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PubMedDate not supplied

Effect of monoamine reuptake inhibiting antidepressants on major histocompatibility complex expression on macrophages in normal rats and rats with experimental allergic neuritis (EAN).

This study examined the modulation of IFN-gamma induced MHC class I and II expression on normal Lewis rats and rats with EAN peritoneal macrophages cultured in the absence or presence of 10(-4)-10(-8) M of the 5-HT reuptake inhibiting antidepressants zimeldine, and its metabolites norzimeldine and cpp200 oxalate as well as the antidepressants clomipramine and imipramine, in addition amitriptyline, nortriptyline and maprotiline in EAN rats. In normal rats, MHC class I expression was suppressed by the antidepressants zimeldine, norzimeldine and cpp200 oxalate at concentrations up to 10(-5) M. At concentrations between 10(-6) to 10(-8) M, the same drugs significantly enhanced MHC class expression. Clomipramine at 10(-8) M and imipramine at 10(-6)-10(-7) M enhanced MHC class I expression, while the MHC class II expression was not significantly influenced by concentrations < or = 10(-5) M of these two drugs. In EAN rats, MHC class I expression was enhanced by zimeldine, cpp200, imipramine, and nortriptyline at 10(-5)-10(-8) M, amitriptyline at 10(-5)-10(-7) M as well as by norzimeldine and clomipramine at 10(-6) M-10(-8) M. However, maprotiline at 10(-4)-10(-6) M suppressed class I expression in the presence of 0.5 U/ml and 1.0 U/ml of IFN-gamma. MHC class II expression was suppressed by cpp200 and clomipramine at 10(-4)-10(-5) M in presence of 0.5 U/ml of IFN-gamma. At concentrations < 10(-5) M most tested drugs significantly enhanced IFN-gamma induced MHC class II expression. Compared to the results in normal rats, drug effects on EAN macrophages were more pronounced and reached higher levels of significance. The 5-HT reuptake inhibiting antidepressants also exerted a modulatory effect on MHC class I and II in EAN rat macrophages even in the absence of IFN-gamma. The modulatory effect of antidepressant drugs on IFN-gamma induced MHC class I and II expression may contribute to their influence on demyelinating autoimmune diseases, and may have implications for their clinical use.

Amitriptyline↗
PubMed1986

3H-imipramine binding in depressed elderly: relationship to family history and clinical response.

Platelet 3H-imipramine binding (Bmax) was determined in 34 elderly (mean age 64.8) unipolar depressed outpatients who were being treated with either nortriptyline or interpersonal psychotherapy for 10 to 16 weeks, and in nondepressed elderly controls. Bmax values were decreased in the depressed group. In addition, Bmax values were depressed further in subjects with a history of depression in first degree relatives. Good clinical response with either nortriptyline or psychotherapy was associated with lower Bmax compared to those subjects who had a poorer response to treatment. Treatment nonresponders and those with a negative family history of depression had Bmax values that were somewhat decreased but not significantly different from controls. This study extends to the elderly the potential applicability of platelet 3H-imipramine binding as a marker of depressive illness, and proposes a predictor for treatment response in elderly unipolar depressed patients.

Aged↗
PubMed1988

Antidepressant-induced weight gain: a comparison study of four medications.

Body weight change was monitored in 73 hospitalized depressed patients treated with one of four antidepressants for 1 month. After a 2-week medication-free period, patients were randomly assigned to treatment with amitriptyline, nortriptyline, desipramine, or zimelidine. By the end of 1 month, treatment with all three tricyclic compounds promoted weight gain, with the greatest increase observed during amitriptyline treatment; less weight was gained by patients treated with nortriptyline and desipramine. In contrast, most patients treated with zimelidine showed no weight gain and, in many cases, demonstrated weight loss. Weight change during treatment was not associated with age, sex, severity of depression, obesity, weight loss during depression, or clinical response.

Adult↗
PubMed1990

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.

Amitriptyline↗
PubMed1990

Substitution of psychoactive drugs in pentobarbital-dependent rats.

The substitution of either bromazepam, diazepam, methaqualone, mazindol, nortriptyline or bupropion for pentobarbital, in dependent rats, was assessed using a continuous drug infusion method. Male, Sprague-Dawley rats were made dependent on pentobarbital during 12 days of continuous, intraperitoneal, pentobarbital infusion. On Day 13, pentobarbital was replaced with either saline, vehicle, or one of the drugs of interest and rats were infused for 24 h. On Day 14, all rats were infused, for 24 h, with saline. Changes in both body weight and behavioral indices of withdrawal were assessed during Day 13 and 14. It was observed that bromazepam and methaqualone substituted for pentobarbital in a dose-dependent fashion. Diazepam also substituted in pentobarbital dependent rats but, inexplicably, the low dose of diazepam provided better substitution than did the higher dose. On the other hand, neither mazindol or nortriptyline substituted for pentobarbital and there was a tendency for exacerbation of the withdrawal signs. Finally, it was noted that the low dose of bupropion appeared to decrease the severity of the withdrawal symptoms. The data supports the view that the substitution of compounds for pentobarbital, in dependent rats, is limited to those compounds which, presumably, possess similar mechanisms of action in the CNS.

Animals↗
PubMedDate not supplied

Effects of some antidepressants on the volume-induced reflex contractions of the rat urinary bladder: lack of correlation with muscarinic receptors affinity.

It has been suggested that tricyclic antidepressants such as imipramine, might exert their anti-enuretic action by a blockade of muscarinic receptors in the detrusor muscle of the urinary bladder. We have therefore investigated the effects of two tricyclic (imipramine and nortriptyline) and three atypical (citalopram, amineptine and mianserin) antidepressants on the micturition reflex and muscarinic receptors in rats. The micturition reflex pathway was monitored indirectly by recording the rhythmic intravesical pressure waves which occurred when the bladder was distended and maintained under constant saline-volume. The activity of the antidepressants was correlated to their potencies as antagonists of [3H]QNB binding to rat brain (mainly M1 receptors) and bladder (mainly M2 receptors) membranes, as well as antagonists of carbachol-induced contractions of rat bladder strips. Only imipramine and citalopram dose dependently inhibited the voiding contractions, whereas nortriptyline, imipramine and mianserin (in order of potency) were active both in binding studies and as competitive antagonists of carbachol-induced bladder contractions, but were inactive in inhibiting the micturition reflex. The present data seem to suggest that affinities for muscarinic receptors are unrelated to the inhibition of micturition reflex.

Animals↗
PubMed2005

Placental passage of tricyclic antidepressants.

BACKGROUND: The use of antidepressants during pregnancy continues to garner considerable attention, though there are limited investigations that have sought to quantify fetal exposure. METHODS: Maternal and umbilical cord sera were collected at delivery from ten women taking nortriptyline and seven taking clomipramine. Placental passage was calculated as the ratio of umbilical cord to maternal serum concentration. Obstetrical outcome data were gathered from subjects at delivery. RESULTS: The placental passage ratio of nortriptyline and its active metabolite, cis-10-hydroxynortriptyline, were .68 +/- .40, 1.40 +/- 2.40, respectively. Clomipramine and desmethylclomipramine ratios were .60 +/- .50, .80 +/- .60. Obstetrical complications, such as pre-term delivery and pregnancy induced hypertension, were increased compared to the national average. CONCLUSIONS: The in vivo ratios of umbilical cord to maternal serum drug concentrations demonstrate considerable fetal exposure and differ greatly from previous results utilizing ex vivo perfusion.

Antidepressive Agents, Tricyclic↗
PubMed2005

Antidepressant-like effects of selegiline in the forced swim test.

Although selegiline, a monoamine oxidase (MAO)-B inhibitor, is reported to exert antidepressant effects in depressant patients, evidence in rodents for effects of selegiline is quite limited. The purpose of the present study was to assess effects of selegiline in the forced swim test (FST) and on locomotor activity, and to investigate whether MAO inhibition or stimulation of receptors contributes to antidepressant-like effects of selegiline. Drugs were subcutaneously administrated. The single administration of reference drug nortriptyline at 5 mg/kg reduced locomotor activity without effects in FST and brain MAO activities. But nortriptyline repeatedly given 24, 5 and 1 h before behavioral tests significantly decreased an immobility time in FST without effects in motor activities, and showed weak brain MAO-B inhibition. Single and following repeated (24, 5 and 1 h before behavioral tests) administrations of selegiline at 10 mg/kg significantly decreased the immobility time in FST, with little motor stimulant effect. In contrast, (+)-methamphetamine caused a marked decrease in immobility time and an increase in locomotor activity. Selegiline at 1 and 3 mg/kg, which failed to decrease immobility time, markedly inhibited brain total-MAO and MAO-B activities. A dopamine D1 receptor antagonist SCH 23390 completely blocked antidepressant-like effects of selegiline, but not dopamine D2, serotonergic or noradrenergic receptor antagonists. These results suggest that selegiline exerts the antidepressant-like effects by prolonging escape-directed behavior rather than by a motor stimulant effect and D1 receptor activation contributes to its effect.

Animals↗
PubMed2005

Tryptophan and tyrosine availability and response to antidepressant treatment in major depression.

BACKGROUND: It has been suggested that the ratio of tryptophan (TRP) and tyrosine (TYR) to other large neutral amino acids may predict response to antidepressant drugs with predominantly serotonergic compared with predominantly noradrenergic activity and that this may be clinically useful. METHOD: 147 subjects with a DSM-III-R diagnosis of major depression underwent a detailed clinical evaluation and prior to treatment had baseline measures of TRP, TYR and other large neutral amino acids (LNAA), prolactin and cortisol. Subjects entered a 6-week randomised treatment trial comparing fluoxetine and nortriptyline. RESULTS: There was no main effect on 6-week outcome of TRP/LNAA ratio or TYR/LNAA ratio and no interaction between these factors and treatment (fluoxetine vs nortriptyline). LIMITATIONS: Alterations in antidepressant dose were allowed therefore possibly reducing the effect of TRP or TYR availability on response. CONCLUSIONS: Previous findings that TRP/LNAA and TYR/LNAA ratios may predict differential response to antidepressants were not replicated and neither was our previous finding of a complex relationship between TRP/LNAA and baseline prolactin in predicting 6-week response.

Adrenergic Uptake Inhibitors↗
PubMed2000

Effect of fluoxetine on contractile activity of pregnant rat uterine rings.

OBJECTIVE: We sought to compare the effects of fluoxetine, imipramine, and nortriptyline on spontaneous and serotonin-activated contractile activity of the uterine rings from midterm and term pregnant rats. STUDY DESIGN: Uterine rings from timed-pregnant Sprague-Dawley rats on day 14 (midgestation) and day 22 (term gestation) were used for isometric tension recording. Responses to cumulative concentrations of fluoxetine, imipramine, nortriptyline, and serotonin in the absence and presence of the monoamine reuptake inhibitors were studied. RESULTS: Neither of the monoamine reuptake inhibitors significantly influenced spontaneous contractile activity, whereas the concentration-dependent increase in activity induced by serotonin was inhibited in rings from both midterm and term pregnant rats. CONCLUSIONS: The reported increase in preterm delivery in women receiving fluoxetine during the third trimester cannot be explained by a direct effect on uterine contractility.

Adrenergic Uptake Inhibitors↗
PubMed1978

Ion-pair liquid chromatography of amitriptyline and metabolites in plasma.

A method is described for the determination of amitriptyline and nortriptyline in the plasma of patients during treatment. The method is based on liquid chromatography of the amines as ion-pairs with perchlorate. The separation column is packed with silica gel, and a mixture of diisopropyl ether, dichloromethane, methanol and water containing the counter ion is used as eluent. High efficacy and stability of the system is achieved. The separation of metabolites is demonstrated. The cis- and trans-10-hydroxy isomers of amitriptyline and nortriptyline are easily resolved with this chromatographic system.

Amitriptyline↗
PubMed2001

Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline.

1. The safety and efficacy of sertraline in the treatment of moderate-to-severe major depression in elderly outpatients, aged 60 years and older, with comorbid vascular disease was evaluated. 2. An analysis of the pooled results for the sertraline treatment group drawn from two prospective, randomized, double-blind studies (sertraline vs. fluoxetine, and sertraline vs. nortriptyline) was done. Patients were retrospectively categorized into one of 3 clinical groups: 1) patients with a current diagnosis of hypertension but no other past or present cardiovascular illness (HTN), 2) patients reporting a current or past history of cardiovascular illness, but excluding hypertension (VASC), and 3) patients with no hypertension, and no other comorbid vascular illness (NoVASC). Patients received 12-3. weeks of double-blind treatment with sertraline in flexible daily doses in the range of 50 - 150 mg (in the nortriptyline comparator trial) or 50 - 100 mg (in the fluoxetine comparator trial). 4. Sertraline treatment yielded comparable levels of response in all 3 groups (response criterion: CGI-much or very much improved) at treatment endpoint on both a completer analysis (HTN, 86%; VASC, 89%; NoVASC, 77%) and significantly higher response rates on a 12-week endpoint analysis (HTN, 74%; VASC, 69%; NoVASC, 58%; p < 0.05). Sertraline treatment was well-tolerated, with no between-group differences in rates of adverse events, or in discontinuation due to adverse events. Patients taking 5 or more concomitant medications showed no difference, when compared with patients taking none-or-one concomitant medication, either in rates of adverse events, or in discontinuation due to adverse events. 5. Sertraline was found to be a safe, well-tolerated, and effective as an antidepressant in elderly patients suffering from hypertension and other forms of vascular comorbidity.

Age of Onset↗
PubMed2003

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.

Amines↗
PubMed2000

Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression.

The relationship of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) to antidepressant response was examined in 95 elderly patients receiving a protocolized treatment for depression with paroxetine or nortriptyline. Patients were treated for up to 12 weeks and assessed weekly with clinical ratings and measurements of plasma drug concentrations. Twenty-one of the paroxetine-treated subjects were found to have the ll genotype and 30 had at least one s allele. There were no baseline differences between these groups in pretreatment Hamilton Rating Scale for Depression (HRSD) scores or anxiety symptoms. During acute treatment with paroxetine, mean reductions from baseline in HRSD were significantly more rapid for patients with the ll genotype than for those possessing an s allele, despite equivalent paroxetine concentrations. Onset of response to nortriptyline was not affected. Allelic variation of 5-HTTLPR may contribute to the variable initial response of patients treated with a selective serotonin reuptake inhibitor.

Adrenergic alpha-Agonists↗
PubMed2002

Inhibition of acetylcholinesterase from Electrophorus electricus (L.) by tricyclic antidepressants.

The effects of tricyclic antidepressants drugs (TCA) amitriptyline, imipramine and nortriptyline, on purified Electrophorus electricus (L.) acetylcholinesterase (AChE; acetylcholine hydrolase, EC 3.1.1.7) were studied using kinetic methods and specific fluorescent probe propidium. The antidepressants inhibited AChE activity by a non-competitive mechanism. Inhibition constants range from 200 to 400 microM. Dimethylated amitriptyline and imipramine were more potent inhibitors than the monomethylated nortriptyline. Fluorescence measurements using bis-quaternary ligand propidium were used to monitor ligand-binding properties of these cationic antidepressants to the AChE peripheral anionic site (PAS). This ligand exhibited an eight-fold fluorescence enhancement upon binding to the peripheral anionic site of AChE from E. electricus (L.) with K(D)=7 x 10(-7)M. It was observed that TCA drugs displaced propidium from the enzyme. On the basis of the displacement experiments antidepressant dissociation constants were determined. Similar values for the inhibition constants suggest that these drugs have similar affinity to the peripheral anionic site. The results also indicate that the catalytic active center of AChE does not participate in the interaction of enzyme with tricyclic antidepressants. These studies suggest that the binding site for tricyclic antidepressants is located at the peripheral anionic site of E. electricus (L.) acetylcholinesterase.

Acetylcholinesterase↗
PubMed1983

Labelling and drug effects in the treatment of neurotic affective disorders: an experimental investigation.

This study investigates the effects of assigned diagnostic labels, with their accompanying predictions of therapeutic response, and prescribed psychotropic drugs. It was thought that such 'labelling' effects might be important in ambiguous situations, such as neurotic anxiety-depressive states, where diagnoses of 'reactive depression' or 'anxiety state' might justifiably be made and treatment with either diazepam or nortriptyline legitimately given. The depression label and its concomitant two-weekly prediction of improvement with antidepressants produced a set towards slower response with higher self-report depression. Nortriptyline produced significantly more improvement in self-report depression than diazepam in the first 2 weeks of treatment. No significant interaction effects were detected between diagnosis or drug. One month after the initial diagnostic evaluation there were no significant effects from either diagnostic label or drug.

Adolescent↗
PubMed1998

Melancholia with onset during treatment with SSRIs.

A defined group of medical records was surveyed for patients who showed onset of major depression with melancholic features while taking an antidepressant medication. Nine cases resulted. In all the antidepressants being taken while melancholia began were SSRIs and the melancholic depression remitted rapidly with the first treatment given, bupropion in five males, nortriptyline with triiodothyronine in two females, and ECT in one male and one female. This suggests that patients who take SSRIs and are melancholic respond well to bupropion, nortriptyline, or ECT. These observations complement reports of low responsivity of melancholic depression to SSRIs and distinctions between melancholic and nonmelancholic depressions.

Adult↗
PubMed1997

Treatment of major depression in later life: a life cycle perspective.

The goal of this article is to provide a life-cycle perspective on the treatment of major depressive episodes in later life. Our studies have suggested that older patients appear to benefit as much, though perhaps more slowly, than mid-life patients from acute combined treatment (nortriptyline+interpersonal psychotherapy) of major depression. Given also the apparently higher relapse rate among the elderly, however, continuation treatment needs to be vigorous and closely monitored. The occurrence of severe life events prior to the index episode and the co-existence of an anxiety disorder both appear to prolong treatment response times, while chronic medical burden per se neither compromises response rates nor prolongs time to response. Self-rated perception of health improves with remission of depression in the elderly. As in mid-life patients, both antidepressant medication (nortriptyline) and interpersonal psychotherapy appear to possess chronic efficacy with respect to the prevention of recurrent episodes and prolongation of wellness. Finally, treatment of depression in the elderly results in improved quality of life, especially in domains of well being and coping. Particular challenges in the treatment of elderly patients are noncompliance and the prevention of suicide. The latter is closely linked to feelings of hopelessness, and these may be persistent in some patients.

Aged↗