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PubMed1988

Effects of a controlled-release formulation of trazodone on psychomotor and autonomic functions in healthy volunteers: comparison with trazodone (conventional formulation), amitriptyline and placebo.

Eight healthy male volunteers participated in four experimental sessions. In each session the subjects ingested a single dose of one of the following drugs: trazodone (controlled-release formulation), trazodone (conventional formulation), amitriptyline and placebo. Both trazodone and amitriptyline reduced subjectively rated alertness and increased digit cancellation time, and amitriptyline also reduced critical flicker fusion frequency. Both antidepressants reduced salivation, trazodone also caused miosis. There were no consistent differences between the effects of the two formulations of trazodone. The results of the psychological tests are indicative of the sedative properties of the antidepressants. It is likely that the reduction in salivation and pupil diameter by trazodone reflect alpha-adrenoceptor blockade, whereas the reduction in salivation by amitriptyline may be due to both cholinoceptor and alpha-adrenoceptor blockade.

Administration, Oral↗
PubMed1990

The activity of amitriptyline as a differential inhibitor of amine secretion from rat peritoneal mast cells: the contribution of amine uptake.

Amitriptyline, at a concentration of 10(-4) M, significantly inhibited the release of histamine from purified peritoneal rat mast cells in response to compound 48/80, but was without effect upon the output of 5-HT. The reduction was not extensive, and concentrations of the drug above or below 10(-4) M were without effect. Amitriptyline (10(-8)-10(-4) M) inhibited uptake of exogenous 5-HT in a concentration dependent manner. Paradoxically, however, histamine uptake was significantly increased in the presence of this drug, but only at a concentration of 10(-4) M. This effect was observed at 4 degrees C for both amines. Concentrations of amitriptyline in excess of 10(-4) M caused lysis of the mast cells. These results suggest that the observed selective inhibitory effect of amitriptyline upon histamine output may be a function of altered amine uptake rather than differential inhibition and 5-HT secretion.

Amitriptyline↗
PubMed1982

Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man.

We have measured the metabolites (demethylated and hydroxylated) of amitriptyline in a group of seven normal volunteers. They were phenotyped as extensive or poor metabolizers using debrisoquine and bufuralol. The results demonstrate that the oxidative metabolism (aliphatic hydroxylation) of amitriptyline is under the same genetic control as that of debrisoquine and bufuralol. However, phenotypic polymorphism cannot be used to predict amitriptyline blood concentration after a single oral dose, since the principal metabolic pathway of amitriptyline is demethylation and not aliphatic hydroxylation.

Adult↗
PubMed1996

Reflexes of the cutaneous microcirculation in amitriptyline and in fluoxetine treated patients.

Cutaneous microcirculation was investigated in 30 major depressed inpatients receiving either 150 mg amitriptyline (n = 15) or 30 mg fluoxetine (n = 15) as monotherapy, and in 15 normal control subjects matched for age and sex. The laser Doppler flux (LDF) was recorded while resting and under the condition of a sudden deep breath ("inspiratory gasp response"). In normal subjects this autonomic function test caused a marked decrement of LDF signal, which rapidly returned to the baseline value. In both groups of drug treated patients the decrements of LDF signal after a sudden deep breath did not differ from those found in the normal control subjects. However, in the amitriptyline-treated patients the return of LDF-signal to the baseline values was significantly delayed (P = 0.0007), while patients treated with fluoxetine showed the same behaviour as normal subjects. With a discriminant analysis using the results of the inspiratory gasp responses, 100% of the amitriptyline treated patients were correctly classified. Since both groups of depressed patients revealed comparable depression scores, the differences found are probably due to the side effects of amitriptyline. Possible clinical implications of these findings are discussed.

Adult↗
PubMed1989

A comparison of alprazolam with amitriptyline in the treatment of patients with neurotic or reactive depression. A report of a randomised, double blind study by a General Practitioner Working Party.

104 patients suffering from neurotic or reactive depression were treated with either alprazolam or amitriptyline in randomised, double-blind fashion. Seventeen patients were either lost to follow-up or withdrawn before week 2 (13 due to side effects and 1 because she was feeling better). A further 7 patients did not comply with the protocol, giving a total of 24 patients whose data were not considered suitable for inclusion in the analysis of therapeutic assessments. Evaluation of the 80 patients (40 in each group) who completed at least 2 weeks of the 4-week study demonstrate that both treatments produced a statistically significant response rate. There was a more rapid effect in those patients who received amitriptyline, but there was no significant difference in response between the treatment groups after 4 weeks treatment. Analysis of safety and side effect data on 101 patients (50 treated with alprazolam and 51 with amitriptyline) shows no statistically significant difference in the overall number of side effects experienced in each group, although 11 of those patients who received amitriptyline withdrew because of adverse reactions before completing the study compared to 6 in the alprazolam group. These results suggest that alprazolam may be a useful treatment for patients with neurotic or reactive depression not requiring hospitalisation.

Adult↗
PubMed2001

Amitriptyline and clomipramine activate Gi-protein signaling pathway in the induction of analgesia.

The post-receptorial mechanisms of the analgesic action of amitriptyline and clomipramine, two tricyclic antidepressants, were investigated in the mouse hot plate test by using an antisense strategy. Mice were injected i.c.v. with antisense oligonucleotides (aODN), complementary to the sequence of the mRNA sequence of the alpha-subunit of Gi1, Gi2 and Gi3-proteins, 18-24 h prior to the hot plate test. Treatment with aODN against Gi1alpha, Gi2alpha and Gi3alpha dose-dependently reduced the analgesia induced by both amitriptyline (15 mg/kg s.c.) and clomipramine (25 mg/kg s.c.). This antagonistic effect disappeared 7 days after the end of the i.c.v. treatment, indicating the absence of irreversible damage or toxicity. Treatment with aODN against Gi1alpha, Gi2alpha and Gi3alpha, at the active doses, did not modify the animals' pain threshold, indicating the absence of any hyperalgesic effect. Amitriptyline, clomipramine and the aODN employed, at the maximal effective doses, did not produce any alteration of motor coordination of the mice, as revealed by rotarod experiments, and spontaneous motility, as revealed by the Animex apparatus. These results indicate that amitriptyline and clomipramine induce their analgesic effect by activating all three subtypes of the Gi-proteins.

Amitriptyline↗
PubMed2003

Gender difference in the prevention of hyperanxiety in adult prenatally stressed rats by chronic treatment with amitriptyline.

OBJECTIVE: The study determined whether oral administration of amitriptyline for 6 weeks from before puberty to prenatally stressed (PS) male and female rats could prevent hyperanxiety in adulthood. METHODS: Sprague-Dawley (12) rat dams were stressed by restraint in cylinders thrice daily for 45 min during the last week of pregnancy. Their offspring and those from unstressed dams (12) were given amitriptyline (4.5 mg/kg per day) in the drinking water between 4 and 10 weeks of age. Behaviour was assessed in the elevated plus maze (EPM) in week 10 in group 1 while still receiving the drug; in group 2, 2 weeks after stopping the drug, and in group 3, as in group 2, but after prior exposure to an open field (OF). RESULTS: When tested while receiving the drug, no clear anxiolytic effect was seen in PS rats, and anxiety was actually increased in control rats, as indicated by the greater amount of time in closed arms of the EPM. Significant anxiolytic effects of amitriptyline (increase in time in open arms of EPM) were seen 2 weeks after stopping the drug in PS females. It could only be demonstrated in PS males after their anxiety in the EPM had been increased as a result of prior exposure to the open field. CONCLUSIONS: Chronic early treatment with amitriptyline can prevent the development of hyperanxiety in PS rats in adulthood. This effect is only detectable after cessation of drug treatment. The anxiolytic effect is more readily detected in females.

Amitriptyline↗
PubMed2000

Acute administration of amitriptyline and mianserin increases dopamine release in the rat nucleus accumbens: possible involvement of serotonin2C receptors.

Previous studies of conventional tricyclic and non-tricyclic antidepressants have suggested that a number of these drugs display considerable pharmacological activity at 5-HT2C receptors in the brain. There is evidence that 5-HT2C receptors are involved in the control of the activity of the central dopaminergic system. Therefore, the effects of amitriptyline (5 mg/kg and 10 mg/kg i.p.) and of the atypical antidepressant mianserin (2.5 mg/kg and 5 mg/kg i.p.) were studied on the extracellular concentration of dopamine (DA) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. Amitriptyline and mianserin significantly increased DA release (+31.1 +/- 7.9% and +33.6 +/- 4.3%, respectively) at the higher doses. In addition, lower doses of mianserin (2.5 mg/kg i.p.) and amitriptyline (5 mg/kg i.p.) blocked the inhibitory action of RO 60-0175 (1 mg/kg i.p.), a selective 5-HT2C receptor agonist, on DA release. The effect of RO 60-0175 (1 mg/kg i.p.) was completely blocked by SB 242084 (2.5 mg/kg i.p.), a selective and powerful 5-HT2C receptor antagonist. Taken together, these data indicate that amitriptyline and mianserin increase DA release in the nucleus accumbens by blocking 5-HT2C receptors.

Adrenergic Uptake Inhibitors↗
PubMed2000

Comparison of the antidepressants reboxetine, fluvoxamine and amitriptyline upon spontaneous pupillary fluctuations in healthy human volunteers.

RATIONALE: Spontaneous fluctuations in the size of the pupil in darkness are a recognised index of "sleepiness". OBJECTIVE: To evaluate the effects of single oral doses of three antidepressants: reboxetine (4 mg), a selective noradrenaline reuptake inhibitor, fluvoxamine (100 mg), a selective serotonin reuptake inhibitor, and amitriptyline (100 mg), a tricyclic antidepressant of known sedative property, upon spontaneous pupillary fluctuations in healthy male volunteers (n=16). METHODS: Using the recently developed pupillographic sleepiness test (PST), resting pupil diameter was recorded and two measures of pupillary fluctuations were obtained: total power obtained from a fast Fourier transform and spectral analysis, and the pupillary unrest index (PUI), a cumulative measure of changes in pupil size. Subjects also rated themselves on a battery of visual analogue scales for "alertness", "anxiety" and "contentedness". RESULTS: Resting pupil diameter was enhanced by reboxetine, but remained unaffected by the other two antidepressants. Amitriptyline, consistent with its sedative property, increased the total power of pupillary fluctuations and showed a tendency to increase PUI. These pupillary effects of amitriptyline were paralleled by reduced scores on the "alertness", "contentedness" and "anxiety" self ratings. Neither fluvoxamine nor reboxetine affected pupillary fatigue waves or subjective ratings of "alertness". Reboxetine caused a small reduction in subjectively rated "anxiety". CONCLUSIONS: The mydriatic effect of reboxetine may be due to noradrenaline reuptake blockade in the iris and/or in the central nervous system. The enhancement of pupillary fatigue waves by the sedative antidepressant amitriptyline, but not by the non-sedative antidepressants fluvoxamine and reboxetine, indicates that the PST is a suitable quantitative objective test for the detection of drug-induced changes in the level of arousal.

Adult↗
PubMed2005

Effects of amitriptyline and intra-oral device appliance on clinical and laser-evoked potentials features in chronic tension-type headache.

In the present study, we examined clinical and laser-evoked potentials (LEP) features in two groups of chronic tension-type headache (CTTH) patients treated with two different approaches: intra-oral appliance of prosthesis, aiming to reduce muscular tenderness, and 10 mg daily amitriptyline. Eighteen patients suffering from CTTH (IHS, 2004) participated in the study. We performed a basal evaluation of clinical features and LEPs in all patients (T0) vs. 12 age- and sex-matched controls; successively, patients were randomly assigned to a two-month treatment by amitriptyline or intra-oral device appliance. The later LEPs, especially the P2 component, were significantly increased in amplitude in the CTTH group. Both the intra-oral prosthesis and amitriptyline significantly reduced headache frequency. Total Tenderness Score was significantly reduced in the group treated by the prosthesis. The amplitude of P2 response elicited by stimulation of pericranial zones showed a reduction after amitriptyline treatment. The results of this study may confirm that pericranial tenderness is primarily a phenomenon initiating a self-perpetuating circuit, favoured by central sensitisation at the level of the cortical nociceptive areas devoted to the attentive and emotive compounds of pain. Both the interventions at the peripheral and central levels may interrupt this reverberating circuit, improving the outcome of headache.

Administration, Oral↗
PubMed1987

Amitriptyline supersensitizes a central cholinergic mechanism.

The withdrawal of tricyclic antidepressants produces symptoms characteristic of cholinergic overdrive states. The authors previously proposed that these states are the consequence of the pharmacological induction of cholinergic system supersensitivity by chronic treatment with antidepressants, combined with a reduction in the plasma level of a competitive muscarinic receptor antagonist when the dose of a tricyclic is decreased. This is consistent with the facts that all tricyclic antidepressants are antimuscarinic agents and that classical antimuscarinic compounds, such as scopolamine, up-regulate and supersensitize muscarinic cholinergic systems. The authors present evidence that chronic treatment with amitriptyline supersensitizes a central cholinergic mechanism. Core body temperature is subject to influence by a central (hypothalamic) muscarinic mechanism, which is rendered supersensitive to cholinomimetic challenge by treatment with scopolamine. The authors telemetrically measured the hypothermic responses of adult male rats to various doses of the muscarinic agonist oxotremorine before and in the course of chronic treatment with amitriptyline. Treatment with amitriptyline resulted in marked enhancement of the cholinomimetic-induced hypothermia. Methylscopolamine nitrate, a peripherally active antimuscarinic agent, did not block the hypothermic response to oxotremorine, whereas scopolamine, a centrally active antimuscarinic compound, did. This study indicates that the chronic administration of amitriptyline can produce supersensitivity of a central muscarinic cholinergic mechanism. Clinical and theoretical implications of this finding are discussed.

Amitriptyline↗
PubMedDate not supplied

Clovoxamine in the treatment of depressed outpatients: a double-blind, parallel-group comparison against amitriptyline and placebo.

In a double-blind, random-assignment, parallel-group trial, outpatients with major depression received either the new antidepressant clovoxamine, the tricyclic amitriptyline, or placebo for 6 weeks. By an "improvement" criterion of 50% or greater improvement in the Hamilton Depression Scale (HAM-D) total score, 88% of clovoxamine completers improved versus 75% with amitriptyline and 43% with placebo; however, due to small numbers, the differences failed to reach statistical significance. Diminished salivary flow was significantly greater with amitriptyline, as were complaints of dry mouth, somnolence, dizziness, and headache. Nausea and vomiting were more common in the clovoxamine-treated group. With amitriptyline, but not with clovoxamine, memory performance declined over a month. However, psychomotor performance was not affected.

Adult↗
PubMed1983

Bupropion, d-amphetamine, and amitriptyline-induced conditioned taste aversion in rats: dose effects.

Nine groups of rats (n = 6 per group) were adapted to a daily one-half hour period of water availability. When intake had stabilized, they were allowed access to a 0.1% (w/v) solution of saccharin, and immediately afterward were given IP injections of isotonic saline; bupropion HCl (10.0, 20.0, or 40.0 mg/kg); d-amphetamine-sulfate (0.5, 1.0, 2.0 mg/kg); or amitriptyline HCl (5.0, 10.0, or 20.0 mg/kg) in a volume of 1 ml. The lowest dose of each compound as chosen to be equipotent in screening tests used to identify potential antidepressants. Following 2 days of access to water alone, all groups were given a choice between water and saccharin for 3 consecutive days. All compounds induced taste aversions in a dose-related manner, but amitriptyline induced greater and longer-lasting aversions than either bupropion or d-amphetamine which were equipotent over the dose range studied. As such, this is the first demonstration that bupropion and amitriptyline, two clinically effective antidepressants, can induce taste aversions and replicates as well the common finding that d-amphetamine has substantial taste aversion-inducing properties. The ability of these compounds to induce taste aversions could be mediated through their effects on central catecholaminergic processes although amitriptyline has significant peripheral anticholinergic effects.

Amitriptyline↗
PubMed1985

Effects of chronic lithium, amitriptyline and mianserin on glucoregulation, corticosterone and energy balance in the rat.

Major negative side-effects reported for mood-stabilizing and antidepressant drugs in humans are excess weight gain and carbohydrate craving. The aim of the present study was to establish whether the rat could usefully be employed in investigation of these phenomena. Three experiments investigated the effects of chronic lithium (40 mg/kg LiCl), amitriptyline (2.5 mg/kg), mianserin (2.5 mg/kg) and saline administration (15-20 days, one subcutaneous injection/day) on body weight, food intake and fluid intake. Water and food cubes were provided in all experiments. Additionally available, as separate fluid sources, in Experiment 2 were 24% sucrose and 0.6% saccharin and in Experiment 3, 0.6% saccharin. Blood was collected for plasma glucose and insulin determinations 20-24 hours after the final injections. Lithium administration resulted in a marked increase in weight gain but only if both sucrose and saccharin were available (Experiment 2). Saccharin intake was increased with lithium treatment as was total caloric intake with sucrose available. Amitriptyline induced a sweetness craving; however, weight gain was somewhat depressed with just cubes available (Experiment 1) and only normalised by the additional availability of sucrose and saccharin (Experiment 2). With amitriptyline, total caloric intake was never different from controls. Weight gain was slightly suppressed and caloric intake slightly elevated by mianserin but importantly the two effects combined for a decrease in metabolic efficiency which was particularly exaggerated under the condition of carbohydrate availability (Experiment 2). Lithium and amitriptyline both produced hyperinsulinemia with normoglycemia whether or not the rate of weight gain was changed and whether or not intake was increased. Corticosterone levels were elevated by all drug treatments in Experiment 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMed1989

Central post-stroke pain--a controlled trial of amitriptyline and carbamazepine.

A double-blind, 3-phase, cross-over, placebo-controlled trial of the pain-relieving effect of amitriptyline and carbamazepine was carried out in 15 patients with central post-stroke pain (CPSP) but without signs of depression. Treatment was given, in randomized order, for periods of 4 weeks, separated by 1 week wash-out. The final doses were 75 and 800 mg/day, respectively, for amitriptyline and carbamazepine. The treatment effects were assessed by daily ratings of pain intensity on a 10-step verbal scale and at the end of each treatment period by a global rating of the analgesic effect on a 5-step verbal scale. For the assessment of depression the Comprehensive Psychopathological Rating Scale (CPRS) was used. Amitriptyline produced a statistically significant reduction of pain when compared to placebo. According to the global rating, 10 of the 15 patients were responders to this drug. The effect could already be noticed during the second treatment week and it appeared to be correlated to the plasma concentration, since the median total ami- and nortriptyline concentrations were 497 and 247 nmol/l, respectively, for responders and non-responders. The early onset, together with the fact that the patients were not depressed, nor did they obtain reduced scores on ratings of depressive symptoms and signs, provides strong support for the conclusion that the pain relief was not caused by an antidepressive effect. Five of the 14 patients treated with carbamazepine reported some pain relief, but the effect did not reach statistical significance when compared to placebo. No correlation was found between effect and plasma concentration. In general, the patients tolerated the planned final dose of amitriptyline well. No final dose reduction was necessary. Carbamazepine caused more side effects and the final dose had to be reduced in 4 patients. However, only 1 patient had to be taken off medication, on day 25, due to drug interaction.

Aged↗
PubMed1990

A controlled study of psychotherapy and amitriptyline used individually and in combination in the treatment of chronic intractable, 'psychogenic' pain.

This paper reports an investigation into the efficacy of flexible dosage amitriptyline (AMI) and brief psychotherapy individually and together in the treatment of chronic 'psychogenic' pain. The patients included in the study were drawn from those referred to a pain clinic and were randomly assigned to 1 of 4 groups: (1) AMI + psychotherapy (N = 26), twelve 45 min weekly sessions; (2) AMI + support (N = 26), six 15 min fortnightly sessions; (3) placebo tablet + psychotherapy (N = 26), twelve 45 min weekly sessions; (4) placebo tablet + support (N = 24), six 15 min fortnightly sessions. Outcome was assessed on categorical and continuous variables administered immediately post treatment. The results indicate that amitriptyline is effective in increasing the patients' activity level and the reduction of pain intensity. Psychotherapy increases pain intensity, but tends to improve productivity. There also appears to be a role for the use of amitriptyline in combination with psychotherapy, but their interaction is a complex one. Baseline factors associated with withdrawal from treatment are reported, as well as those associated with a positive response to amitriptyline and psychotherapy respectively. Our findings offer tentative guidelines for choosing between therapies and also underline the importance of assessing more than one outcome variable in evaluating outcome. The importance of carrying treatments out in the context of a multidisciplinary pain clinic is emphasised.

Adult↗
PubMed1994

Chronic tension-type headache: amitriptyline reduces clinical headache-duration and experimental pain sensitivity but does not alter pericranial muscle activity readings.

In a double-blind, placebo-controlled trial, the effect of 75 mg of a slow-release formulation of amitriptyline on the clinical severity of chronic tension-type headache and on headache-associated neurophysiological parameters (EMG activity, exteroceptive suppression of temporal muscle activity, contingent negative variation (CNV) and experimental pain sensitivity) was investigated. All of the patients treated had a history of headaches of many years' standing and many of them had failed attempts at treatment. In the amitriptyline group, a significant reduction in daily headache duration was already found in the 3rd week of treatment, while in the placebo group no significant changes in headache duration were to be seen. In week 6 the amitriptyline group had a significantly shorter daily duration of headache than did the placebo group. Treatment did not result in any significant effects on EMG recordings of pericranial muscle activity either during relaxation or contraction, on exteroceptive suppression of the temporal muscle and on CNV. The sensitivity to suprathreshold experimental pain, however, was significantly reduced. The data show a statistically relevant reduction of daily headache duration. However, they also show that amitriptyline can only partly alleviate chronic headaches but cannot cure them.

Adult↗
PubMed1992

High-performance liquid chromatographic determination of amitriptyline and its main metabolites using a silica column with reversed-phase eluent. Application in mice.

A method was developed for the assay of amitriptyline, amitriptyline N-oxide, nortriptyline, desmethylnortriptyline and E (trans) and Z (cis) isomers of 10-hydroxyamitriptyline and of 10-hydroxynortriptyline in plasma and brain of animals, using high-performance liquid chromatography with ultraviolet detection (254 nm). Single extraction was performed at pH 10.5 from 0.25 ml of plasma or 1 ml of brain mixture. Chromatographic separations were achieved with a silica column and an aqueous methanol mobile phase containing ammonia. This procedure offers high sensitivity (8-10 ng/ml), high linearity (r > 0.99) and acceptable precision (coefficient of variation < or = 13.3%). The method was used to determine levels of amitriptyline and its major metabolites in mice 30 min after a single intraperitoneal administration of amitriptyline (20 mg/kg).

Amitriptyline↗