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PubMed1987

Two tricyclic antidepressant poisonings: levels of amitriptyline, nortriptyline and desipramine in post-mortem biological samples.

Two deaths due to amitriptyline and desipramine overdoses are reported. The first case deals with a 20-year-old Caucasian male who was found dead at his residence. Toxicological analysis of the blood, urine, liver and kidney revealed the presence of amitriptyline (1.7 mg/l, 0.13 mg/l, 36.0 mg/kg and 98.0 mg/kg) and nortriptyline (0.66 mg/l, 0.74 mg/l, 12.0 mg/kg and 37.0 mg/kg). The gastric content contained only 220 mg of amitriptyline. The urine also contained norverapamil, which was consistent with previous verapamil therapy. The second case involved a 19-year-old Caucasian male who attempted suicide earlier and was on desipramine medication. The blood, urine, liver and gastric content disclosed the presence of desipramine in the concentrations of 14.2 mg/l, 33.7 mg/l, 112.5 mg/kg and 180 mg, respectively. The levels of these tricyclics analyzed by high pressure liquid chromatography were in agreement with the levels reported in the literature. Though with the amitriptyline poisoning no significant anatomic changes were noted, the desipramine-caused death was further supported by the multisystem vascular congestion and ischemic changes consistent with cardiopulmonary failure.

Adult↗
PubMed1986

Amitriptyline plasma protein binding: effect of plasma pH and relevance to clinical overdose.

Reversing ventricular ectopy with plasma alkalinization following acute tricyclic antidepressant overdose is a recognized mode of therapy. The mechanism responsible for this effect is unclear. Changes in plasma protein binding of free drug, effects of the sodium ion on the myocardium, and alterations of plasma concentrations of alpha-1-acid glycoprotein may all interact to alter toxicity of tricyclics in overdose. An in vitro investigation using equilibrium dialysis was designed to examine the effect of altering plasma pH on percentage of free amitriptyline at clinical overdose plasma concentrations. A 1973 report on this effect lacked adequate controls and was faulty in experimental protocol. The current investigation used plasma concentrations typically present in amitriptyline overdose, a sensitive gas liquid chromatographic assay to detect total and free drug, and adequate control of plasma pH. The results of two separate experiments demonstrated a significant decrease in percentage of free amitriptyline of 20% over a pH range of 7.0-7.4 (P less than 0.05) and 42% over a pH range of 7.4-7.8 (P less than 0.05). The rate of change in slope in both experiments was not significantly different (P less than 0.01) indicating similar effects of pH change on plasma protein binding of amitriptyline within the two groups.

Amitriptyline↗
PubMed2005

Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cortex, and the treatment of depression is one of its potential therapeutic applications. Three recent meta analyses strongly suggest its benefits in the treatment of depression. The present study investigates whether repetitive TMS (rTMS) accelerates the onset of action and increases the therapeutic effects of amitriptyline. METHODS: Forty-six outpatients meeting DSM-IV criteria for nonpsychotic depressive episode were randomly assigned to receive rTMS (n = 22) or sham repetitive TMS (sham) (n = 24) during 4 weeks over dorsolateral prefrontal cortex (DLPFC) in this double-blind controlled trial. All patients were concomitantly taking amitriptyline (mean dose 110 mg/d). The rTMS group received 20 sessions (5 sections per week) of 5 Hz rTMS (120% of motor threshold and 1250 pulses per session). Sham stimulation followed the same schedule, however, using a sham coil. The efficacy variables were the Hamilton Depression Rating Scale-17 items (HAM-D/17), the Montgomery-Asberg Depression Rating Scale (MADRS), a Visual Analogue Scale (VAS), and the Clinical Global Impression (CGI). Tolerability was assessed by clinical examination and a safety screening of TMS side effects. RESULTS: Repetitive TMS had a significantly faster response to amitriptyline. There was a significant decrease in HAM-D/17 scores, already after the first week of treatment (p < .001 compared with baseline and p < .001 compared with sham). The decrease in HAM-D/17 scores in the rTMS group was significantly superior compared with the sham group throughout the study (p < .001 at fourth week). CONCLUSIONS: Repetitive TMS at 5 Hz accelerated the onset of action and augmented the response to amitriptyline.

Adult↗
PubMed2004

Amitriptyline administration transforms tumor necrosis factor-alpha regulation of norepinephrine release in the brain.

The present study demonstrates that the mixed action antidepressant drug amitriptyline enhances norepinephrine (NE) release by transforming the nature of the response of neurons to both tumor necrosis factor-alpha (TNF) as well as to an alpha(2)-adrenergic agonist in an area of the central nervous system (CNS) rich in adrenergic neurons. Administration of the antidepressant drug amitriptyline for 1 day or 14 days to rats significantly increases TNF bioactivity in total homogenates of the locus coeruleus (LC) and the hippocampus as assessed by the WEHI-13VAR bioassay. Superfusion and electrical field stimulation of rat hippocampal brain slices were used to study the regulation of NE release. Exposure to TNF, as well as activation of the alpha(2)-adrenergic autoreceptor inhibits stimulation-evoked norepinephrine (NE) release from adrenergic neurons of the CNS from naïve rats. Superfusion of hippocampal slices isolated from rats chronically (14 days) administered amitriptyline demonstrates that TNF inhibition of NE release is transformed, such that TNF facilitates NE release, dependent upon alpha(2)-adrenergic activation. Furthermore, chronic administration of amitriptyline increases stimulation-evoked NE release and decreases alpha(2)-adrenergic autoreceptor inhibition of NE release, an effect not observed with acute drug administration. These data support the hypothesis that chronic antidepressant drug administration, through regulation of TNF expression, transforms alpha(2)-adrenergic receptors such that they function to facilitate NE release, suggesting a mechanism of action of antidepressant drugs.

Amitriptyline↗
PubMed2004

Effects of the suppression of acute herpetic pain by gabapentin and amitriptyline on the incidence of delayed postherpetic pain in mice.

The inoculation of mice with herpes simplex virus type-1 (HSV-1) causes herpes zoster-like skin lesions and pain-related responses (tactile allodynia and mechanical hyperalgesia) from day 5 after inoculation. Skin lesions completely heal by day 15 after inoculation, but about half of mice with acute herpetic pain show pain-related responses long after the lesions heal. Using this mouse model, we examined the effects of repeated administration of gabapentin and amitriptyline on the acute herpetic pain and the incidence of postherpetic pain. Gabapentin and amitriptyline were administered three times daily from day 5 to 11 after inoculation. Postherpetic pain-related responses were assessed on day 30 after inoculation. Gabapentin (10-100 mg/kg) produced the dose-dependent inhibition of acute herpetic pain-related responses. This medication produced marked reduction in the incidence of delayed postherpetic pain and the dose of 100 mg/kg produced the complete inhibition. Amitriptyline (10 mg/kg) did not affect the acute pain-related responses in the initial 3- and 2-day periods and then gradually inhibited them. This dosage produced a substantial but non-significant decrease in the incidence of postherpetic pain-related responses. Amitriptyline (1 and 3 mg/kg) was without effects on acute herpetic and postherpetic pain-related responses. The results strongly support the idea that the severity of the acute herpetic pain is a risk factor of postherpetic neuralgia. It may be worth testing the effects of gabapentin on acute herpetic pain and the incidence of postherpetic neuralgia in human subjects.

Acetates↗
PubMed2004

Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study.

OBJECTIVE: To evaluate whether amitriptyline is more effective than placebo in improving phantom limb pain or residual limb pain. DESIGN: Randomized controlled trial of amitriptyline for 6 weeks. SETTING: University hospital. PARTICIPANTS: Thirty-nine persons with amputation-related pain lasting more than 6 months. INTERVENTION: Six-week trial of amitriptyline (titrated up to 125 mg/d) or an active placebo (benztropine mesylate). MAIN OUTCOME MEASURES: Analyses were conducted to examine whether there was a medication group effect on the primary outcomes (average pain intensity) and secondary outcome measures (disability, satisfaction with life, handicap). RESULTS: No significant differences were found between the treatment groups in outcome variables when controlling for initial pain scores. CONCLUSIONS: Our findings do not support the use of amitriptyline in the treatment of postamputation pain.

Adult↗
PubMed2003

Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT(2) receptors.

The centrally acting muscle relaxant cyclobenzaprine decreases the amplitude of monosynaptic reflex potentials by inhibiting the facilitatory descending serotonergic influences in the spinal cord. Interestingly, the structure of cyclobenzaprine is much similar to those of amitriptyline and cyproheptadine. In the present study, we attempted to elucidate the relationship between 5-HT(2) receptor antagonistic and inhibitory effects of cyclobenzaprine, amitriptyline, cyproheptadine and ketanserin on the spinal reflexes. Cyclobenzaprine, amitriptyline, cyproheptadine, and ketanserin significantly inhibited facilitatory effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on flexor reflexes and mono- and polysynaptic spinal reflex potentials in spinalized rats. In intact rats, these drugs significantly reduced the mono- and polysynaptic reflex potentials. 5-HT depletion significantly prevented the depression of the spinal reflex potentials induced by these drugs. These results suggest that the inhibitory effects of cyclobenzaprine, amitriptyline, and cyproheptadine on mono- and polysynaptic reflex potentials are due to the inhibition of descending serotonergic systems through 5-HT(2) receptors in the spinal cord.

Amitriptyline↗
PubMed1997

Blockade of clomipramine and amitriptyline analgesia by an antisense oligonucleotide to mKv1.1, a mouse Shaker-like K+ channel.

The effect of an antisense oligonucleotide to the K+ channel coding mKv1.1 mRNA on antinociception induced by the tricyclic antidepressants, clomipramine (20-35 mg kg(-1) s.c.) and amitriptyline (10-25 mg kg(-1) s.c.), was investigated in the mouse hot-plate test. Antisense oligonucleotide (0.5-1.0-2.0-3.0 nmol per i.c.v. injection) produced a dose-dependent inhibition of clomipramine and amitriptyline antinociception 72 h after the last i.c.v. injection. The sensitivity to both analgesic drugs returned 7 days after antisense oligonucleotide injection, indicating the absence of irreversible damage or toxicity. Treatment with a degenerated oligonucleotide did not modify the clomipramine- and amitriptyline-induced antinociception in comparison with that in naive (unpretreated controls), vector and saline i.c.v.-injected mice. A quantitative reverse transcription-polymerase chain reaction (RT-PCR) study demonstrated a reduction in mRNA levels only in the antisense oligonucleotide treated group. Antisense oligonucleotide, degenerated oligonucleotide or vector pretreatment, in the range of doses used, did not produce any behavioural impairment as revealed by the mouse rotarod and hole-board tests. The present results indicate that modulation of the mKv1.1 K+ channel plays an important role in the central analgesia induced by the tricyclic antidepressants, clomipramine and amitriptyline.

Amitriptyline↗
PubMed1976

Determination of plasma amitriptyline by electron-capture gas chromatography after oxidation to anthraquinone.

A selective procedure is described for the determination of amitriptyline in plasma. The method involves extraction, separation of amitriptyline from its metabolites and subsequent oxidation by ceric sulphate in 5.4 M sulphuric acid. The oxidation product, anthraquinone, is determined by means of electron-capture gas chromatography. The metabolites were separated by a column chromatographic extraction technique. The choice of oxidation reagent, optimum conditions for the oxidation, and the electron-capture properties of anthraquinone are discussed. The method can be used to determine down to 2 ng of amitriptyline in a plasma sample; the relative standard deviation at the 50-ng level was 4.0% (n = 8). The levels of amitriptyline found in a series of plasma samples are compared with those obtained by gas chromatography with use of nitrogen-specific detection; the two techniques gave coincident results.

Amitriptyline↗
PubMedDate not supplied

The effect of guided imagery and amitriptyline on daily fibromyalgia pain: a prospective, randomized, controlled trial.

OBJECTIVE: The effectiveness of an attention distracting and an attention focusing guided imagery as well as the effect of amitriptyline on fibromyalgic pain was studied prospectively. METHODS: Fifty-five women with previously diagnosed fibromyalgia were monitored for daily pain (VAS) in a randomized, controlled clinical trial. One group received relaxation training and guided instruction in "pleasant imagery" (PI) in order to distract from the pain experience (n=17). Another group received relaxation training and attention imagery upon the "active workings of the internal pain control systems", "attention imagery" (AI) (n=21). The control group (CG) received treatment as usual (n=17). Patients were also randomly assigned to 50-mg amitriptyline/day or placebo. Some psychological and socio-demographic variables were also measured initially. The slopes of diary pain ratings over a 4-week period were used as the outcome measures. RESULTS: We found significant differences of the pain-slopes between the three psychological conditions (P=0.0001). The pleasant imagery (P<0.005), but not the attention imagery group's slope, declined significantly when compared with the control group (P>0.05). There was neither a difference between the amitriptyline and placebo slopes (main effects, P=0.98) nor a significant amitriptyline x psychological interaction (P=0.76). CONCLUSION: Pleasant imagery (PI) was an effective intervention in reducing fibromyalgic pain during the 28-day study period. Amitriptyline had no significant advantage over placebo during the study period.

Adult↗
PubMed1999

Effect of medications on taste: example of amitriptyline HCl.

Use of medications is a major factor that contributes to taste losses in the elderly. Epidemiological studies suggest that community-dwelling elderly over the age of 65 use an average of 2.9 to 3.7 medications, and this number increases significantly for elderly living in retirement and nursing homes. The tricyclic antidepressant amitriptyline HCl is used by at least half a million people aged 65 years or more. In human studies performed here, amitriptyline HCl was found to have a bitter, unpleasant taste of its own. In addition, it blocked responses to other taste stimuli in both humans and gerbils. This blockage in humans was greater when amitriptyline HCl was applied continuously to the tongue than when it was applied intermittently. Continuous application of the drug affected all of the taste qualities to varying degrees, while intermittent application led to taste decrements only for salts. Electrophysiological studies in gerbils also revealed taste decrements after a short adaptation to amitriptyline HCl.

Adaptation, Physiological↗
PubMedDate not supplied

A double-blind, randomized, fixed-dose trial of fluoxetine vs. amitriptyline in the treatment of major depression complicating Alzheimer's disease.

The objective of this study was to determine the relative efficacy and safety of fluoxetine and amitriptyline in the treatment of major depression complicating Alzheimer's disease (AD). The sample included 37 patients with AD and major depression. The study design was a double-blind, fixed-dose, randomized clinical trial with 45 days of follow-up. The outcome measures were the Hamilton Depression Rating Scale (Ham-D), the Mini-Mental State Exam (MMSE), and the number of dropouts from each arm of the study. Efficacy was similar for fluoxetine and amitriptyline. At Day 45, there was a mean 9.4-point reduction in Ham-D scores (t[df,62] = 9.68, P < 0.0001) and a 2.4-point mean increase in MMSE scores as compared to baseline (t[df,2] = 2.69, P = 0.009). Eleven (58%) of the amitriptyline-treated patients dropped out, compared with 4 (22%) of the fluoxetine-treated patients (chi 2[df,2] = 8.9, P = 0.017). The authors conclude that antidepressant treatment for major depression complicating AD is effective. While fluoxetine and amitriptyline are equally effective, fluoxetine is better tolerated.

Aged↗
PubMed1999

Attenuation by nimodipine of amitriptyline-induced avoidance impairment in mice.

The effects of the dihydropyridine calcium channel blocker nimodipine on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box training and in previously trained mice of the DBA/2 strain. Nimodipine (0, 0.5, 1, 2.5, or 5 mg/kg) had no effect alone, but attenuated the avoidance impairment induced by 5 mg/kg amitriptyline on avoidance acquisition, as well as on a previously learned avoidance response. The avoidance improving action of the calcium channel blocker was less evident in mice receiving a larger dose (7.5 mg/kg) of the antidepressant drug. The effect of nimodipine did not appear to be specifically related to the avoidance impairment induced by amitriptyline, because the calcium antagonist also attenuated the avoidance impairing action of the neuroleptic chlorpromazine. The avoidance impairment induced by amitriptyline and chlorpromazine, and the related ameliorating action of nimodipine, seem imputable to drug effects on the performance of the avoidance response, rather than to interferences with learning processes. The results suggest that, in the case of concomitant administration, nimodipine could alleviate adverse side effects of tricyclic antidepressant, i.e., psychomotor disturbances.

Amitriptyline↗
PubMed1988

Blood disorders and suicide in patients taking mianserin or amitriptyline.

26,781 patients who had been prescribed mianserin and 42,082 prescribed amitriptyline were followed up by means of a questionnaire addressed to their general practitioners. No patient had aplastic anaemia, agranulocytosis, or leucopenia severe enough to endanger life, and in only 2 patients in each group was a causal association likely. If either drug dose cause leucopenia, the incidence is likely to be in the range of 1 in 10,000 to 1 in 100,000 patients. Among patients who were reported to have attempted suicide, 56 of 246 survivors of amitriptyline overdoses required intensive care, compared with none of 92 patients who overdosed with mianserin. 4 patients who overdosed with amitriptyline alone died, compared with none of the patients who overdosed with mianserin alone. Both drugs are associated with a low risk of blood disorders, but mianserin is appreciably safer than amitriptyline because of its low toxicity in overdosage.

Amitriptyline↗
PubMed1986

Experimental amitriptyline intoxication: treatment of cardiac toxicity with sodium bicarbonate.

Overdose with amitriptyline and other tricyclic antidepressants can result in ventricular conduction abnormalities as well as severe ventricular arrhythmias. The arrhythmogenic effects of these compounds may be attributed to their direct local anesthetic actions in blocking sodium channels in cardiac membranes. Thus tricyclic-induced ventricular arrhythmias usually do not respond well to therapy with standard Class I antiarrhythmic drugs that also have the same direct local anesthetic action and may potentiate the adverse effects of tricyclic antidepressants. Cardiac toxicity was produced in dogs by the administration of amitriptyline, both orally and IV. At serum concentrations less than 2,000 ng/mL, sinus tachycardia occurred with widened QRS complexes. At higher concentrations, QRS duration became more markedly prolonged and was followed by ventricular tachyarrhythmias. Occurrence of ventricular tachyarrhythmias was associated with QRS durations of more than 0.11 second. Sodium bicarbonate (18 to 36 mEq) administered IV over either 30 seconds or two minutes rapidly converted ventricular tachycardia to normal sinus rhythm. Conversion was associated with abbreviation of the QRS complex and was accompanied by a rise in both systolic and diastolic pressures. The duration of sodium bicarbonate effect paralleled the duration of the changes in arterial pH and plasma bicarbonate concentrations. In vitro studies in cardiac Purkinje fibers suggested that reversal of amitriptyline-induced cardiac membrane effects by sodium bicarbonate may be attributed not only to alkalinization but also to increased in extracellular sodium concentration, diminishing the local anesthetic action of amitriptyline and resulting in less sodium channel block.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMed1999

Chronic treatment with the antidepressant amitriptyline decreases CRF-R1 receptor mRNA levels in the rat amygdala.

Using semi-quantitative in situ hybridization, corticotropin-releasing factor (CRF) and CRF receptor 1 (CRF-R1) mRNA levels were determined in the rat hypothalamus and amygdala after short-term (10 days) and chronic (4 weeks) treatment with the antidepressant amitriptyline. We found that chronic treatment with amitriptyline produced a significant decrease in CRF mRNA (to 33% of control) in the hypothalamic paraventricular nucleus (PVN). Short-term or chronic amitriptyline treatment had no effect on CRF-R1 mRNA levels in the PVN. However, after chronic treatment, there was a significant decrease of CRF-R1 mRNA levels in the lateral + basolateral (to 60% of control), and in the medial (to 70% of control) amygdala nuclei. These results suggest that the tricyclic antidepressant amitriptyline may exert part of its effects through modulation of hypothalamic CRF and of CRF-R1 gene expression in the amygdala.

Amitriptyline↗
PubMed2000

The effect of repeated amitriptyline and desipramine administration on cytokine release in C57BL/6 mice.

This study examines the effects of repeated amitriptyline and desipramine administration (10 mg/kg, IP) on the immunoreactivity of saline-injected C57BL/6 mice, as evaluated by the ability of splenocytes to reduce a tetrazolium salt to formazan (MTT test), to proliferate, and to produce cytokines, such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-10 and interferon gamma (IFN-gamma). Desipramine and amitriptyline administered for one or two weeks enhance the biochemical (estimated by MTT test) and proliferative activities of splenocytes. One and two weeks administration of desipramine significantly reduces the secretion of IL-4, an anti-inflammatory cytokine. Amitriptyline administration for four weeks stimulates the proliferative activity of splenocytes and enhances IL-2 bioactivity, whereas four weeks desipramine aministration does not change these parameters in comparison to saline treated control mice. Prolonged desipramine administration (seven and 28 days) significantly increased the bioactivity of IL-1. Four weeks of prolonged administration of amitriptyline and desipramine induces a significant increase in the secretion of IL-10, a cytokine with immunosuppressive and anti-inflammatory activities. The results show that the immunoregulatory effects of tricyclic antidepressants in C57BL/6 mice depend on the drugs used and on the duration of administration.

Amitriptyline↗
PubMed1986

Development of a rapid extraction and high-performance liquid chromatographic separation for amitriptyline and six biological metabolites.

The development of a rapid high-performance liquid chromatographic method for the determination of amitriptyline, amitriptyline-N-oxide, 10-hydroxyamitriptyline, 10-hydroxynortriptyline (E and Z isomers), nortriptyline and desmethylnortriptyline in plasma and liver tissue is described. A liquid--liquid extraction with hexane--butanol and back-extraction into phosphoric acid provides efficient extraction of amitriptyline-N-oxide along with amitriptyline and the other metabolites. A Supelcosil C8 reversed-phase column with 5-micron packing and a methanol--sodium phosphate buffer--amine modifier mobile phase was used. The combination of mobile phase pH and amine modifier concentration for the best separation within a reasonable analysis time for all seven solutes plus an internal standard was determined using a factorial design coupled with a multi-factor window diagram technique. Ultraviolet detection at 214 nm provided limits of detection of approximately 1 ng/ml.

Amitriptyline↗