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I report a case of intestinal pseudo-obstruction, spontaneous caecal perforation and faecal peritonitis caused by an overdose of amitriptyline. This rare but serious complication should be borne in mind in patients who remain constipated while convalescing after self-poisoning with tricyclic antidepressants.
A case of venlafaxine-induced serotonin syndrome is described with relapse following the introduction of amitriptyline, despite a 2-week period between the discontinuation of one drug and the commencement of the other. Electroencephalography may play an important part in diagnosis. With the increasing use of selective serotonin re-uptake inhibitors, greater awareness of the serotonin syndrome is necessary. Furthermore, the potential for drug interactions which may lead to the syndrome needs to be recognised.
The electrically stimulated release of [3H]acetylcholine from the parasympathetic nerve terminals of the rat iris in vitro is increased in a dose-dependent manner by scopolamine but is decreased by the tricyclic antidepressants amitriptyline and imipramine. The increased release in the presence of scopolamine seems to be due to the blockade of a presynaptic muscarinic autoreceptor that, in the drug-free state, inhibits the release of acetylcholine. However, at drug concentrations that should have comparable antimuscarinic potency, the antidepressants inhibit the release of acetylcholine. This suggests that the anticholinergic side effects of the antidepressants may be due to the reduced release of acetylcholine from parasympathetic nerve terminals as well as a possible direct postsynaptic muscarinic receptor blocking action. Whatever the mechanism of this action, the antidepressants do not have the same effect as scopolamine at the presynaptic muscarinic autoreceptor in the rat iris.
Although atypical antipsychotics are on the rise, traditional treatment of psychotic (or delusional) depression mostly includes the addition of classical antipsychotics to antidepressants. As there are only few data supporting this approach compared with antidepressant monotherapy, and almost no data comparing it with antidepressants of the latest generation, we conducted a retrospective chart analysis and a prospective, randomized open study on the efficacy and tolerability of nefazodone monotherapy versus combined treatment with amitriptyline and haloperidol in psychotic depression. The results suggest that the addition of classical antipsychotics should be reserved for those with very severe psychotic symptoms, but may not be needed in milder forms.
BACKGROUND: There is evidence for activation of the hypothalamus-pituitary-adrenal system in depressed patients to be associated with increased secretion of adrenal androgens. However, there is only limited information about the effect of different classes of antidepressants on the course of adrenal androgens. METHODS: Dehydroepiandrosterone sulfate (DHEA-S) serum concentrations were measured in 80 patients being treated with amitriptyline (AMI) or paroxetine (PAROX) for a period of 35 days. RESULTS: Using analysis of variance with repeated measures, we found a significant effect of treatment upon DHEA-S serum concentrations that declined more in AMI-treated (before vs. after: 1.89+/-1.16 vs. 1.46 +/- 0.96 mg/l), compared to PAROX-treated patients (1.56+/-1.09 vs. 1.50+/-1.04 mg/l). CONCLUSIONS: Our results show changes in DHEA-S serum concentrations during antidepressant treatment to depend on medication.
Thirty-eight depressed female inpatients, treated intramuscularly with 100 mg/day amitriptyline (AMT), were monitored to investigate the relationships between plasma levels of the drug and its metabolite nortriptyline (NT), the urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), side effects and clinical response. Considering the whole group, the clinical improvement was better within an intermediate range of AMT plus NT plasma concentrations (100-200 ng/ml). A more favorable outcome was also observed at NT plasma levels below 55 ng/ml. No significantly different percent clinical response among the patient clinical subgroups was observed as well as no significant correlations between MHPG decrease and drug plasma levels.
An automatic procedure for the online recognition of REM sleep appears to be a necessary tool for selective REM sleep deprivation in depressive patients. To develop such a procedure we applied an artificial neural network to preprocessed single-channel EEG activity. EOG and EMG information was purposely not provided as input to the network. A generalized back-propagation algorithm was used for computer simulation. The sleep profile scored manually according to Rechtschaffen and Kales served as the desired output during the training period and as standard for the judgement of the network output during working mode. Polysomnographic recordings from 5 healthy subjects were pooled to train the network, whereas second-night EEG recordings from the same subjects were used as independent working data sets. We further applied the network to the data of 5 depressive patients without medication and 6 depressive patients treated with amitriptyline. For these groups between 84.9 and 88.6% out of all time periods consisting of 20 s of continuous EEG activity were correctly classified. The indicator function of REM sleep was well approximated by the network output in the course of the night. Especially the REM onset was excellently recognized. The inclusion of patient data in the training set yielded a different network, which was evaluated and compared.
The two structurally similar tricyclic antidepressant drugs amitriptyline (AT) and chlorimipramine (CI) were administered to 15 patients in a cross-over study. Approximately equimolar daily doses of the two drugs (5 mumol/kg body weight) were given as commercial tablets. Steady state plasma levels of the parent drugs and the demethyl metabolites were determined by high performance liquid chromatography. An about 5-fold interindividual variation was found in plasma levels of all four compounds. As the reciprocal plasma level during multiple dosing is proportional to the clearance of a compound, this parameter was used for linear regression analysis. In the 15 patients there was a significant correlation between the reciprocal plasma levels of CI and its metabolite demethylchlorimipramine (r = 0.76; p less than 0.001) and also between AT and its metabolite nortriptyline (r = 0.52; p less than 0.05). The reciprocal plasma levels of the parent compounds AT and CI were closely correlated (r = 0.87; p less than 0.001). A similar correlation was found for the demethyl metabolites (r = 0.77; p less than 0.001). The results indicate that similar factors control the plasma levels of AT and CI during treatment and that similar enzymes may be involved in the metabolism of the two drugs.
The amitriptyline (ATL) distribution in 12 rat brain regions was examined during 2-, 7- and 14-day continuous ATL infusion, starting with 18 mg/kg/day on the first day. The concentration of nortriptyline, a demethylated metabolite of ATL, in brain and serum was very low in comparison with ATL. The brain/serum concentration ratio of ATL and absolute ATL concentration in the brain were lower on the 2nd day than on the other 2 days. On the other hand, the ATL serum level on the 2nd day was higher than on the other 2 days. The ATL distribution in brain was heterogeneous on each of the three days and there were changes with time in its distribution in two brain portions, the anterior basal ganglia and the medulla oblongata + pons.
The authors report the case of a patient who received amitriptyline on 2 occasions. On both occasions, she had fever and jaundice. On the second episode, hepatitis was severe with hepatic encephalopathy, ascites, increased prothrombin time, and massive hepatic necrosis. After interruption of the drug administration, the patient made a slow but complete recovery.
The cardiovascular effects of trazodone ( TZD ), amitriptyline (AMT) and placebo were studied in out-patients with major depression. AMT was shown to have the expected effects on the electrocardiograph and on systolic time intervals consistent with its proven anticholinergic and quinidine-like properties. TZD , in contrast, had no quinidine-like effects and minor effects on systolic time intervals. However, it was not without any cardiovascular effects. Although TZD was shown to be a safer preparation than the reference drug AMT, long-term monitoring is needed to explain the minor effect on heart rate and T wave changes.
Changes in the uptake of 3H-serotonin into platelets, serotonin receptor activity on platelets, and plasma free and bound tryptophan concentrations were determined in a group of 54 moderately to severely depressed patients (mean Hamilton Rating Scale 17) before and during treatment with either trazodone or amitriptyline. No difference was found between the free and bound tryptophan concentrations of the depressed patients or their controls nor was any change detected during drug treatment. Platelet serotonin receptor activity and uptake were significantly lower in the depressed patients than in the controls and in those patients which subsequently responded to drug treatment. There was no apparent correlation between the ability of trazodone to inhibit the uptake of serotonin into the platelets and the antidepressant response; all patients responding to drug treatment showed an enhanced serotonin uptake. There is evidence from this study that changes in serotonin receptor function and uptake into platelets may correlate with the clinical status of depressed patients.
This paper reports a replication study of prediction of outcome by a cluster-analysis derived four-group typoloy of depression. 143 acutely depressed women were treated with amitriptyline for 4 weeks. In replication of the earlier findings, anxious depressives showed the worst response, hostile depressives and young depressive with personality disorder the best, with psychotic depressive intermediate. The findings provide further validating evidence for the typology, and for the view that nonpsychotic depressives are heterogenous.
A double-blind clinical trial was performed in which 27 patients suffering from endogenous depression were included. Randomized assignment resulted in 11 patients treated with amitriptyline and 16 patients treated with nomifensine. The duration of treatment was 4 weeks and the dosage of both drugs ranged from 50 to 150 mg/day. Using the Hamilton Depression Scale both compounds were found to have similar antidepressant activity. The Clinical Global Impression demonstrated a somewhat faster onset of action with nomifensine. The frequency of anticholinergic side effects was lower in the group treated with nomifensine. Laboratory analyses did not reveal changes which could clearly be attributed to the effects of either compound.
The authors describe a 26-year-old woman who became hypomanic after awakening from a semicomatose state induced by an overdose of amitriptyline-perphenazine (Triavil). She had been depressed and had a strong family history of manic-depressive illness. The case is reported to support previous evidence that dopamine is a mediator for mania.
Although a 1-week supply of tricyclic antidepressants is generally considered safe, the author shows that this amount can be severely toxic. Six of 12 instances of low-dose (500-1000 mg) amitriptyline overdoses were life threatening. The author suggests that prescription guidelines for tricyclic antidepressants be tightened and that physicians prescribe less than a 1-week supply to potentially suicidal patients.
In this study 10 of 17 patients receiving long-term amitriptyline treatment (average duration: 3.7 years, average dose: 138 mg) had their medication tapered and discontinued under double-blind conditions. Eight became depressed within 3 to 15 weeks. None of the 7 control subjects became depressed during the 6 months of the study. Those who became depressed also showed psychomotor retardation and sleep disturbance. Relief of longstanding anticholinergic side effects followed medication discontinuation. Some patients whose amitryptyline was discontinued experienced a mild withdrawal syndrome within the first 2 weeks, consisting of irritability, dream and sleep disturbance, and restlessness during the first few weeks.
A paradoxical increase in suicide threats, paranoid ideation, and demanding and assaultive behavior occurred among 15 borderline inpatients receiving amitriptyline in a double-blind study. This pattern differed significantly from that of 14 nonresponding patients receiving placebo.