperidinyl nitrogen may tolerate bulky aromatic substitutions (e.g., benzyl or phenethyl) as well or better than straight chain or branched alkyl substitutions (e.g., n-propyl or isopropyl).