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PubMed2004

Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy.

BACKGROUND: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. METHODS: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. RESULTS: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >or=5; area under the curve, 0.733; P = 0.008). Carriers of two functional CYP2D6 alleles had a significantly lower risk of side effects than carriers of only one functional allele (12.1% vs 76.5%; P = 0.00001). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele [0 of 13 (0%) vs 9 of 11 (81.8%) for the high-risk group; P = 0.00004]. We found no correlations between drug concentrations or genotypes and therapeutic response. CONCLUSIONS: Combined pharmacogenetic testing for CYP2D6 and CYP2C19 identifies patients with low risk for side effects in amitriptyline therapy and could possibly be used to individualize antidepressive regimens and reduce treatment cost. Identification of genotypes associated with slightly reduced intermediate metabolism may be more important than currently anticipated. It could also be the key to demonstrating cost-effectiveness for CYP2D6 genotyping in critical dose drugs.

Adult↗
PubMed1976

The measurement of plasma levels of tricyclic antidepressant drugs.

A double-isotope derivative dilution procedure for measuring plasma levels of Nortriptyline is described. The assay is specific, sensitive, precise and reproducible. Studies on the variation in steady-state plasma levels are described on a fixed oral dosage of nortriptyline. Between individual variations in steady-state plasma levels are large. Between day within individual variation is 15-20%. Dosage regime, time of blood sampling after last oral dose and the method of blood handling are unlikely to affect the steady-state plasma levels. Within an individual, the oral dose, duration of treatment and concomitant drug treatment are all important determinants of the steady-state plasma level.

Blood Preservation↗
PubMed1982

Experimental studies on the effects of physostigmine and of isoproterenol on toxicity produced by tricyclic antidepressant agents.

The IV infusion of nortriptyline and amitriptyline (0.5 mg/kg/min) in anesthetized cats produced death within 60 min of continuous infusion. The tricyclic antidepressant agents produced a quinidine-like depression of the myocardium characterized by bradycardia, depression of contractile force, conduction defects, bradyarrhythmias, and hypotension. The simultaneous IV infusion of isoproterenol (0.1 microgram/ kg/min) produced significant protection against death produced by the TCA drugs. The results suggested that the positive chronotropic, inotropic, and dromotropic actions of isoproterenol may all be contributory factors in the protection. Pretreatment with a large dose of physostigmine (0.2 mg/kg) produced a rightward shift of the nortriptyline time-mortality curve. The small degree of protection produced by the anticholinesterase drug may be due to a respiratory stimulant action rather than a cardiac action.

Amitriptyline↗
PubMed1992

Severe amitriptyline overdose: relationship between toxicokinetics and toxicodynamics.

The clinical features and toxicokinetics of amitriptyline were studied in nine patients with severe amitriptyline poisoning. Amitriptyline and amitriptyline metabolites were studied in plasma, red blood cells, and cerebral spinal fluid. Eight patients were intubated and six required assisted ventilation. Two patients had ventricular arrhythmias, three patients convulsions and two were hypotensive. All complications developed within four hours of admission. Early in the course of the intoxication the QRS duration correlated with plasma, unbound and red blood cell nortriptyline concentration. The QRS duration also correlated with unbound but not the plasma amitriptyline concentration. The level of consciousness correlated with the plasma and unbound amitriptyline both in alpha and beta phase and with red blood cell amitriptyline in alpha phase. There was no correlation between nortriptyline concentration and level of consciousness. No correlation between coma grade or QRS duration and cerebral spinal fluid concentration of amitriptyline was found. There was no correlation between any hydroxymetabolite in blood or cerebral spinal fluid and QRS duration or coma grade. The beta half-life for amitriptyline was shorter for two patients with high concentrations of hydroxymetabolites. Although intubated, neither patient required assisted ventilation or developed complications. Because of the wide range of concentrations of amitriptyline and amitriptyline metabolites observed between individuals, it is not possible to predict outcome based on a single tricyclic antidepressant concentration.

Amitriptyline↗
PubMed1999

Which elderly depressed patients remain well on maintenance interpersonal psychotherapy alone?: report from the Pittsburgh study of maintenance therapies in late-life depression.

The aim of this study was to identify elderly depressed patients who can remain well on maintenance Interpersonal Psychotherapy (IPT) alone, after discontinuation of antidepressant medication. Using Cox proportional hazards models, increased severity of depression at pretreatment was associated with increased recurrence rates, to an extent greater in patients maintained on monthly IPT than in those maintained on nortriptyline. The long-term response to maintenance IPT was correctly identified in 20/25 cases by a pretreatment Hamilton score of > or = 20. Fourteen of sixteen patients with pretreatment scores of > or = 20 experienced recurrence of major depression on maintenance IPT, while 6/9 patients with pretreatment scores of less than 20 did not. (Fisher exact P = .01). The same pattern of recurrence in relation to severity was not evident in maintenance placebo, nortriptyline, or combination treatment. In addition, Hamilton scores during continuation treatment were lower (< or = 7) among those who remained well on maintenance IPT than among those who had recurrences. Elderly patients whose depressions are milder at baseline and who show excellent symptomatic remission during acute and continuation therapy may be good candidates for monthly maintenance IPT after initial successful treatment with antidepressant medication and psychotherapy.

Age Factors↗
PubMed2001

Continuation treatment of delusional depression in older adults.

Delusional depression responds poorly to acute antidepressant monotherapy but appears to respond to intensive combination pharmacotherapy, however with poor short-term outcomes after initial improvement, particularly in later life. The authors compared the efficacy and safety of continuation combination therapy to monotherapy among older patients after remission from a delusional depression. Twenty-nine older adults with SCID-diagnosed major depression with delusions received continuation treatment with nortriptyline-plus-perphenazine or nortriptyline-plus-placebo under randomized double-blind conditions after achieving remission after ECT. Of the 28 subjects included in efficacy analyses, 25% suffered relapses. The relapse frequency was nonsignificantly greater in combination therapy than in monotherapy subjects. However, combination subjects had significantly more extrapyramidal symptoms, an increased incidence of tardive dyskinesia, and a greater number of falls. Continuation treatment with a conventional antipsychotic does not decrease relapse rates but is associated with significant untoward adverse events in older persons after recovery from a delusional depression.

Aged↗
PubMed1992

[Serum concentrations of amitriptyline and its metabolites and clinical effect in depressive patients].

The serum concentrations of amitriptyline and its 3 metabolites--nortriptyline, 10-hydroxy-amitriptyline and 10-hydroxy-nortriptyline were determined in 18 depressive patients treated with amitriptyline for 6 weeks. The relationships between the serum concentrations and the clinical effects were statistically analyzed and showed significant correlations. The authors suggest that the total TAD serum concentration (280 ng/ml) can be used as the index for clinical efficacy, so far as the above data are concerned.

Adult↗
PubMed2006

[A case of Brugada syndrome with convulsive seizure during antidepressant administration: relation of antidepressant agents and arrhythmia leading to sudden death].

Brugada syndrome is an arrhythmogenetic disease characterized by electrocardiographic ST segment elevation in right precordial leads, which is called "coved type", and an increased risk of sudden death as the result of ventricular fibrillation. We presented a case of Brugada syndrome with a convulsive seizure, during administration of a tricyclic antidepressant for the treatment of a depressive state. A 43-year-old man with bipolar II disorder and obsessive-compulsive disorder was admitted to our hospital for the treatment of a depressive state. There was no medical history of heart failure. Nortriptyline was effective for his depressive as well as for obsessive symptoms. During the treatment, however, he presented a convulsive syncope. Electrocardiography (ECG) showed "coved type" ST segment elevation, and the patient consulted a cardiologist. Electrophysiological study revealed Brugada syndrome, and an implantable cardioverter defibrillator was placed. An overdose of antidepressants has been reported to produce a Brugada-type ECG because of its Na channel antagonism. However, in the present case, the abnormal ECG findings occurred following a usual dosage of nortriptyline. Thus, it is suggested that Brugada syndrome is related to a susceptibility to antidepressants in the present case. Every psychiatrist managing antidepressant therapy should be aware of Brugada syndrome and this ECG pattern, which may be a marker of sudden death.

Adult↗
PubMed1991

Treatment choice after one antidepressant fails: a survey of northeastern psychiatrists.

BACKGROUND: Because limited evidence exists to help clinicians choose the next step after a depressed patient fails to respond to an adequate trial of an antidepressant, I conducted a survey to explore psychiatrists' treatment choices. METHOD: I asked 118 northeastern psychiatrists what they would do next in response to a clinical vignette of an inpatient with DMS-III-R major depression who failed to respond to 4 weeks of nortriptyline at adequate blood levels. RESULTS: Lithium augmentation was chosen by more than a third (33.9%) of psychiatrists. Other choices, in order of decreasing frequency, were continuing nortriptyline for another 2 weeks (17.8%) and switching to either fluoxetine (16.1%), electroconvulsive therapy (11.0%), or a monoamine oxidase inhibitor (6.8%). Only one psychiatrist each chose thyroid augmentation or bupropion. CONCLUSIONS: The surveyed psychiatrists overwhelmingly preferred lithium augmentation over other strategies to manage treatment-resistant depression. Research on comparative strategies is lacking and urgently needed.

Antidepressive Agents↗
PubMed1987

Immunologic mimicry by a monoclonal antibody of the tricyclic anti-depressants' binding site on muscarinic acetylcholine receptors.

Inhibition constants of tricyclic anti-depressants and related drugs determined for a monoclonal anti-nortriptyline antibody were close to those previously calculated with the same compounds for the brain acetylcholine muscarinic receptor. A highly significant correlation was found between these two series of inhibition constants when no correlation existed between the inhibition constants for the antibody and those for other receptors. This suggests that the binding site for tricyclic anti-depressants on the antibody mimics the binding site for these ligands on muscarinic receptors. Although nortriptyline reveals a noncompetitive inhibition of N-methyl-scopolamine binding to muscarinic receptors, muscarinic ligands display weak or no binding to the antibody. These findings indicate that the binding site for tricyclic anti-depressants on the receptor is distinct from that for the muscarinic ligands.

Animals↗
PubMed1988

Pretreatment systolic orthostatic blood pressure (PSOP) and treatment response in elderly depressed inpatients.

This study evaluated the utility of morning pretreatment systolic orthostatic blood pressure (PSOP) in predicting clinical response to treatment with nortriptyline (N = 11) or electroconvulsive therapy (N = 6) in 17 depressed geriatric inpatients (mean age, 70.4 +/- 5.1). Morning PSOP showed a significant inverse correlation with percent change in Hamilton depression ratings (rho = -0.59, p less than 0.01; r = -0.52, p less than 0.02). In nortriptyline-treated patients (N = 10, excluding one outlier), PSOP was significantly correlated with percent change in Hamilton ratings (rho = -0.55, p less than 0.05); a similar association was also found in the subsample of electroconvulsive therapy-treated patients (N = 6, rho = -0.77, p less than 0.05). Patients with PSOP less than or equal to 10 mm Hg averaged 83% improvement in Hamilton depression ratings versus 64% improvement in patients with PSOP less than or equal to 10 mm Hg (p less than 0.05). In an age-equated contrast group of 15 inpatients with mixed clinical pictures of depression and cognitive impairment (11 with primary degenerative dementia with depressive features and four with major depressive disorder with cognitive impairment), no relation between PSOP and treatment response (as measured by Hamilton ratings) was found. The current findings extend earlier work in medically healthy, nonsuicidal geriatric depressed outpatients and suggest that PSOP may also be useful in predicting treatment response in older, cognitively intact depressed inpatients (many with concurrent medical illness and/or suicidal) but not in mixed depression-dementia.

Aged↗
PubMedDate not supplied

[Controlled clinical trial of nomifensine in treatment of depression (author's transl)].

Therapeutic efficacy of Nomifensine and Nortriptyline was compared with a double blind study on 29 patients suffering from several kinds of depression. The patients were admitted to the Institute of Nervous and Mental Diseases of the University of Florence. Drugs were administered according to a flexible dosage varying from 50 mg to 125 mg/day, subdivided in 2-3 doses. The experiment is referred to the first 15 days of treatment. In order to estimate the effect of the drugs, the Hamilton's scale for depression was used. This scale was administered before treatment and on the 5th, 10th, 15th, day of therapy. Scores of Hamilton's scale and of some "Clusters" were computerized. It was found that Nomifensine has an antidepressant effect comparable to that of Nortriptyline. No relevant differences were noted in the range of action of these drugs. No side-effects were detected in the doses employed.

Adjustment Disorders↗
PubMed1979

Monitoring tricyclic antidepressant plasma concentrations.

Plasma concentrations of tricyclic antidepressants were monitored during treatment of 126 patients. Noncompliance in taking medication was suspected in 19 patients because of unusually low plasma concentrations in relation to the presumed dose. Determinations of plasma concentrations may also be useful for detecting inadequate treatment as judged by levels below the presumed therapeutic range. Attempts to correlate plasma concentrations with clinical response to amitriptyline hydrochloride and nortriptyline hydrochloride failed, probably because of the heterogeneity of depressive syndromes being treated. Plasma concentrations were correlated highly with dose in the case of amitriptyline, less so in the case of other drugs. Amitriptyline and imipramine hydrochloride generally produced plasma concentrations of the parent drug and metabolite higher in nanograms per milliliter than was the daily dose in milligrams; nortriptyline and desipramine hydrochloride did the opposite.

Amitriptyline↗
PubMed1979

The effect of tricyclic antidepressants on cerebral fluid dynamics.

Tricyclic antidepressants are thought to act primarily via effects on adrenergic neurotransmitters. Recent research supports the concept that a major function of the central adrenergic system is the modulation of cerebral fluid dynamics. Based on this concept, studies in the rat were conducted to assess the effects of these drugs on cerebral capillary permeability and flow by quantitating changes in the extraction fraction of water (Ew). Amitriptyline and nortriptyline produced significant increased in Ew for the total forebrain (from control values of 0.67 to experimental values as high as 0.99) while protriptyline had no effect on Ew. The amitriptyline-induced increase in Ew occurred at doses which produced plasma levels (500 ng/ml) near the range defined as therapeutic in depression studies. The magnitude of the effect was similar for both amitriptyline and nortriptyline representing a 35--40% increase over control values. The effects were uniformly observed throughout the forebrain: rostral telencephalon, caudal telencephalon, and diencephalon.

Amitriptyline↗
PubMed1980

Potentiation of responses to adrenergic nerve stimulation in isolated rat atria during chronic tricyclic antidepressant administration.

Several weeks of tricyclic antidepressant administration are required to effectively reverse depression. To determine whether there are adaptive changes in andrenergic nerve function which correspond to the clinical onset of antidepressant action, the endogenous norepinephrine content, [3H]norepinephrine uptake and retention, responses to exogenous norepinephrine and the release of norepinephrine during field stimulation were studied using left atrial strips isolated from rats treated with either acutely or chronically with tricyclic antidepressants. Desipramine, nortriptyline, chlorimipramine and iprindole were administered to rats, 10 mg/kg i.p., twice daily. After 14 days of drug administration, the responses to field stimulation were potentiated markedly by all four tricyclics. In contrast, 1 day of tricyclic treatment had only slight potentiating effects. When phenoxybenzamine, 10(-7) M, was added to the organ bath in order to block the inhibitory presynaptic alpha receptor, the responses of control atria and atria from rats treated for 1 day with desipramine were potentiated but those of atria treated for 21 days with desipramine were not potentiated. The development of presynaptic alpha receptor subsensitivity during chronic tricyclic administration would explain these findings. Other possible explanations were also investigated. The uptake and retention of [3H]norepinephrine was markedly inhibited to a similar degree of either 1 or 14 days of desipramine or nortriptyline administration. One day of chlorimipramine treatment decreased the amount of [3H]norepinephrine taken up and retained by left atrial strips, and after 14 days of treatment decreased the amount further. In contrast, neither 1 nor 14 days of iprindole administration had any effect on the uptake and retention of [3H]norepinephrine. These data indicate that the potentiation of the responses to field stimulation cannot be explained by the inhibition of norepinephrine uptake. The inotropic response to exogenous norepinephrine was not altered by any duration of administration of any of the four tricyclics studied. Furthermore, the endogenous norepinephrine content of atria did not change after as many as 21 days of desipramine administration. The present results indicate that the potentiation of the effects of adrenergic nerve transmission during chronic tricyclic administration is the result of an increase in norepinephrine release which occurs due to the development of presynaptic alpha receptor subsensitivity. The time course of development of presynaptic receptor subsensitivity corresponds well with the onset of clinical activity of these drugs.

Animals↗
PubMed1978

Effects of prazosin and phentolamine on responses to field stimulation and to noradrenaline in vas deferens and anococcygeus muscle of the rat.

The effects of phentolamine (10(-6)M) and prazosin (10(-7)M) on contractile responses, in the presence of cocaine or nortriptyline, were investigated in vas deferens and anococcygeus muscle of rat. Cocaine (10(-5)M) and nortriptyline (10(-6)M) had no effect on maximum responses to field stimulation, (--)-noradrenaline, methoxamine, and acetylcholine in anococcygeus muscle. However, both cocaine (3.3 x 10(-5)M) and nortripthline (10(-6)M) potentiated maximum responses to (--)-noradrenaline without altering the maximum response to field stimulation in vas deferens. In vas deferens, phentolamine potentiated or inhibited the responses to field stimulation depending on the frequency whereas prazosin inhibited all responses to field stimulation. In anococcygeus muscle, both phentolamine and prazosin inhibited all responses to field stimulation. In vas deferens and anococcygeus muscle, prazosin was a more potent antagonist of responses to (--)-noradrenaline than phentolamine. These results show that prazosin is a more potent postsynaptic alpha-adrenoceptor antagonist than phentolamine and suggest that prazosin has little or no affinity for presynaptic alpha-adrenoceptors.

Animals↗
PubMed1978

High-performance liquid-chromatographic simultaneous determination of commonly used tricyclic antidepressants.

We report a method for simultaneous measurement of five commonly used tricyclic antidepressant drugs (doxepin, desipramine, nortriptyline, imipramine, and amitriptyline) in serum by paired-ion high-performance liquid chromatography, with use of a reversed-phase column and ultraviolet detection at 254 nm. The drugs are extracted from 2 ml of serum at pH 14 into hexane/isoamyl alcohol (99/1 by vol) and re-extracted into 200 microliter of 0.1 mol/liter HCI. An aliquot of the aqueous acid phase is chromatographed with use of a methanol/acetonitrile/water (41/15/44) solvent system, containing 5 mmol of pentanesulfonic acid per liter of phosphate buffer (0.1 mol/liter, pH 6.5), at a flow rate of 1,5 ml/min. Analytical recoveries of the drugs from serum increase with increasing concentration, from 62% at 25 microgram/liter to 93% at 300 microgram/liter. Linear response is observed for drug concentrations up to 1500 microgram/liter and the detection limit is 2-3 microgram/liter. Within-run precision ranges from 1.4 to 2.9% and day-to-day precision from 1.7 to 7%, depending on the specific drug. The entire procedure can be completed within 45 min and is well adapted to the routine clinical laboratory. Of 48 common basic and several neutral drugs tested for possible interferences, only three benzodiazepines, three phenothiazines, and three antihistamines interfere with the assay of doxepin, desipramine, and nortriptyline, respectively.

Amitriptyline↗
PubMed1980

Plasma levels and clinical improvement--a comparative study of clomipramine and amitriptyline in depression.

To see if the clinical efficacy of amitriptyline and clomipramine is related to plasma level of the active drug or its main metabolite, or to the balance between them, plasma levels and clinical progress have been studied in 48 patients taking standard dosage. Dose for dose, plasma levels of clomipramine and desmethylclomipramine are usually higher than those of amitriptyline and its main metabolite nortriptyline, but no significant relationship between plasma levels and clinical improvement was found following clomipramine administration. By contrast, optimum responses to amitriptyline therapy were obtained at plasma levels of 50--100 micrograms/l for amitryiptyline itself and 25--75 micrograms/l for nortriptyline, but when their ratio exceeded 0--7 improvement declined. Steady states were reached after two to three weeks but a crude measure could be obtained from the plasma level after four days' treatment. Clomipramine and amitriptyline appeared to be equally effective, with clomipramine taking slightly longer to relieve depression.

Amitriptyline↗