Plasma and erythrocyte levels of tricyclic antidepressants in depressed patients.

Plasma and red blood cells (RBCs), amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and desmethyl doxepin levels were measured in depressed inpatients during steady-state kinetics. A strong positive correlation between the drug levels in plasma and RBCs was found for amitriptyline, nortriptyline, desipramine, and desmethyl doxepin. However, at a given plasma level, up to a 6-fold interindividual variation in the RBC drug levels was found. The correlations between plasma and RBC imipramine and doxepin levels were low. The interindividual variation in the RBC-plasma tricyclic level ratios was large enough to warrant further clinical studies on the relationship between efficacy and pharmacokinetics of tricyclic antidepressants.     

Therapeutic monitoring of treatment with antidepressants

The present status of the relationship between blood plasma concentrations of tricyclic antidepressants and clinical outcome is reviewed. Plasma levels of imipramine, desmethylimipramine and nortriptyline are generally accepted as useful clinically but it is more difficult to establish a well-defined relationship between clomipramine and amitriptyline blood levels and clinical outcome. These assays are clinically relevant, particularly in cases of treatment failure, but also in the treatment of the elderly and of overdosage. The technical problems of the assay have practically been solved with the development of new analytic methods.     

Valpromide-amitriptyline interaction. Increase in the bioavailability of amitriptyline and nortriptyline caused by valpromide

Valpromide is largely used in the therapy of affective disorders for its presumed thymoregulating activity. So, it is often associated with tricyclic antidepressant treatment. Previous clinical studies lead us to consider the possibility of an interaction between valpromide and tricyclic antidepressants, interaction which could result in an increase of antidepressant plasma concentrations. But no pharmacokinetic study has been realized up to now in order to clearly demonstrate such a phenomenon. The authors studied amitriptyline and nortriptyline plasma levels in two groups of ten patients receiving 125 mg amitriptyline, once a day, during 20 days. In the second group, patients also received 600 mg valpromide daily after ten days on amitriptyline. In the first group amitriptyline and nortriptyline plasma concentrations remained stable between the tenth and the twentieth day. In the second group, addition of valpromide resulted in a significant increase of antidepressant plasma levels: from 70.5 +/- 35 to 105.5 +/- 49 ng/ml (p less than 0.0003) for amitriptyline, and from 61.0 +/- 34 to 100.5 +/- 65 ng/ml (p less than 0.01) for nortriptyline.     

Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity.

Studies investigating a possible relationship between the plasma concentration of tricyclic antidepressants and clinical response have measured only the tertiary and secondary amine forms of these drugs. The present study shows that the hydroxy metabolites of tricyclic antidepressants might also be active. Hydroxylated imipramine, desipramine, chlorimipramine, and nortriptyline inhibit the uptake of norepinephrine and serotonin into synaptosomes to the same extent as do their parent compounds. Hydroxylated nortriptyline and imipramine reverse or prevent reserpine-induced motor retardation and ptosis. Following chronic imipramine, significant steady-state concentrations of unconjugated hydroxylated metabolites are present in rat tissues including the cerebrospinal fluid. Accounting for steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in man may help to clarify whether there is a relationship between active drug concentration and clinical effect.     

Treating delusional depressives with amitriptyline

Thirty-five delusional depressed patients were treated for either 28 or 35 days with amitriptyline. The 12 responders could not be differentiated from the nonresponders on a variety of demographic and clinical characteristics. Patients with amitriptyline+nortriptyline plasma levels above 250 ng/ml were significantly more likely to be responders than were patients with levels below that value (p less than .05). A review of the relevant literature revealed that, although some delusional depressives do respond to treatment with tricyclic antidepressants, the presence of delusions is a predictor of poor response to tricyclic antidepressants.     

An inverse correlation between serum levels of desmethylimipramine and melatonin-like immunoreactivity in DMI-responsive depressives

The relationship between plasma levels of the tricyclic antidepressant desmethylimipramine (DMI) and plasma levels of melatonin-like immunoreactivity was studied in 32 endogenously depressed patients. An inverse correlation between plasma levels of DMI and plasma levels of melatonin-like immunoreactivity was found in the group of clinical responders to the chronic administration of the drug. The nonresponders had higher levels of melatonin-like immunoreactivity at comparable levels of DMI. This findings is consistent with the hypothesis that chronic high plasma levels of DMI may down-regulate the β-adrenergic receptors in man. However, some other homeostatic mechanisms may be involved in the clinical response.     

Simultaneous measurement of various antidepressants in the plasma of depressed patients by high performance liquid chromatography

A simultaneous analytical method was reported for measuring the plasma levels of amitriptyline, imipramine, clomipramine, maprotiline, nortriptyline, desipramine, desmethylclomipramine, desmethylmaprotiline and amoxapine by high performance liquid chromatography (HPLC). The total plasma levels of each parent drug plus its desmethyl metabolite were monitored in 29 depressed patients administered with amitriptyline, maprotiline or amoxapine using the present analytical method. There were significant linear correlations between the dose per kg body weight and the total plasma levels with amitriptyline and maprotiline, but no such correlation was found with amoxapine. The ratios of total plasma levels to dose per kg body weight of these three drugs were lower in outpatients than in inpatients. These results indicate that the monitoring of plasma levels of antidepressants is useful in treating depression.     

Excess fatality from desipramine in children and adolescents

OBJECTIVE: To compare the case fatality rate (CFR) from desipramine ingestion in children and adolescents with that of other tricyclic antidepressants. METHOD: All mentions of desipramine, amitriptyline, imipramine, nortriptyline, and doxepin in children and adolescents recorded in the American Association of Poison Control Centers Toxic Exposure Surveillance System from 1983 to 2002 were analyzed. The CFR for each drug was defined as the ratio of the number of deaths/number of mentioned exposures. RESULTS: There were 24 fatalities in children younger than 6 years old (desipramine, n=10; amitriptyline, n=7; doxepin, n=3; imipramine, n=3; nortriptyline, n=1) and 144 fatalities in older children and adolescents (desipramine, n=56; amitriptyline, n=30; doxepin, n=16; imipramine, n=31; nortriptyline, n=11). The CFR from desipramine was significantly higher compared with the other tricyclic antidepressants in children younger than 6 years old (chi=36, p<.001) and in older children and adolescents (chi=155, p<.001). The CFR from desipramine exceeded that of amitriptyline, doxepin, imipramine, and nortriptyline by 7- to 8-, 4-, 6- to 12-, and 7- to 10-fold, respectively. CONCLUSIONS: The excess CFR from desipramine in children and adolescents and the reports of sudden death in children treated with therapeutic doses call for caution in prescribing desipramine to children and adolescents.     

Grapefruit juice as a contraindication? An approach in psychiatry

The authors investigated in this preliminary study the influence of grapefruit juice on the metabolism of two tricyclic antidepressants. An increase of plasma concentrations is observed indeed for many drugs when administered concomitantly with grapefruit juice. This effect was mainly attributed to inhibition of cytochrome P450 1A2 and 3A4 enzymes by naringenin. These isoenzymes are involved too in the metabolism of many psychotropic drugs. Only two benzodiazepines (midazolam and triazolam) were studied in the conditions of grapefruit juice association. All these studies are performed in healthy subjects and with a study design very different from the clinical conditions. On the basis of these considerations, the authors hypothesized that grapefruit juice should inhibit tricyclic antidepressant metabolism and thus increase the bioavailability of these drugs. They want to precise if this possible drug plasma level increase could be clinically important for depressed patients. Fourteen depressed inpatients were selected for the study. Seven of them received amitriptyline (100 to 150 mg/d) and the seven others clomipramine (112.5 to 225 mg/d). Tricyclic antidepressant and desmethylated metabolite plasma levels were determined on four occasions. The first and second day samples were obtained to determined the plasma level intraindividual variability of antidepressants. On the third and fourth days, plasma levels were determined after an oral coadministration of the antidepressant and 250 ml of pure and fresh grapefruit juice. One patient was excluded from the study due to the coadministration of clomipramine and fluvoxamine. There is indeed a major drug-interaction between these two drugs, and the tricyclic antidepressant plasma levels of this patient were in the toxic range, without side effect. In this group of patients, there was no metabolic interaction between amitriptyline and grapefruit juice. But the mean plasma levels of clomipramine and desmethylclomipramine increased after coadministration of this juice (+4.5% and +10.5% respectively). The authors concluded that with these preliminary results, the potential clinical relevance of this interaction cannot be estimated.     

Absence of anticholinergic activity of rolipram, an antidepressant with a novel mechanism of action, in three different animal models in vivo

Rolipram, in contrast to the tricyclic antidepressants amitriptyline and imipramine or the acetylcholine receptor antagonist atropine, failed to antagonize the salivation, hypothermia, or tremor caused in mice by the muscarinic receptor agonists pilocarpine or oxotremorine. The absence of anticholinergic activity, the extremely low therapeutic dose, and the novel mechanism of antidepressant action suggest that rolipram may also be a well tolerable antidepressant suitable for the treatment of problematic subpopulations of depressives such as elderly patients.     

Therapeutic implications of tricyclic antidepressant plasma levels.

Methodological advances in drug assay techniques and their increasing availability have made the measurement of tricyclic antidepressant plasma levels more frequent and even fashionable. Plasma levels of tricyclics have been correlated with diagnosis, prognosis, clinical response, and side effects. But even in the area most extensively examined, the correlation between plasma level and clinical response, the results have been conflicting. Different studies have suggested that there is no relationship between plasma level and clinical response, as well as positive and negative correlations, and even a curvilinear relationship. On the basis of available evidence, it is impossible to define a therapeutic range of plasma levels that will be applicable to depressed patients as a group. For the moment, the problem of finding a suitable therapeutic dose for the individual patient remains of paramount importance. Studies to date suggest the need to take into consideration genetic factors, previous and present use of other drugs, the possibility that therapeutic failure might be a result of too high as well as too low a dose, as well as the possible relationship between high plasma levels and side effects. Also, since for the specific individual, the metabolism of different tricyclic antidepressants is similar, it may be useful to adjust dosages until a therapeutic one is obtained instead of immediately switching to another medication. Finally, although the usefulness of routine plasma level determination remains to be established, this technique may be indicated in cases of intractable depression and remains an important research tool.     

Depression,antidepressants, and plasma DBH

Plasma levels of dopamine-β-hydroxylase (DBH) were determined in 16 unmedicated patients with major depressive episodes (nonpsychotic) and in an equal number of normal subjects, before and after 4 weeks of treatment with tricyclic antidepressants. Some eight patients were treated with amitriptyline, and the remainder received desipramine. The controls remained medication free during the entire experimental period. Degrees of depression were quantified before and after treatment with the Hamilton Rating Scale of Depression (HRSD). There were no significant differences between the depressed patients and the controls on levels of DBH. Similarly, there were no within-group, pre-posttreatment differences on the enzyme levels in either group. Pre-and posttreatment HRSD scores did not correlate with corresponding plasma DBH levels. Plasma levels of amitriptyline, nortriptyline (product of amitriptyline in the body), and desipramine at the end of 4 weeks of treatment also failed to correlate with the enzyme levels.     

TEMPORAL DEVELOPMENT OF 2'',3''-DIDEOXYINOSINE (DDI)-INDUCED PERIPHERAL MYELINOPATHY

Postherpetic neuralgia (PHN) is a chronic pain syndrome that is often refractory to treatment and can last for years, causing physical and social disability, psychological distress, and increased use of the healthcare system. In this paper we provide an update on recent developments in the treatment of PHN. We emphasize the results of recent studies that provide an evidence-based approach for treating PHN that was not available until very recently. In randomised, controlled clinical trials, the topical lidocaine patch, gabapentin, and controlled release oxycodone have been shown to provide superior pain relief in patients with PHN when compared with placebo. It has also recently been demonstrated that the tricyclic antidepressant nortriptyline provides equivalent analgesic benefit when compared with amitriptyline, but is better tolerated. Based on these results, nortriptyline can now be considered the preferred antidepressant for the treatment of PHN, although desipramine may be used if the patient experiences unacceptable sedation from nortriptyline. The topical lidocaine patch, gabapentin and controlled release oxycodone all appear to be as effective as tricyclic antidepressants in the treatment of patients with PHN, and the results of these recent studies suggest that each of these treatments should be considered early in the course of treatment. Additional controlled trials are needed to compare the efficacy and tolerability of these 4 treatments—tricyclic antidepressants, gabapentin, the topical lidocaine patch and controlled release opioid analgesics—used singly and in various combinations in the treatment of patients with PHN.     

High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation.

BACKGROUND: A wide variety of antidepressants act as noncompetitive antagonists of nicotinic acetylcholine receptors (nAChRs), but the relationship between this antagonism and the therapeutic effects of antidepressants is unknown. METHODS: Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral models to determine whether these receptors are required for behavioral effects of amitriptyline in common models of antidepressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation. RESULTS: Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drugs were used in combination. Mice lacking high-affinity nAChRs showed no behavioral response to amitriptyline. Finally, after chronic treatment with amitriptyline, nAChR knockout mice did not show the increase in hippocampal cell proliferation seen in wild-type mice. CONCLUSIONS: These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.     

Adequate treatment with imipramine in continuation treatment

Maintenance treatment studies done with tricyclic antidepressants have used the equivalent of 150 mg or less of imipramine in prophylactic clinical trials. In an ongoing 3-year maintenance trial, the authors are using imipramine in dosages greater than 150 mg/day for both acute and continuation treatment (4 to 6 months) of recurrent depression in order to test the efficacy of this dosage level. Fifty-seven depressed patients who received tricyclic drug treatment and interpersonal psychotherapy during the acute and continuation phases of the study tolerated this dosage level well (mean dose, 217 mg/day of imipramine), reported few adverse effects on a somatic symptom checklist, and demonstrated a high level of compliance as shown by plasma concentration/dosage (L/D) ratios. The authors found that the time course of the L/D ratio is associated with higher steady-state plasma concentrations than those observed with similar dosages in shorter-term tricyclic antidepressant treatment.     

Cardiac antiarrhythmic effect of nortriptyline

With a quinidine-like cardiac action, the tricyclic antidepressant drugs, imipramine in particular, have been proposed as potentially antiarrhythmic agents. The antiarrhythmic activity of nortriptyline is described in a depressed patient with premature ventricular complexes, and the basis for this activity is discussed.     

Imipramine and tinnitus

Although tinnitus is listed among the rare neurologic side effects of tricyclic antidepressants, little is known about its prevalence, mechanism of development, course, and management. A chart review of 475 patients treated with tricyclic antidepressants indicated that tinnitus occurred in about 1% of the patients. The case vignettes of 5 patients who developed tinnitus in the course of imipramine therapy are presented. Each developed tinnitus in the second or third week of treatment with imipramine at daily dosages of 150-250 mg and at combined plasma imipramine-desipramine levels between 200-450 ng/ml. In each patient, tinnitus subsided spontaneously within 2-4 weeks of onset without any specific treatment, even though the daily dosage of imipramine and the plasma tricyclic levels were constant or increased. Possible mechanisms of development of tinnitus and implications for tricyclic antidepressant therapy are discussed.     

A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients.

Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind randomized comparison in 116 psychiatric inpatients and outpatients (mean age: 72+/-8 years) who presented with a major depressive episode or melancholic depression. Discontinuation and response rates were compared in patients who began or who completed treatment. The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine (33% vs. 16%). There were no significant differences between the rates of response in the Intent-to-Treat analysis (nortriptyline: 57% vs. paroxetine: 55% ), or the Completer analysis (nortriptyline: 78% vs. paroxetine: 84%). Although paroxetine appears to be better tolerated than nortriptyline, the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients, including hospitalized patients and those with melancholic features.     

Tricyclic antidepressants for children with cancer

Eight depressed children with cancer had a rapid clinical response to low doses of imipramine or amitriptyline. Because of the many variables affecting cancer patients, the mechanism by which tricyclic antidepressant treatment produced this response is unclear.     

Charcoal enhancement of treatment for tricyclic-induced mania

Induction of mania by tricyclic antidepressants (TCAs) is controversial, with indirect evidence for and against it. Unusual direct evidence of it was observed in a 77-year-old female patient having ingested an amitriptyline overdose. Mania developed while the TCA blood levels were high, and responded to a combination of charcoal and valproate. However, mania reappeared when charcoal was discontinued, and disappeared again when it was restarted. This time course suggests a therapeutic advantage for adding charcoal to valproate in treating tricyclic-induced mania. Presumably, charcoal might have removed a mania-inducing metabolite of amitriptyline. Moreover, repeated doses of oral activated charcoal accelerated the elimination of TCA from the blood stream to several times its original rate, which is consistent with interruption of the enterohepatic circulation. This enhanced elimination and improved outcome illustrate the value of repeated charcoal doses after TCA overdose, and suggest its use when mania develops in a patient who takes an antidepressant, at least amitriptyline or nortriptyline.