Suppression of histamine-induced adrenocorticotropic hormone release by antihistamines and antidepressants

The antihistaminic activity of many antidepressant drugs is well documented in vitro but has not been investigated as thoroughly in vivo. In the course of an investigation of the roles of H1 and H2 receptors in histamine-induced adrenocorticotropic hormone (ACTH) release in rats, it was observed that several antidepressants were potent inhibitors of this response. Male Sprague-Dawley rats were injected with test drugs and then with histamine or histamine agonists. Serum ACTH concentrations were determined by radioimmunoassay. ACTH secretion was induced by both H1 and H2 receptor stimulation. Histamine-induced ACTH release was markedly attenuated by several H1 antihistamines, whereas the H2 antagonists were not as effective. The antidepressants imipramine, doxepin, mianserin, desipramine and amitriptyline suppressed histamine-induced ACTH release. However, iprindole and the antianxiety agent diazepam were without effect. ACTH release induced by histamine agonists was also diminished by pretreatment with some of these blocking agents.     

Differential effects of hallucinogenic drugs on the activity of serotonin-containing neurons in the nucleus centralis superior and nucleus raphe pallidus in freely moving cats

Using radioligand binding techniques, we determined the equilibrium dissociation constants (KDS) for a series of antidepressants at the histamine H1, muscarinic acetylcholine, alpha-1 and alpha-2 adrenergic and dopamine (D-2) receptors of normal human brain tissue obtained at autopsy. Twenty-five different antidepressants were studied at all but the D-2 receptor at which the number was 13 (including a metabolite of an antidepressant). Of all the receptor interactions studied, that at the histamine H1 receptor was in general the most potent interaction of this class of compounds, corresponding to results from studies using animal tissue as the source of receptors. At the human brain histamine H1 receptor, antidepressants remained among the most potent histamine H1 antagonists known, although their affinities for human receptors were lower than those for animal receptors. The most potent and the least potent compounds at the receptors were doxepin (KD = 0.24 nM) and fluvoxamine (KD = 109 microM) at the histamine H1 receptor, amitriptyline (KD = 18 nM) and trazodone (KD = 324 microM) at the muscarinic receptor, doxepin (KD = 24 nM) and viloxazine (KD = 14 microM) at the alpha-1 receptor, mianserin (KD = 73 nM) and bupropion (KD = 81 microM) at the alpha-2 receptor and amoxapine (KD = 160 nM) and trazodone (KD = 3800 nM) at the D-2 receptor, respectively. In general, compared to older drugs, the newer compounds tended to have lower affinities for these receptors.     

The effects of the H1 and H2 antihistamines on "allergic" histamine release and its inhibition by histamine.

Antigen-induced, IgE-mediated release of histamine from human basophiles is an in vitro model of allergic reacttions; it is blocked by extracellular histamine, presumably as a result of its ability to increase adenosine 3',5'-monophosphate (cyclic AMP) levels. The H1 antihistamines do not antagonize these effects of histamine but at approximately equal to 1 mM cause histamine release and at approximately equal to 0.1mM inhibit antigen-induced histamine release. The phenothiazine antihistamines are 10-30 fold more potent inhibitors than the rest; other tricyclic antidepressant drugs share this activity. The mechanism of this inhibition, which occurs in both the 1 degree and 2 degree stages of histamine release, is not known but it is not due to partial agonist activity since the anti-H1 drugs cause a significant fall in cyclic AMP levels. The anti-anaphylactic effects of the H1 antagonists probably play no therapeutic role but we suggest that drugs structurally similar to the phenothiazine antihistamines should be developed for clinical testing. The H2 antihistamines block histamine-induced inhibition of histamine release and the increase in cyclic AMP levels, but neither cause nor inhibit histamine release. The K-B values for the anti-H2 drugs (burimamide approximately equal to 5 muM); metiamide approximately equal to 0.5muM); are similar to those described for other H2 receptors.     

Pharmacological profile of binedaline, a new antidepressant drug

The interactions of binedaline (binodaline), a new antidepressant drug, and its main metabolites with neurotransmitter receptors and monoamine uptake sites were studied. In receptor binding assays, binedaline was compared to amitriptyline, imipramine, maprotiline and mianserin. Unlike these drugs binedaline did not show any significant affinity for an alpha adrenergic, muscarinic cholinergic, histamine H1 or serotonin2 (5-HT2) receptors. Binedaline and desmethylbinedaline were potent inhibitors of the uptake of norepinephrine in synaptosomes from rat cerebral cortex (Ki = 25 and 29 nM, respectively). Binedaline also inhibited 5-HT uptake with a weak affinity (Ki = 847 nM) but was inactive as an inhibitor of dopamine uptake in synaptosomes from rat striatum (Ki greater than 2 microM). No specific binding was found using [3H]binedaline. After 2 weeks of daily administration of binedaline (20 mg/kg i.p.), the number of beta adrenergic recognition sites labeled with [3H]CGP 12177 remained constant in rat forebrain, as did 5-HT2 receptors and benzodiazepine receptors. In contrast a prolonged treatment with maprotiline (20 mg/kg i.p.) increased the apparent Kd value of [3H]CGP 12177 by 43% and the apparent maximal binding value of [3H]RO 15-1788 by 20% as compared to control. Our results indicate that binedaline is comparable to a tricyclic antidepressant drug in inhibiting the norepinephrine uptake but, however, it is devoid of affinity for neurotransmitter receptors. This probably explains why this drug does not induce the classical side effects of tricyclic antidepressant drugs. These results also suggest that a reduction in beta adrenergic, 5-HT2 or benzodiazepine receptors is not always related to an antidepressant chronic treatment.     

Desipramine enhances opiate postoperative analgesia

In a double-blind, placebo-controlled study the analgesic efficacy of the combination of a tricyclic antidepressant and morphine was investigated. One of two tricyclic antidepressants (either amitriptyline, a relatively selective serotonin uptake inhibitor or desipramine, a relatively selective noradrenaline uptake inhibitor) or a placebo, was given for 1 week prior to surgery, followed by a single postoperative dose of morphine. Desipramine, but not amitriptyline, both increased and prolonged morphine analgesia. Neither tricyclic antidepressant reduced dental postoperative pain in the absence of morphine. We propose that desipramine enhances opiate analgesia by enhancing a noradrenergic component that contributes to endogenous opioid-mediated analgesia systems.     

A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain

LY135252, (+/-)-N-methyl-gamma-(2-methylphenoxy) phenylpropylamine hydrochloride, is a competitive inhibitor of norepinephrine uptake in synaptosomes of rat hypothalamus. The resolved optical (-)-isomer, LY139603, is 2 and 9 times more effective than the racemate and the (+)-isomer, LY139602, with inhibitor constants (Ki) of 1.9, 3.4 and 16.8 nM, respectively. All three compounds are relatively weak in the inhibition of dopamine and serotonin uptake, with Ki values at least two orders of magnitude greater. The racemate and the two optical isomers in vivo are potent inhibitors of norepinephrine uptake with relative effectiveness being parallel with their K1 values. The most potent and long-acting compound was the (-)-isomer, LY139603, which inhibited norepinephrine uptake ex vivo with an ED50 value of 2.2 mg/kg i.p, and a half-life of 6.4 hr. In comparison with the tricyclic antidepressants desipramine and imipramine, LY139603 is a relatively weak ligand for alpha-1, alpha-2, and beta adrenergic receptors, acetylcholine-muscarinic receptors, histaminergic H1 receptors and the receptors of gamma-aminobutyric acid and benzodiazepines. Thus, LY139603 is a remarkably specific inhibitor of norepinephrine uptake. Its potential as an antidepressant is discussed.     

Antihistaminic and antimuscarinic effects of amitriptyline on guinea pig ileal electrolyte transport and muscle contractility in vitro

Amitriptyline, a tricyclic antidepressant, was tested for antimuscarinic and antihistamine effects against bethanechol and histamine-stimulated contractility and secretion in the guinea pig ileum in vitro. Comparisons were made with muscarinic-receptor antagonists, as well as with H1 and H2 histamine-receptor antagonists. Amitriptyline (0.01-5.0 microM) produced a parallel rightward shift in the concentration-response curves to histamine in muscle (Ki 0.4 nM) and mucosa (Ki 450 nM). The H1-receptor antagonists pyrilamine and diphenhydramine were less potent against histamine in the muscle and more potent against histamine in the mucosa than was amitriptyline. The H2-receptor antagonist cimetidine was ineffective in the muscle and mucosa. Amitriptyline (0.1-2 microM) also produced a parallel rightward shift in the concentration-response curve to bethanechol in muscle (Ki 133 nM) and mucosa (Ki 143 nM). Against bethanechol, in both tissues, atropine and 4-diphenylacetoxy-N-methyl piperidine methiodide were more potent competitive antagonists than was amitriptyline. Pirenzepine produced a competitive blockade of bethanechol in the muscle and a noncompetitive blockade in the mucosa. The data indicate that amitriptyline exerts more potent antihistaminic effects on guinea pig ileal muscle than the mucosa but that the tricyclic drug is equipotent as an antimuscarinic in both tissues.     

Treatment response in antidepressant-na?ve postherpetic neuralgia patients: double-blind, randomized trial.

In 47 patients with postherpetic neuralgia (PHN) who had never had an adequate trial of any antidepressant, we performed a randomized, double-blind, parallel design trial comparing desipramine, amitriptyline, and fluoxetine. Patients were titrated to a maximum of 150 mg/day for desipramine and amitriptyline and 60 mg/day for fluoxetine over a 3-week period and then treated for an additional 3 weeks before tapering off study medication. A total of 38 subjects (81%) completed the entire trial. The modified intent-to-treat analysis of percent change in daily diary pain intensity scores showed no significant differences among the 3 drugs (ANOVA P = .120). Desipramine produced the greatest reduction in pain intensity (47%), followed by amitriptyline (38%) and fluoxetine (35%). Clinically meaningful pain relief (moderate or better) was significantly more likely with desipramine (12/15 patients) than with amitriptyline (9/17) or fluoxetine (5/15); chi(2)P = 0.036). The 11 subjects using opioids at study entry had smaller reductions in pain than those not using concomitant opioids. The fluoxetine group had the highest noncompletion rate (33%), with 1 subject hospitalized for hyponatremia. Although the magnitude of pain reduction and the category pain relief rating was not significantly different among the 3 drugs, the tricyclics desipramine and amitriptyline were well tolerated and provided clinically meaningful pain relief in 53% to 80% of subjects. PERSPECTIVE: Few clinical trials focus on patients who are na?ve to an entire class of medication. In this randomized blinded trial, the tricyclic antidepressants desipramine and amitriptyline were compared to the serotonin-selective antidepressant fluoxetine. All 3 drugs reduced PHN pain, with desipramine providing satisfactory relief in 80% of those treated.     

Results compared for tricyclic antidepressants as assayed by liquid chromatography and enzyme immunoassay

The tricyclic antidepressants amitriptyline, nortriptyline, imipramine, and desipramine in serum of patients taking one of the drugs were quantified in two laboratories by high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay (EMIT; Syva). Results for split samples were highly correlated, but EMIT gave higher results in most cases, and the slopes of the correlation lines for each analyte were greater than 1. Detection limits for the two procedures were such that 18% of the EMIT results for the drug(s) were considered negative, as compared with 4% of the HPLC results. Additional assay of desmethyl or hydroxy antidepressant metabolites by HPLC did not explain the higher EMIT results. The relatively high detection limit for EMIT greatly limits its use in therapeutic drug monitoring, where low concentrations of tricyclic antidepressants are as important as high ones for dose adjustment or determination of compliance. Other problems with EMIT measurement of tricyclic antidepressants are discussed.     

Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial

Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double-blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect.     

Meta-analyses of the efficacy and tolerability of the tricyclic antidepressant lofepramine.

Lofepramine is a tricyclic antidepressant related to imipramine. Meta-analyses were carried out with respect to efficacy and tolerability by combining outcome and adverse reaction from over 20 controlled trials comparing lofepramine with other tricyclic antidepressants. Lofepramine was at least as effective as the comparators with fewer adverse effects. In particular, the risk/benefit ratio seemed superior to the comparators amitriptyline, imipramine, clomipramine, maprotiline and desipramine.     

Treatment of neuropathic pain with venlafaxine

OBJECTIVE: To report a case of successful treatment of neuropathic pain with venlafaxine. CASE REPORT: A 39-year-old white woman presented with neuropathic back pain. The patient obtained 50% pain relief with consecutive use of amitriptyline, desipramine, and imipramine. Anticholinergic effects prompted a switch to extended-release venlafaxine 75 mg/d. Pain relief was as effective with this therapy as with the tricyclic antidepressants. The absence of adverse effects allowed the patient to discontinue all laxatives. DISCUSSION: Venlafaxine is an antidepressant that inhibits reuptake of norepinephrine and serotonin. This is the major mechanism by which tricyclic antidepressants relieve neuropathic pain. Venlafaxine does not bind to muscarinic-cholinergic, histaminic or alpha1-adrenergic receptors responsible for the common adverse effects seen with tricyclic antidepressants. CONCLUSIONS: This report describes the efficacious use of venlafaxine in the treatment of neuropathic pain. Double-blind, randomized, controlled trials are needed to explore this further.     

Effects of antidepressants in rats trained to discriminate centrally administered isoproterenol

Previous work has shown that the discriminative stimulus effects of centrally administered isoproterenol are mediated primarily via beta1-adrenergic receptors. In the present study, this model was used to investigate the ability of antidepressant drugs displaying various pharmacological profiles to stimulate beta1-adrenergic receptors in vivo; this was assessed by determining whether they substituted for the discriminative stimulus effects of isoproterenol. Rats were trained to discriminate centrally administered isoproterenol (10 microg i.c.v.) from artificial cerebral spinal fluid using a water-reinforced, two-lever operant task (fixed ratio 10 schedule). After acquisition of the discrimination, drugs were tested for substitution (i.p.). The tricyclic antidepressants protriptyline and desipramine, the norepinephrine uptake inhibitor nisoxetine, the monoamine oxidase inhibitor phenelzine, and the atypical antidepressants bupropion, mirtazapine, and venlafaxine all produced greater than 90% isoproterenol-appropriate responding. The serotonin uptake inhibitor fluoxetine, the atypical antidepressants buspirone and trazodone, and the novel, putative antidepressants N(G)-nitro-L-arginine and N-acetyl-L-tryptophan 3,5-bis benzyl ester failed to substitute for isoproterenol at the dose ranges tested. Antagonism studies carried out with betaxolol for those drugs that fully generalized to isoproterenol's cue verified mediation by beta1-adrenergic receptors. The present results indicate that drugs with noradrenergic activity generalize to isoproterenol's discriminative stimulus. Although this suggests a role for central beta1-adrenergic receptors in the mechanism of action of certain antidepressant drugs, it does not seem that stimulation of these receptors is an effect shared by antidepressants from all pharmacological classes.     

Regulation of serotonin2 (5-HT2) receptors labeled with [3H]spiroperidol by chronic treatment with the antidepressant amitriptyline

Recently, we reported that chronic administration of several antidepressants of different classes produced larger reductions in numbers of serotonin2 (5-HT2) receptors in rat brain labeled by [3H[spiroperidol than in beta adrenergic receptors. In the present study, we examine detailed properties of 5-HT2 receptor regulation by chronic treatment with amitriptyline. Chronic but not acute treatment with the tricyclic antidepressant amitriptyline reduces binding to 5-HT2 receptors by [3H]spiroperidol and beta adrenergic receptor binding of [3H]dihydroalprenolol in brain membranes. The decrease is time-dependent, gradually reversible and represents a change in the number of binding sites with no alteration in drug affinities for 5-HT2 receptors. The effect can be observed at daily doses of 2.5 mg/kg, similar to clinically effective doses in humans. At all doses and time intervals, the decrease in 5-HT2 receptors is more marked than the concurrent change in total beta adrenergic receptor binding. The properties of 5-HT2 receptor reduction after chronic antidepressant treatment indicate that this alteration could be associated with therapeutic response.     

Pharmacologic profile of fezolamine fumarate: a nontricyclic antidepressant in animal models

Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, nontricyclic agent under investigation as a potential antidepressant. In vitro, it was 3 to 4 times more selective in blocking synaptosomal uptake of [3H]norepinephrine than uptake of [3H]serotonin or [3H]dopamine. In classical behavioral tests using monoamine-depleted animals, it prevented the depressant effects of reserpine and tetrabenzine. In addition, it was active in the "behavioral despair" procedure. Its potency in three of these models was similar to that of standard tricyclics (e.g., imipramine, amitriptyline) or newer nontricyclic antidepressants (e.g., bupropion). In the mouse mydriasis and oxotremorine antagonism models, anticholinergic properties of fezolamine were weak or absent compared with imipramine and amitriptyline. Locomotor activity in mice was not increased by fezolamine at doses 2 to 16 times greater than effective antidepressant doses, suggesting the absence of central nervous system stimulant properties. Fezolamine did not inhibit monoamine oxidase activity in ex vivo studies and, unlike pargyline, did not produce locomotor hyperactivity in mice pretreated with L-tryptophan. In vitro studies using canine Purkinje tissue suggest that fezolamine has significantly less ability to depress myocardial conduction parameters than similar concentrations of imipramine. In a myocardially infarcted cat model, plasma levels of fezolamine 19 to 28 times greater than those achieved with imipramine were required before inducing significant depression of cardiac function and mean arterial pressure. Fezolamine, unlike imipramine, did not increase sinus rate. Fezolamine may thus show antidepressant efficacy in man with minimal anticholinergic or cardiovascular side effects common to tricyclic antidepressants.     

ANTIDEPRESSANTS IN THE ELDERLY

Antidepressants are effective in the treatment of depression but their use in the elderly merits special attention. In general, the tertiary amine tricyclic antidepressants (TCAs) tend to produce significant side-effects in the elderly. In contrast, nortriptyline, desipramine and lofepramine are better tolerated than other TCAs. The newer antidepressants including the selective serotonin reuptake inhibitors are useful alternatives in the treatment of depression in the elderly. As pharmacokinetic studies show that higher steady-state plasma levels of tertiary amine antidepressants may be found in the elderly than in the younger population, a lower dosage is recommended. However, the need for a lower dose in the elderly is less certain for the secondary amine TCAs. The optimum duration of continuation and maintenance antidepressant therapy requires further study. For delusional depression, there is evidence to support the superiority of ECT and combination antipsychotic/antidepressant treatment over antidepressant alone. The ultimate choice of antidepressant will be a balance of efficacy, safety, acceptability and cost.     

Studies on the effects of antidepressant drugs on the antinociceptive action of morphine and on plasma morphine in rat and man

In the rat we studied the effect of 3 tricyclic antidepressants: chlorimipramine, amitriptyline and nortriptyline, and the atypical antidepressant trazodone on pain thresholds when administered alone or together with morphine. Moreover, we evaluated the effect of the antidepressants on free morphine plasma concentrations both in the rat and in man. We observed that chlorimipramine and amitriptyline, two tricyclic antidepressants active on the serotoninergic system, induce analgesia and potentiate morphine analgesia in a dose-related fashion. The noradrenergic tricyclic nortriptyline and trazodone did not elicit analgesia and inconsistently affected morphine analgesia. In the rat, all drugs tested increased plasma concentrations of morphine with the exception of amitriptyline. In man, only chlorimipramine and amitriptyline increased the plasma concentration of the free opiate.     

Altered effects of desipramine on operant performance after 6-hydroxydopamine-induced depletion of brain dopamine or norepinephrine

Performance maintained by differential-reinforcement-of-low-rate operant schedules has been found to be sensitive to antidepressant drugs. Tricyclic antidepressants, monoamine oxidase inhibitors and atypical antidepressants reduce response rate and increase reinforcement rate under long differential-reinforcement-of-low-rate schedules. In order to study the neurochemical mechanism by which the tricyclic antidepressant desipramine alters differential-reinforcement-of-low-rate performance, the effect of desipramine was determined before and after brain catecholamine depletion was induced by 6-hydroxydopamine administration. Before lesioning, desipramine reduced response rate and increased reinforcement rate in a dose-dependent manner. Brain norepinephrine depletion (produced by 6-hydroxydopamine injection into the dorsal noradrenergic bundle) attenuated the ability of desipramine to reduce response rate, but did not alter its ability to increase reinforcement rate, but did not alter its ability to increase reinforcement rate. Brain dopamine depletion, (produced by i.c.v. 6-hydroxydopamine administration after pargyline and desipramine pretreatment) attenuated the ability of desipramine to increase reinforcement rate. These results suggest that the sedative effect of desipramine could be mediated by its interaction with central norepinephrine neurons and that the reinforcement rate-increasing effect may involve central dopamine neurons.     

Effect of cyclobenzaprine on tricyclic antidepressant assays

OBJECTIVE: To evaluate cyclobenzaprine interference on tricyclic antidepressant assays. DATA SOURCES: Literature was identified through a MEDLINE search (1966-August 2004) using the search terms cyclobenzaprine, tricyclic antidepressant, toxicology, and assay. DATA SYNTHESIS: Cyclobenzaprine is structurally similar to tricyclic antidepressants and is often identified as a tricyclic antidepressant on toxicology assays. Older chromatographic assays demonstrate retention time differences of only seconds and nearly identical color stains between cyclobenzaprine and individual tricyclic antidepressants. In comparison, ultraviolet absorption ratios of 4.18 for amitriptyline and 1.85 for cyclobenzaprine are easily distinguished. Spectroscopy also consistently identifies cyclobenzaprine's unique mass-to-charge ratio peaks of 275 and 215 compared with those of amitriptyline. Available bioanalytic techniques are reviewed for their ability to correctly identify cyclobenzaprine and differentiate the drug from tricyclic antidepressants. CONCLUSIONS: When assays are positive for tricyclic antidepressants without a history of their use, an attempt should be made to identify confounders, such as cyclobenzaprine. Newer bioanalytic techniques, such as ultraviolet absorption and mass spectroscopy, accurately identify cyclobenzaprine in such instances.     

Tricyclic antidepressants as long-acting local anesthetics

Amitriptyline, nortriptyline, imipramine, doxepin, desipramine, protriptyline, trimipramine, and maprotiline are tricyclic antidepressants (TCAs) used orally in treating major depressive disorders. Recent studies showed that amitriptyline is more potent in blocking the sciatic nerve functions in vivo by local injection than bupivacaine, a long-acting local anesthetic. We therefore tested whether various TCAs could likewise act as local anesthetics in vivo after single injection via the rat sciatic notch. The duration of complete sciatic nerve blockade by TCAs and the time to reach full recovery were measured with neurobehavioral assays and compared with results from bupivacaine. Amitriptyline, doxepin, and imipramine at 5mM elicited a longer complete sciatic nerve blockade than did bupivacaine at 15.4mM (0.5%), whereas trimipramine and desipramine at 5mM produced a shorter blockade. In contrast, nortriptyline, protriptyline, and maprotiline failed to elicit complete sciatic nerve blockade. Thus, TCAs have very different efficacy as local anesthetics in vivo. The duration of rat sciatic nerve blockade in vivo by TCAs is not well correlated with the 50% inhibitory concentration (IC(50)) of TCAs in blocking human cardiac Nav1.5 Na(+) channels expressed in human embryonic kidney cells. With this in vitro expression system, TCAs appear more potent than bupivacaine as Na(+) channel blockers in Nav1.5 Na(+) channels. We suggest that the ability of TCAs to pass through various membrane barriers within peripheral nerve trunks is crucial to their local anesthetic efficacy in vivo. TCAs with a tertiary amine appear more effective in penetrating these membrane barriers than TCAs with a secondary amine.