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PubMed2003

Effects of antidepressants on function and viability of human neutrophils.

BACKGROUND: Antidepressants are frequently used in chronic pain therapy and are under investigation as long-acting local anesthetics. Because of the structural similarities between antidepressants and local anesthetics, the authors hypothesized that these compounds act similarly, and they investigated the effects of nortriptyline, amitriptyline, imipramine, and fluoxetine on priming and activation of human polymorphonuclear neutrophils (hPMNs). METHODS: Effects of 30-, 120-, and 240-min preincubation with nortriptyline (10(-7)-10(-4) M), amitriptyline (10(-6)-10(-3) M), imipramine (10(-6)-10(-3) M), or fluoxetine (10(-7)-10(-4) M) on O(2)- generation of platelet activating factor-primed (10-6 M) and/or formyl-methionyl-leucyl-phenylalanine-activated (10(-6) M) isolated hPMNs were determined. All data are reported as mean +/- SD (statistics: t test, P < 0.05). RESULTS: Brief incubation in low concentrations of nortriptyline, amitriptyline, or fluoxetine (all at 10(-5) M) did inhibit priming but not activation of hPMNs. Imipramine (10(-5) M) affected neither priming nor activation. Prolonged incubation in lower concentrations of all antidepressants influenced neither priming nor activation. However, at higher concentrations, all four compounds exerted cytotoxic effects: virtually all hPMNs were killed by amitriptyline and imipramine (both at 10(-3) M) or nortriptyline and fluoxetine (both at 10(-4) M). CONCLUSION: Antidepressants, in low concentrations, inhibited priming but not activation of hPMNs. However, at concentrations similar to those attained after local injection, and in marked contrast to local anesthetics, antidepressants are profoundly toxic to hPMNs.

Antidepressive Agents↗

PubMed1975

Tricyclic antidepressant agents. I. Comparison of the inhibition of the uptake of 3-H-noradrenaline and 14-C-5-hydroxytryptamine in slices and crude synaptosome preparations of the midbrain-hypothalamus region of the rat brain.

The simultaneous uptake of 3-H-l-noradrenaline (NA) and 14-C-5-hydroxytryptamine (5-HT) in slices from the midbrain-hypothalamus region of the rat brain was compared with the corresponding uptake in crude synaptosome preparations of the same brain region. In both preparations the uptake of the two amines was selective at the concentration used (1 times 10- minus 7 M or lower). The KM values for the amines (NA: 2 times 10- minus 7 M in synaptosomes and 5 times 10- minus 7 M in slices; 5-HT: 8 times 10- minus 8 M in synaptosomes and 6 times 10- minus 7 M in slices) and the inhibitory concentrations (IC50) of the antidepressant agents were lower in the synaptosome experiments than in the slices experiments. Moreover the order of the inhibitory activities differed between the two preparations. In the slices experiments the NA uptake was inhibited most markedly by desipramine followed by imipramine greater than chlorimipramine = nortriptyline greater than or equal to amitriptyline greater than or equal to chlordesipramine whereas in the synaptosome experiments the order was desipramine greater than nortriptyline greater than or equal to chlordesipramine greater than or equal to imipramine greater than amitriptyline greater than or equal to chlorimipramine. For the 5-HT uptake in slices the order of activity was: chlorimipramine greater than imipramine greater than or equal to amitriptyline greater than or equal to chlordesipramine = desipramine greater than or equal to nortriptyline whereas in the synaptosome preparations the order was: chlorimipramine greater than imipramine greater than or equal to amitriptyline greater than or equal to chlordesipramine greater than nortriptyline = desipramine. The role of protein binding and diffusion barriers in the causation of the difference in the results obtained with the two preparations is discussed.

Amitriptyline↗

PubMed1993

Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study.

OBJECTIVE: This study was undertaken to test the reliability and validity of the Pathological Laughter and Crying Scale and the effectiveness of nortriptyline treatment for patients with emotional lability following stroke. METHOD: Eighty-two patients with ischemic brain injury-54 who had been hospitalized with acute stroke and 28 others who requested treatment for pathological laughing and crying--were given standardized psychiatric and neurological assessments and then administered the Pathological Laughter and Crying Scale. The 54 acute stroke patients were used to evaluate the Pathological Laughter and Crying Scale, and the 28 patients with pathological emotional display were randomly assigned to nortriptyline treatment or placebo in a 6-week double-blind trial to assess the efficacy of a tricyclic antidepressant in treatment of this disorder. RESULTS: The interrater reliability on the Pathological Laughter and Crying Scale for a subgroup of 15 patients was 0.93, and the test-retest reliability of the scale was excellent. After 4 and 6 weeks of treatment, scores on the Pathological Laughter and Crying Scale showed significantly greater improvement in the 14 patients given nortriptyline than in the 14 given placebo. Although almost one-half of these patients also had major depression, the improvement in emotional lability was independent of depression status. In addition, response to treatment was not significantly affected by lesion location or time since stroke. CONCLUSIONS: The severity of symptoms in pathological emotional display can be reliably quantified with the Pathological Laughter and Crying Scale, and treatment with nortriptyline can effectively ameliorate this emotional disorder.

Affective Symptoms↗

PubMed2001

[Therapies for smoking cessation (antidepressants, nicotine-replacement and counseling) and implications for the treatment of patients with chronic obstructive pulmonary disease].

Only a small percentage of smokers who state they want to stop smoking in the next half year, succeed in doing so. This is not only due to the addictive nature of smoking cigarettes, but also because of psychological and social factors. Approximately 80% of the people who have used nicotine-replacement therapy return to smoking after some time. Therefore, the interest in non-nicotine pharmacotherapy has increased considerably in recent years. The antidepressants bupropion and nortriptyline are, compared to a placebo, particularly effective smoking cessation aids (relative risk (RR)nortriptyline: 2.7; 95% CI: 1.3-5.3; RRbupropion: 1.5; 95% CI: 1.1-2.6). A combined strategy of nicotine-replacement therapy with counselling or antidepressants (bupropion or nortriptyline) with counselling, in which the physiological as well as the psychological aspects of smoking cessation are treated, seems to be the most effective. Although smoking cessation is seen as the single most important way of preventing a further deterioration of the lung function at all stages of chronic obstructive pulmonary disease (COPD), little research has been conducted amongst COPD patients. Especially the use of the antidepressants bupropion or nortriptyline seems particularly interesting for the treatment of patients with COPD. This is not only because smoking cigarettes is the major risk factor for the development of the disease, but also because COPD patients have a higher than normal prevalence of depression. Furthermore, an association has been found between smoking cigarettes and depression, and the presence of depression or depressive symptoms appears to be an important cause of relapse.

Administration, Cutaneous↗

PubMed1992

Using tricyclic antidepressants in the elderly.

Only a few of the eight tricyclic antidepressants available today have been studied systematically in the elderly. Tertiary amine tricyclics such as amitriptyline and imipramine have been reported to be effective in depressed geriatric patients, but because of their potential for side effects, it is not advisable to use them in the elderly. Desipramine has a less toxic side effect profile, especially with respect to anticholinergic effects, but its efficacy has not been well studied. This does not mean, however, that it is not an effective drug for the elderly depressed. Nortriptyline is the tricyclic that has been the most studied. The results of those studies show that it should be recommended as an antidepressant for older patients. It is effective in both the acute and continuation treatment of depression in the elderly. As far as its use in maintenance treatment, the results are mixed but at this moment there is nothing with which to compare it. It has a favorable side effect profile: low anticholinergic activity; relatively few cardiac side effects, even in patients with preexisting cardiac disease; and relatively less orthostatic hypotension. Nortriptyline also has the virtue of an established therapeutic range for its steady-state plasma level. The role of its 10-hydroxy metabolite needs to be further explored, but when its contribution to efficacy and toxicity is better understood, it may be possible to use nortriptyline in a more precise and safe way in elderly patients. The bulk of evidence suggests, partly by default, that nortriptyline should probably the tricyclic-of-first-choice in treating an elderly patient with major depression.

Aged↗

PubMed1987

Lack of interaction of ranitidine with amitriptyline.

The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.

Adult↗

PubMed1985

Cimetidine interaction with amitriptyline.

The interaction of cimetidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, standing blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Cimetidine increased plasma amitriptyline concentrations and decreased plasma nortriptyline concentrations, apparently by inhibiting presystemic metabolism. The changes in blood pressure, pulse rate and digit symbol substitution correlated with changes in concentrations of amitriptyline in plasma and expected changes based on a dose ranging preliminary experiment. Changes in subjective ratings of effects correlated with changes in nortriptyline concentrations in plasma.

Adult↗

PubMed1986

Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly.

This comprehensive study investigated both the role of antidepressant drugs in the treatment of affective disorders of later life and their safety with careful clinical and pharmacological monitoring. A 7-week double-blind comparison was made of the efficacy and safety of nortriptyline (a tricyclic), phenelzine (a monoamine oxidase inhibitor), and placebo. The results indicated a response rate of approximately 60% for both nortriptyline and phenelzine versus a 13% response rate for placebo. Anticholinergic side effects were more frequently reported in the nortriptyline group. Orthostatic symptoms were reported with similar frequency in both drug groups. Overall, both drugs were well tolerated.

Aged↗

PubMed1987

A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs.

The analgesic effect of acute or chronic nortriptyline, amitriptyline and their effects on morphine induced analgesia were evaluated in the rat. Clomipramine and amitriptyline, but not Nortriptyline, induce analgesia, while all potentiate the effect of morphine when administered acutely. The analgesic effect of clomipramine is blunted by both the serotonin antagonist metergoline and the opiate receptor blocker naloxone, thus indicating an involvement of both the serotoninergic and endogenous opioid system. The involvement of the serotoninergic system is confirmed by the similar results obtained with the serotonin precursor 5-hydroxytryptophan administered alone or together with morphine. A relation between the serotoninergic and the endogenous opioid systems is also shown by the increase in hypothalamic beta-endorphin concentrations elicited by all the drugs used after acute or chronic treatment, with the only exception of nortriptyline, that has been shown to exert its effects mainly through the noradrenergic system. In conclusion, the analgesic effect of clomipramine and amitriptyline and their potentiation of morphine induced analgesia seems to be related to an activation of the endogenous opioid system mediated by serotonin.

5-Hydroxytryptophan↗

PubMed1996

The effect of sequential antidepressant treatment on geriatric depression.

This study evaluated the outcome of elderly depressed patients who were refractory to, or intolerant of, an initial trial of nortriptyline and who then underwent systematic treatment with other antidepressant therapies. 101 patients entered the study and 61% responded to nortriptyline, 64% of patients who did not improve with nortriptyline eventually responded to other antidepressant treatments. Response to second-line treatment (phenelzine) was significantly slower than response to the tricyclic antidepressant. Treatment nonresponders were more likely to have a longer episode length at index assessment and higher baseline anxiety scores compared with responders. This study demonstrates the importance of persisting with systematic antidepressant therapy in elderly patients who do not respond to the first trial of treatment.

Aged↗

PubMed1989

Open-trial maintenance pharmacotherapy in late-life depression: survival analysis.

We report preliminary findings from an ongoing, open trial of maintenance nortriptyline pharmacotherapy in 27 elderly depressed patients (median trial length: 18 months). While patients were on maintenance nortriptyline (mean dose: 50 mg/day) with steady-state plasma levels in the range of 50-150 ng/ml, 58% of Q-6 monthly ratings on the Hamilton Rating Scale for Depression have been 10 or lower, Folstein Mini-Mental State ratings have remained above 27, and a minimal level of side effects with no increase over time has been observed. Four of 27 patients (14.8%) have suffered recurrences and have required rehospitalization at 6, 9, 10, and 13 months. Survival analysis showed an 85% survival rate (without recurrence) at 12 months and 81.5% at 18 months. Mean survival time without recurrence is 21.3 months to date. Although our pilot experience with maintenance nortriptyline in late-life depression appears more favorable than outcomes reported in earlier naturalistic studies (where no attempt was made to keep patients in systematic maintenance therapy), the need for controlled studies of maintenance therapies in late-life depression is nonetheless underscored by the current data and other naturalistic data from the United Kingdom.

Aged↗

PubMed1996

Pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites in streptozocin-induced diabetic rats.

Plasma and brain levels of amitriptyline (AMI), its demethylated and hydroxylated metabolites were determined after acute IP administration of AMI (20 mg/kg) in streptozocin-induced diabetic Sprague-Dawley rats. Results showed 1. in plasma: rapid AMI absorption, but slow elimination; the proportion of AMI similar to those of the rest of compounds; the proportion of its demethylated metabolite, nortriptyline, 1.8-fold higher than that of 10-hydroxy-nortriptyline. 2. in brain: the proportions of AMI and nortriptyline were 9.5- and 2.6-fold higher respectively, than those of whole hydroxylated metabolites, which represented 7.4% of the total amount.

Amitriptyline↗

PubMed1991

Effects of a secondary and a tertiary amine tricyclic antidepressant on cerebral biogenic amines as a function of mouse strain: a comparative neurotoxicological evaluation.

The effect of equal-dose regimens of amitriptyline and nortriptyline on the concentrations of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline increased to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs increased serotonin levels but decreased cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential increase in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an increase in dopamine turnover particularly in brain areas associated with motor function and posture which may account for tricyclic-antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

The study of tricyclic antidepressants in formalin-fixed human liver and formalin solutions.

The stability of amitriptyline, nortriptyline, desipramine and imipramine in formalin-fixed human liver tissue and formalin solutions was investigated. The levels of the tricyclic and its primary demethylated metabolite in the frozen liver were determined and compared with levels obtained in the formalin-fixed liver and formalin solutions in which the liver was stored. It was obvious that some methylation of the secondary amine, nortriptyline, to the corresponding tertiary amine, amitriptyline, and of desipramine to imipramine took place in the formalin environment. Nortriptyline was not detected in most cases, suggesting that it may degrade more rapidly than desipramine. There was no consistent ratio between the concentration of the drug in the frozen liver tissue versus formalin-preserved tissue or versus formalin solution. The methylation rates of the secondary amines could not be quantitated. Storage of the liver tissue in formalin at room temperature resulted in leaching of the drugs into the formalin solution. The drugs tested may be detected for up to 22 months in the formalin-fixed liver and in the formalin medium.

Amitriptyline↗

PubMed2006

Treatment of bereavement-related depression and traumatic grief.

In the bereaved, approximately 40% meet criteria for major depression within a month of the death. At a year, approximately 15% of the bereaved are depressed and at 2 years, the figure is approximately 7%. Open-label trials of medication for bereavement-related depression have shown promising results for desipramine, nortriptyline, and bupropion SR. One double-blind controlled trial supports the use of nortriptyline, but interpersonal psychotherapy did no better than placebo. In all these trials, depressive symptoms improve more than bereavement symptoms. Effective open-label treatments for traumatic grief include paroxetine, nortriptyline, and a form of psychotherapy called traumatic grief treatment.

Antidepressive Agents, Tricyclic↗

PubMed1982

Monitoring of tricyclic antidepressant therapy.

During the three-year period 1978-1980, 2141 plasma samples from 1055 patients receiving therapy with amitriptyline (77%) or nortriptyline (23%) were analysed using GLC with nitrogen selective detection. Compared to the recommended therapeutic ranges, wild inter-individual differences were observed in plasma drug concentration, even when corrections for dosage were made. Concentrations ranged from below the limit of sensitivity of the assay (5 microgram.1(-1)) to greater than 1 mg.1(-1). The reporting of toxic symptoms subjective side-effects) was found not to reliably predict high drug concentrations. Serious complications, however, were associated with high plasma drug concentrations. Neither nortriptyline nor amitriptyline displayed dose-dependent pharmacokinetics over the concentration ranges studied. Treatment with either drug produced age-related increases in drug concentration, which were more pronounced in female patients. With amitriptyline therapy, there was an age-related decrease in the plasma nortriptyline:amitriptyline ratio, suggesting that demethylation may be more influenced by increasing age than hydroxylation. Plasma drug monitoring of tricyclic antidepressant therapy is the only reliable means of ensuring that all patients receive a fair opportunity to benefit from these drugs.

Adolescent↗

PubMed2001

Salmon calcitonin potentiates the analgesia induced by antidepressants.

Antidepressants are used in the treatment of a variety of pain syndromes. Most of them act by blocking noradrenaline (NA) and serotonin (5-HT) reuptake. It is also well known that the serotonergic system is also involved in calcitonin (CT) analgesia. Taking these two evidences into account, the modification of the analgesic effect of nortriptyline, amitriptyline, and paroxetine in the presence of salmon CT (s-CT) was examined in mice. The forced-swimming test was carried out in order to choose doses of each drug that did not induce an antidepressant effect under our experimental conditions (nortriptyline: 0.2-5 mg/kg ip, amitriptyline: 2.5-20 mg/kg ip, and paroxetine: 5-30 mg/kg ip). The analgesic effect of each antidepressant was then evaluated using the acetic acid test. At the doses tested, the antidepressants induced a dose-dependent analgesic effect. When mice were pre-treated with a subanalgesic dose of s-CT (2.5 IU/kg), the analgesic effect of amitriptyline and paroxetine was significantly increased though no modification was found for nortriptyline. In summary, s-CT was able to increase the analgesic effect of the antidepressant drugs that reduce the uptake of 5-HT, suggesting that the joint administration of antidepressants and CT may be an interesting alternative in pain management.

Adrenergic Uptake Inhibitors↗

PubMed2002

Melancholia: definitions, risk factors, personality, neuroendocrine markers and differential antidepressant response.

OBJECTIVE: To evaluate the CORE measure of melancholia, against the DSM-IV construct of melancholia. To evaluate the validity of both the CORE and DSM-IV constructs of melancholia against psychosocial risk factors, anxiety and personality disorder comorbidity, neuroendocrine markers and differential anti depressant response to fluoxetine and nortriptyline. METHOD: One hundred and ninety-five outpatients with major depression were evaluated for melancholia with both the DSM-IV criteria and the CORE evaluation. Both constructs were evaluated for validity against psychosocial risk factors, comorbidity, biological markers and differential antidepressant response. RESULTS: The CORE measure has satisfactory interrater reliability when used dimensionally, but has unacceptably low agreement for making a categorical diagnosis of melancholia. There is remarkably poor agreement (kappa = 0.11) between the CORE and DSM-IV criteria for melancholia. Neither the DSM-IV nor CORE criteria for melancholia identified subgroups of patients with better childhood environments or less anxiety or personality disorder comorbidity. The CORE criteria for melancholia, but not DSM-IV, identified patients with neuroendocrine disturbance. CORE scores also were associated with differential responses to fluoxetine and nortriptyline, but not in anticipated directions. Thus, high CORE scores were associated with a higher recovery rate with fluoxetine than nortriptyline. CONCLUSION: While the episode specifier of melancholia should be retained in diagnostic systems, the DSM-IV criteria were not validated against any of the variables examined in this study. The CORE construct of melancholia, was validated against neuroendocrine measures, and was associated with a differential antidepressant response. However, the limits imposed by interrater reliability,suggest the CORE measure should be used dimensionally and not to make a categorical diagnosis of melancholia.

Age Factors↗