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PubMed1977

Tricyclic plasma levels. Effect of age, race, sex, and smoking.

Steady-state plasma tricyclic antidepressant levels were determined in 65 patients undergoing treatment for depression with either amitriptyline hydrochloride or nortriptyline hydrochloride to determine if common factors such as age, race, sex, or smoking status were predictors of steady-state drug levels that have been shown to vary up to 36-fold. Evaluation of these factors did not disclose differences in the rate of demethylation of amitriptyline to nortriptyline, or steady-state tricyclic levels in the amitriptyline-treated patients. No differences were found in the nortriptyline-treated patients except regarding race. Black patients had significantly higher (50%) nortriptyline plasma levels than did white patients, which may explain the more rapid response to tricyclic treatment demonstrated in blacks. Decreased rates of nortriptyline metabolism in blacks can result in increased side effects and treatment failure if the therapeutic plasma range is exceeded.

Amitriptyline↗
PubMed2005

The adsorption mechanism of nortryptiline on C18-bonded Discovery.

The adsorption isotherms of an ionizable compound, nortriptyline, were accurately measured by frontal analysis (FA) on a C(18)-Discovery column, first without buffer (in an aqueous solution of acetonitrile at 15%, v/v of ACN), then with a buffer (in 28%, v/v ACN solution). The buffers were aqueous solutions containing 20 mM of formic acid or a phosphate buffer at pH 2.70. The linear range of the isotherm could not be reached with the non-buffered mobile phase using a dynamic range larger than 40,000 (from 1.2 x 10(-3) g/L to 50 g/L). With a 20 mM buffer in the liquid phase, the isotherm is linear for concentrations of nortriptyline inferior to 10(-3) g/L (or 3 micromol/L). The adsorption energy distribution (AED) was calculated to determine the heterogeneity of the adsorption process. AED and FA were consistent and lead to a trimodal distribution. A tri-Moreau and a tri-Langmuir isotherm models accounted the best for the adsorption of nortriptyline without and with buffer, respectively. The nature of the buffer affects significantly the middle-energy sites while the properties of the lowest and highest of the three types of energy sites are almost unchanged. The desorption profiles of nortriptyline show some anomalies in relation with the formation of a complex multilayer adsorbed phase of acetonitrile whose excess isotherm was measured by the minor disturbance method. The C(18)-Discovery column has about the same total saturation capacity, around 200 g of nortriptyline per liter of adsorbent (or 116 mg/g), with or without buffer. About 98-99% of the available surface consists in low energy sites. The coexistence of these different types of sites on the surface solves the McCalley's enigma, that the column efficiency begins to drop rapidly when the analyte concentration reaches values that are almost one hundred times lower than those that could be predicted from the isotherm data acquired under the same experimental conditions. Due to the presence of some relatively rare high energy sites, the largest part of the saturation capacity is not practically useful.

Acetonitriles↗
PubMed1999

Relaxant effects of antidepressants on human isolated mesenteric arteries.

AIMS: The therapeutic action of tricyclic agents may be accompanied by unwanted effects on the cardiovascular system. The evidence for the effects on vascular and nonvascular smooth muscle comes from animal studies. Whether these studies can be extrapolated to human vessels remains to be determined. Therefore, the present study was designed to investigate the influence of amitriptyline, nortriptyline and sertraline on the contractile responses of human isolated mesenteric arteries to electrical field stimulation, noradrenaline and potassium chloride. METHODS: Arterial segments (lumen diameter 0.8-1.2 mm) were obtained from portions of the human omentum during the course of 41 abdominal operations (22 men and 19 women), and rings 3 mm long were mounted in organ baths for isometric recording of tension. In some artery rings the endothelium was removed mechanically. RESULTS: In precontracted artery rings amitriptyline, nortriptyline and sertraline (3x10(-7)-10(-4) m ) produced concentration-dependent relaxation that was independent of the presence or absence of vascular endothelium. Incubation with indomethacin (3x10(-6) m ) reduced the pD2 values thus indicating the participation of dilating prostanoid substances in this response. Amitriptyline and nortriptyline inhibited both the neurogenic-and noradrenaline-induced contractions. In contrast, only the highest concentration of sertraline reduced the adrenergic responses. Amitriptyline, nortriptyline and sertraline inhibited contractions elicited by KCl and produced rightward shifts of the concentration-response curve to CaCl2 following incubation in calcium-free solution. CONCLUSIONS: These results indicate that amitriptyline and nortriptyline could act as adrenoceptor antagonists and direct inhibitors of smooth muscle contraction of human mesenteric arteries, whereas sertraline might principally exert its action only as direct inhibitor of smooth muscle contraction. This relaxant mechanism involves an interference with the entry of calcium.

Adult↗
PubMed2004

Excess fatality from desipramine and dosage recommendations.

Higher case fatality rates (CFR) were previously reported from desipramine than for 3 other tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, and imipramine. The database of the American Association of Poison Control Centers (AAPCC) Toxic Exposure Surveillance System (TESS) for the 20 years 1983-2002 was used to evaluate the CFR of desipramine and the other TCAs. The CFR of desipramine was 2.25-, 2.31-, and 2.62-fold the CFR for amitriptyline, nortriptyline, and imipramine, respectively (P < 0.001). Mechanisms of desipramine toxicity and its dosage recommendations are discussed. Desipramine and nortriptyline have higher distribution volumes and erythrocyte/plasma ratios than their parent compounds imipramine and amitriptyline. This implies lower therapeutic plasma levels and reduced doses for desipramine and nortriptyline compared with their parent compounds. Such adjustments have been done for nortriptyline, but not for desipramine. The authors suggest that the high CFR of desipramine might be reduced by lowering its dose, therapeutic plasma level, and maximal pill content.

Amitriptyline↗
PubMed1968

The reversal of the central effects of noradrenaline by antidepressant drugs in mice.

1. Noradrenaline given directly into the lateral cerebral ventricles induced hypothermia in mice. This hypothermia was antagonized and eventually reversed to a hyperthermia by imipramine-like antidepressant drugs.2. The mechanism of action involved in this effect of antidepressant drugs has been studied using nortriptyline as a typical representative of antidepressant drugs.3. Nortriptyline pretreatment did not modify either the uptake, subcellular distribution, or the metabolism of (3)H-noradrenaline injected into the lateral cerebral ventricles.4. Nortriptyline had the same order of activity in reversing the hypothermia produced by the intraventricular injection of noradrenaline irrespective of whether it was given directly into the lateral cerebral ventricles or subcutaneously.5. Noradrenaline given subcutaneously caused hyperthermia in mice which antagonized and reversed the hypothermia induced by noradrenaline given directly into the lateral ventricles.6. The antagonism by both noradrenaline given subcutaneously and nortriptyline was reduced to the same degree by alpha- and beta-adrenoceptive receptor blocking agents.7. Nortriptyline, at dose levels required to antagonize and reverse the hypothermia induced by intraventricular injections of noradrenaline, potentiated the hyperthermia caused by noradrenaline given subcutaneously in conscious mice and the pressor responses to noradrenaline given either intravenously or into the lateral ventricles in anaesthetized mice.8. It is suggested that imipramine-like antidepressant drugs antagonize the hypothermia produced by intraventricular injections of noradrenaline by potentiating the hyperthermic effects of that part of the centrally administered noradrenaline that passes to the periphery rather than a direct central antagonism of the effects of noradrenaline.

Animals↗
PubMed1969

The interactions of noradnamine and imipramine-like antidepressant drugs.

1. The hypothesis of Roberts & Broadley (1965) that noradnamine formation in the brain is responsible for endogenous depression has been investigated in mice.2. Injections of noradnamine given directly into the lateral ventricles caused convulsions and profound hypothermia, but were without effect if given subcutaneously.3. The hypothermia, but not the convulsions, induced by noradnamine was reversed by imipramine-like antidepressant drugs given before or after the injection of noradnamine. The convulsions but not the hypothermia were abolished by phenobarbitone.4. Increasing doses of nortriptyline produced a parallel shift of the hypothermic log dose-response curve for intraventricular injections of noradnamine to the right.5 The minimal effective dose of nortriptyline required to reverse noradnamine hypothermia was the same whether the nortriptyline was injected directly into the lateral ventricle or subcutaneously.6. No evidence was found to substantiate the claim that reserpine hypothermia is mediated by noradnamine formation in the brain.7. Intraventricular, but not intraperitoneal, injection of noradnamine caused a depletion of brain noradrenaline and an increase in brain 5-hydroxytryptamine. These changes did not result from the convulsive activity and were not modified by pretreatment with nortriptyline. No effect on heart noradrenaline levels was recorded.8. Noradrenaline, given subcutaneously, also antagonized the hypothermic response to noradnamine.9. The reversal of noradnamine hypothermia by both noradrenaline given subcutaneously and nortriptyline was blocked by alpha and beta-adrenoceptive receptor blocking agents.10. It is considered that the mode of action of the antagonism of noradnamine hypothermia by imipramine-like antidepressant drugs is a peripheral and not a central mechanism and probably results from a potentiation of the effects of circulating noradrenaline released by noradnamine.

Animals↗
PubMed1987

Antifibrillatory action of bretylium: role of the sympathetic nervous system.

This study was performed to assess the role of cardiac sympathetic nerves in the in vivo antifibrillatory action of bretylium using the technique of electrically induced ventricular fibrillation. An initial study determined that 3 mg/kg of nortriptyline, an adrenergic amine uptake inhibitor, was sufficient to prevent the adrenergic neuron blockade produced by 5 mg/kg of bretylium in pentobarbital anesthetized dogs. Electrical ventricular fibrillation threshold (VFT) was then determined in two groups of pentobarbital anesthetized dogs using gated trains of increasing current applied to the epicardial surface of the right ventricle during atrial pacing. After determination of an initial VFT in both groups, one group of dogs (n = 8) received 3 mg/kg nortriptyline, the other group received saline (n = 9). The VFT was redetermined in both groups, after which all dogs received 5 mg/kg of bretylium, intravenously, and VFT was then measured at 15 and 90 min after bretylium. In saline-treated dogs, bretylium produced a significant increase in VFT from a control value of 6.9 +/- 1.6 mA (mean +/- SEM) to 31.0 +/- 0.5 mA at 15 min (p less than 0.05) and 45.1 +/- 4.8 mA at 90 min (p less than 0.05). In nortriptyline-treated dogs, however, nortriptyline itself produced an increase in VFT which was reversed by bretylium, and VFT after bretylium was not significantly elevated until 90 min to a value of 25.2 +/- 9.6 mA (control: 5.2 +/- 0.9 mA). These data demonstrate that pretreatment with nortriptyline attenuates and delays the onset of the acute antifibrillatory effect of bretylium and suggests a role for the cardiac adrenergic neuron as a potential target for part of the beneficial effects to be derived from antifibrillatory drugs.

Animals↗
PubMed2001

Prevention of recurrent postpartum depression: a randomized clinical trial.

BACKGROUND: Women who have suffered one episode of postpartum-onset major depression (PPMD) comprise a high-risk group for subsequent episodes. We conducted a double-blind, randomized clinical trial to test the efficacy of nortriptyline in the prevention of recurrent PPMD. METHOD: Nondepressed women who had at least one past episode of PPMD (Research Diagnostic Criteria) were recruited during pregnancy. Subjects were randomly assigned to nortriptyline or placebo. Treatment began immediately postpartum. Each subject was assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression and Research Diagnostic Criteria for recurrence of major depression. RESULTS: No difference was found in the rate of recurrence in women treated with nortriptyline compared with those treated with placebo. Of 26 subjects who took nortriptyline preventively, 6 (0.23, 95% exact confidence interval [CI] = 0.09 to 0.44) suffered recurrences. Of 25 subjects who took placebo, 6 (0.24, 95% exact CI = 0.09 to 0.45) suffered recurrence (Fisher exact p = 1.00). CONCLUSION: Nortriptyline did not confer additional preventive efficacy beyond that of placebo. The rate of recurrence of PPMD (one fourth of women) was unacceptably high.

Adult↗
PubMed1978

The kinetics of amitriptyline following single oral dose administration to man.

Amitriptyline and its metabolite, nortriptyline, were measured in the plasma of eight humans for 96 hours following oral administration of a 75 mg dose of amitriptyline hydrochloride. Based on the 8 to 96 hour post dosing plasma concentration data, the terminal exponential half life of amitriptyline +/- S.D. was 22.4 +/- 4.3 hr. Based on the 24 to 96 hour concentration data, the "apparent" terminal half time of nortriptyline +/- S.D. was 26.0 +/- 7.4 hours for seven subjects. For these same seven subjects the relative area under the plasma concentration time curve of nortriptyline +/- S.D. was only 0.88 +/- 0.34 times that of amitriptyline. One subject whose apparent nortriptyline half time was 108 hours had a nortriptyline bioavailability 3.83 times that of amitriptyline. Average steady state plasma levels for 12 psychiatric patients who had received a 50 mg oral dose of amitriptyline three times a day for an average of 32 days could be predicted from the single dose plasma clearance of amitriptyline.

Adult↗
PubMed1993

Antidepressant treatment of tinnitus patients: report of a randomized clinical trial and clinical prediction of benefit.

Ninety-two middle-aged and elderly patients with disabling tinnitus participated in a double-blind randomized clinical trial comparing nortriptyline (a tricyclic antidepressant) to placebo. The study was stratified for presence (n = 38) or absence (n = 54) of current major depression (by DSM-III criteria). Both active drug and placebo were given for 6 weeks following a dose adjustment phase; the median nightly dose of nortriptyline was 100 mg. The two primary outcome variables were global satisfaction questions: "Has the medication helped you in any way?" and "Has your tinnitus improved?" Sixty-seven percent of nortriptyline patients stated the drug had helped them, versus 40 percent of placebo patients (chi-square = 7.14, p = 0.008). However, tinnitus severity was not significantly affected by nortriptyline (active: 43%; placebo: 30%; chi-square = 1.567, p = N/S). Benefit was more likely to be reported by depressed patients, by patients with insomnia, by women, and by patients without cervical musculoskeletal disease. Nortriptyline is useful in some patients with disabling tinnitus, but has not been shown to directly affect tinnitus sensation. Placebo effects were strongly significant and must be considered important in tinnitus therapy. It is difficult to specify the most appropriate outcome measures for tinnitus therapeutic trials.

Aged↗
PubMed2000

Differential effects of tricyclic antidepressant drugs on membrane dynamics--a fluorescence spectroscopic study.

The effect of tricyclic antidepressant drugs amitriptyline, nortriptyline, imipramine and desipramine on synaptosomal membrane and lipid bilayer was studied using steady state and time dependent fluorescence spectroscopy of lipid specific fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH). The synaptosomal membrane was prepared from rat brain while liposomes were prepared from dimyristoyl phosphatidyl choline (DMPC) alone and a mixture of DMPC and cholesterol. Upon treatment with amitriptyline and nortriptyline a decrease was observed in the steady state anisotropy of DPH in DMPC liposomes as well as in rat brain synaptosomes. On the other hand, imipramine and desipramine did not cause any significant change. Amitriptyline and nortriptyline also decreased the steady state anisotropy of DPH in liposomes prepared from a mixture of DMPC and cholesterol. Fluorescence decay time and time dependent anisotropy of DPH in both the membranes were measured and the decay of anisotropy was analyzed using wobbling in cone model. Amitriptyline and nortriptyline treatment decreased the limiting anisotropy and order parameter, while the cone angle increased. Imipramine and desipramine did not cause significant change in these parameters. In addition to structural alterations, these drugs inhibited the activity of Na+-K+-ATPase in synaptosomal membrane, however, the decrease was more in case of amitriptyline and nortriptyline as compared to imipramine and desipramine. Our results suggest that the perturbation in membrane order caused by antidepressant drugs could depend on the net charge on the drug molecule.

Animals↗
PubMed2003

Somatic symptoms in treatment-resistant depression.

The purpose of this work was to study the prevalence of somatic symptoms in patients with treatment-resistant depression (TRD) and their impact on the response to antidepressant treatment. Somatic symptoms were assessed during the screen visit with the Symptom Questionnaire (SQ) somatic symptom (SQ-SS) and somatic well-being sub-scales (SQ-SWB) in 40 patients with TRD enrolled in a 6-week open trial of nortriptyline. A logistic regression was used to test whether SQ-SS or SQ-SWB scores predicted clinical response to nortriptyline. Ninety-five percent of patients reported at least one somatic symptom. Higher SQ-SS scores during the screen visit predicted poorer response to nortriptyline. There was a trend for lower SQ-SWB scores to predict poor response to nortriptyline. None of the patients with SQ-SS scores above the mean for the sample responded to nortriptyline. The overwhelming majority of patients with TRD presented with somatic symptoms. In addition, a greater number of somatic symptoms during the screen visit placed patients at risk for further treatment resistance.

Adult↗
PubMed2005

Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline.

Drugs with long terminal half-lives, such as terbinafine, have a potential for involvement in both long-lasting drug-drug interactions and interactions appearing weeks after discontinuation. We present a case report on a 37-year-old white woman with normal CYP2D6 metabolic capacity who was treated with amitriptyline, valproate, and olanzapine when terbinafine was introduced. Shortly thereafter she experienced extreme dryness of the mouth, nausea, and dizziness accompanied by a large increase in the serum concentrations of amitriptyline and nortriptyline. Terbinafine therapy was discontinued, and the amitriptyline dose was reduced. Surprisingly, the serum concentrations of amitriptyline and nortriptyline did not return to baseline until approximately 6 months later. Studies have shown that terbinafine is a highly potent competitive inhibitor of CYP2D6. CYP2D6 is an important intermediate enzyme in metabolism of amitriptyline to nortriptyline. Nortriptyline is further metabolized to 10-hydroxy metabolites, mainly by CYP2D6. It is, therefore, likely that the concomitant use of terbinafine was the major cause of the increased serum concentrations of amitriptyline and nortriptyline. Very different terbinafine elimination half-lives (17-400 hours) are stated in the physicians' reference guides. If the shortest estimates are used when adjusting the dose of interacting drugs, the risk of underestimating the duration of the interaction is large. Based on our data there is a risk of clinically significant drug-drug interactions for at least 3 months after stopping terbinafine intake.

Adult↗
PubMed1998

Two-year outcome of psychotic depression in late life.

OBJECTIVE: The purpose of this study was to determine whether elderly patients with psychotic depression differed in long-term outcome from patients with nonpsychotic depression. METHOD: The study group consisted of 19 patients with psychotic major depression who had responded to ECT (N = 15), nortriptyline and perphenazine (N = 2), or nortriptyline, perphenazine, and adjunctive lithium (N = 2) and 68 nonpsychotic depressed patients who had responded to either nortriptyline alone (N = 61) or nortriptyline and lithium (N = 7). All patients were maintained on regimens of full-dose nortriptyline. When prescribed for the index episode, adjunctive lithium was also maintained, but perphenazine was withdrawn 16 weeks after response. Patients were followed on a monthly basis for 2 years or until relapse or recurrence, whichever occurred first. RESULTS: Patients with psychotic depression had a substantially higher frequency of relapse or recurrence of depression and a shorter time to these events than nonpsychotic depressed patients. At index assessment, patients with psychosis were more severely depressed and had had more prior episodes of depression, but these factors did not account for the difference in outcome between the two groups. Furthermore, before entering the study, none of the psychotic patients had received adequate treatment for the index episode of depression, and so their poor outcome could not be attributed to prior treatment resistance. CONCLUSIONS: Even when they achieved remission and were maintained on a regimen of full-dose antidepressant medication, older patients with psychotic depression were at greater risk of relapse or recurrence than were their nonpsychotic counterparts. In particular, continuation/maintenance treatment with tricyclic monotherapy following response to ECT had limited efficacy in this group of patients. These findings raise important questions about the optimal treatment of psychotic depression in late life.

Age Factors↗
PubMed2002

Psychological intervention and antidepressant treatment in smoking cessation.

BACKGROUND: Sustained-release bupropion hydrochloride and nortriptyline hydrochloride have been shown to be efficacious in the treatment of cigarette smoking. It is not known whether psychological intervention increases the efficacy of these antidepressants. This study compared both drugs with placebo. It also examined the efficacy of these 2 drugs and placebo with and without psychological intervention. METHODS: This was a 2 (medical management vs psychological intervention) x 3 (bupropion vs nortriptyline vs placebo) randomized trial. Participants were 220 cigarette smokers. Outcome measures were biologically verified abstinence from cigarettes at weeks 12, 24, 36, and 52. RESULTS: Psychological intervention produced higher 7-day point-prevalence rates of biochemically verified abstinence than did medical management alone. With the use of point-prevalence abstinence, both nortriptyline and bupropion were more efficacious than placebo. On rates of 1-year continuous abstinence, the 2 drugs did not differ from each other or from placebo. Psychological intervention did not differ from medical management alone on rates of 1-year continuous abstinence. CONCLUSIONS: Both nortriptyline and bupropion are efficacious in producing abstinence in cigarette smokers. Similarly, psychological intervention produces better abstinence rates than simple medical management. Both drugs, and psychological intervention, have limited efficacy in producing sustained abstinence. The data also suggest that combined psychological intervention and antidepressant drug treatment may not be more effective than antidepressant drug treatment alone.

Adult↗
PubMed2000

Nonspecific binding of drugs to human liver microsomes.

AIMS: To characterize the nonspecific binding to human liver microsomes of drugs with varying physicochemical characteristics, and to develop a model for the effect of nonspecific binding on the in vitro kinetics of drug metabolism enzymes. METHODS: The extent of nonspecific binding to human liver microsomes of the acidic drugs caffeine, naproxen, tolbutamide and phenytoin, and of the basic drugs amiodarone, amitriptyline and nortriptyline was investigated. These drugs were chosen for study on the basis of their lipophilicity, charge, and extent of ionization at pH 7.4. The fraction of drug unbound in the microsomal mixture, fu(mic), was determined by equilibrium dialysis against 0.1 M phosphate buffer, pH 7.4. The data were fitted to a standard saturable binding model defined by the binding affinity KD, and the maximum binding capacity Bmax. The derived binding parameters, KD and Bmax, were used to simulate the effects of saturable nonspecific binding on in vitro enzyme kinetics. RESULTS: The acidic drugs caffeine, tolbutamide and naproxen did not bind appreciably to the microsomal membrane. Phenytoin, a lipophilic weak acid which is mainly unionized at pH 7. 4, was bound to a small extent (fu(mic) = 0.88) and the binding did not depend on drug concentration over the range used. The three weak bases amiodarone, amitriptyline and nortriptyline all bound extensively to the microsomal membrane. The binding was saturable for nortriptyline and amitriptyline. Bmax and KD values for nortriptyline at 1 mg ml-1 microsomal protein were 382 +/- 54 microM and 147 +/- 44 microM, respectively, and for amitriptyline were 375 +/- 23 microM and 178 +/- 33 microM, respectively. Bmax, but not KD, varied approximately proportionately with the microsome concentration. When KD is much less than the Km for a reaction, the apparent Km based on total drug can be corrected by multiplying by fu(mic). When the substrate concentration used in a kinetic study is similar to or greater than the KD (Km >/= KD), simulations predict complex effects on the reaction kinetics. When expressed in terms of total drug concentrations, sigmoidal reaction velocity vs substrate concentration plots and curved Eadie Hofstee plots are predicted. CONCLUSIONS: Nonspecific drug binding in microsomal incubation mixtures can be qualitatively predicted from the physicochemical characteristics of the drug substrate. The binding of lipophilic weak bases is saturable and can be described by a standard binding model. If the substrate concentrations used for in vitro kinetic studies are in the saturable binding range, complex effects are predicted on the reaction kinetics when expressed in terms of total (added) drug concentration. Sigmoidal reaction curves result which are similar to the Hill plots seen with cooperative substrate binding.

Amitriptyline↗
PubMed1981

Differentiation of the open and closed states of the ionic channels of nicotinic acetylcholine receptors by tricyclic antidepressants.

The actions of two clinically important dibenzocycloheptane antidepressant drugs, amitriptyline and nortriptyline, were studied on ionic channels of nicotinic acetylcholine (AcCho) receptors at the neuromuscular junction of frog skeletal muscle. Amitriptyline (5-10 microM) and nortriptyline (1-2 microM), like imipramine (5-10 microM), did not react with the nicotinic AcCho receptor but caused a voltage- and time-dependent decrease in the peak amplitude of the endplate current (epc). The time constant of epc decay, however, retained its voltage sensitivity. The voltage- and time-dependent effect of amitriptyline was nonlinear with regard to the current/voltage (I/V) relationship. Nortriptyline also had a more pronounced voltage- and time-dependent effect evidenced by a hysteresis loop in the I/V relationship of the epc was eliminated by the use of 50-msec stepwise changes of the membrane potential. The nonlinearity and hysteresis were due to a time-dependent phenomenon and did not involve previous AcCho receptor activation. The rate constant of the voltage- and time-dependent decrease in epc amplitude was sensitive to the membrane electric field and varied linearly with the membrane potential. Iontophoretically elicited epcs were much more depressed by both drugs than were spontaneous miniature epcs. There was no effect on the time constant of miniature epc decay, single-channel lifetime, or conductance. Thus (as we have pointed out in our histrionicotoxin studies) the primary site of action of these agents presumably is the activated but nonconducting species of the ionic channel of the nicotinic AcCho receptor. These agents, particularly nortriptyline, point to several different binding sites of the ionic channel and are suitable tools for the separation of the effects on peak current amplitude from its time constant of decay.

Amitriptyline↗
PubMed1992

Antidepressant treatment of tinnitus patients. Interim report of a randomized clinical trial.

Previous studies have shown that severe tinnitus is associated with current major depression, and that tricyclic antidepressant therapy reduces tinnitus disability, at least compared to brief placebo treatment. We are completing a randomized clinical trial of nortriptyline, stratified by presence or absence of current major depression, in 100 patients with severe chronic tinnitus. Preliminary analysis of global outcome on the first 52 patients reveals that those receiving nortriptyline were more likely to feel that their drug had been helpful (74% vs. 36%, p less than 0.01), but were equally likely to report that their tinnitus was improved (37% vs. 32%, NS). So far, neither audiometric nor self-report measures of tinnitus have demonstrated statistically significant differences between active drug and placebo. Simply administered visual rating scales, if externally-referenced, correlated better with global outcome than did the Iowa Tinnitus Handicap Questionnaire. As expected, nortriptyline was significantly superior to placebo with respect to reductions in the Hamilton Depression Scale, especially in depressed patients. Paradoxically, depressed patients reported more disability and loudness on all scales, but had lower 1 kHz tinnitus intensity matches and dynamic ranges. Our preliminary conclusions are that: 1) nortriptyline reduces depression in patients with severe tinnitus, 2) placebo effects are very important in the treatment of tinnitus, 3) depression may be associated with decreased tolerance for both internal and external sounds, and 4) it is still difficult to specify the appropriate measures of tinnitus loudness and disability for use in therapeutic trials.

Depressive Disorder↗