Metabolism in adipose tissue in response to citalopram and trimipramine treatment--an in situ microdialysis study.

The intake of antidepressants is often accompanied by weight gain. Antidepressants may influence lipid and carbohydrate metabolism that can result in metabolic changes and obesity. We investigated the effect of citalopram and trimipramine on interstitial glycerol, glucose and lactate concentration and blood flow in subcutaneous adipose tissue of obese subjects by means of the microdialysis technique. In addition, the effect of stimulation with norepinephrine on metabolic response was investigated. Each subject was compared to a control subject matched for BMI and age. Each group comprised 10 subjects. Circulating plasma triglyceride concentrations were higher in drug-treated groups. In subcutaneous adipose tissue, microdialysis experiments revealed a higher and prolonged glycerol release in the presence of norepinephrine, but not under basal conditions. In citalopram treated subjects, basal glucose and lactate concentrations were higher compared with controls or with the trimipramine treated group. Local administration of norepinephrine induced a decrease in glucose levels and an increase in lactate levels, but without significant differences between groups. Local adipose tissue blood flow decreased in control groups following norepinephrine application, but remained constant in the antidepressant groups. In conclusion, citalopram and trimipramine affected glucose and lipid metabolism in adipose tissue and resulted in enhanced release of glycerol and free fatty acids into the circulation.

Maintenance therapy for duodenal ulcer: a randomized controlled comparison of seven forms of treatment.

PURPOSE: We performed a randomized controlled trial to compare the efficacy of seven forms of maintenance treatment of duodenal ulcer, including a mealtime regimen of antacids. PATIENTS AND METHODS: We randomized 785 patients with healed duodenal ulcer to receive: (1) no treatment; (2) mealtime antacids with an acid-neutralizing capacity of 80 mmol/day; (3) an antidepressant, trimipramine 25 mg; (4) an anticholinergic, pirenzepine 50 mg; (5) cimetidine 200 mg; (6) cimetidine 400 mg; (7) ranitidine 150 mg; or (8) sucralfate 1 g twice a day. Symptomatology and side effects were assessed every 2 months and endoscopy was performed every 4 months up to 1 year. RESULTS: The patients were comparable in the majority of clinical characteristics before entry. The cumulative percentages of patients with relapse of ulcers at 12 months by life-table analysis were 61% with no treatment, 38% with mealtime antacids, 60% with trimipramine, 52% with pirenzepine, 46% with cimetidine 200 mg, 44% with cimetidine 400 mg, 30% with ranitidine 150 mg, and 40% with sucralfate. Cimetidine 400 mg, antacids, ranitidine 150 mg, and sucralfate were significantly better than no treatment and the other forms of treatment. Ranitidine was significantly better than antacids, cimetidine, and sucralfate in preventing endoscopically documented duodenal ulcer relapse by multiple comparison at 12 months, but not by life-table analysis nor when symptomatic relapses were compared. No significant difference was detected among antacids, cimetidine, and sucralfate. No major side effects occurred with the seven forms of treatment, but those receiving antacids had the highest incidence of minor adverse events (26%). CONCLUSION: This study suggests that mealtime antacids are as effective as H2-receptor antagonists and sucralfate in the maintenance treatment of duodenal ulcer disease, but have to be taken three times a day and had the highest incidence of reported minor adverse events. The relapse rate was lower with ranitidine than with cimetidine, sucralfate, and antacids, but the difference was small and may not be clinically important.

Safety of liver donation after fatal intoxication with the tricyclic antidepressant trimipramine.

We report the case of a patient receiving long-term treatment with the tricyclic antidepressant trimipramine who died 10 days after a trimipramine overdose. A few hours before death, the serum trimipramine concentration had fallen to 80 microg/L. Similar values are reported for patients taking therapeutic trimipramine doses. At this serum concentration, the liver content of trimipramine and it's 2-hydroxy and N-desmethyl metabolites was 1750 microg/kg, 850 microg/kg, and 225 microg/kg, respectively. The liver was morphologically normal. Back calculations suggest that a liver transplant obtained from a donor dying from a trimipramine overdose should be safe, if the serum trimipramine concentration has fallen below 2000 microg/L. If higher serum trimipramine concentrations are present, harvesting should be delayed to avoid trimipramine toxicity in the recipient.

Clinical originality and new biology of trimipramine.

Trimipramine differs from other antidepressant drugs in a number of ways. Although trimipramine shares equivalent efficacy with doxepin, imipramine, maprotiline and amitriptyline, as evidenced by double-blind studies, it possesses a different side-effect profile. Trimipramine is considered to be less cardiotoxic, and data presented in this paper support its minimal effect on orthostatic hypotension, as compared with clomipramine. In addition, trimipramine has less epileptogenic potential than other antidepressants such as imipramine, amitriptyline and maprotiline. Besides this different side-effect profile, trimipramine exerts differing effects on neurotransmitter functions and their reuptake. For example, trimipramine does not inhibit reuptake of noradrenaline and serotonin, and does not down-regulate beta 1-adrenoceptors. Furthermore, in common with lithium, trimipramine produces enhancement of antidepressant action in treatment-resistant depressed patients. There is evidence that trimipramine enhances the sensitivity of cortical neurons to noradrenaline after prolonged administration and may also increase the activity of serotonin neurons.

A comparison of trimipramine and imipramine: a controlled study.

Trimipramine, a new tricyclic antidepressant, was compared to imipramine in 38 hospitalized depressives. Both groups improved, with no major differences seen between the drugs. Analysis of the power of the statistical analysis shows that it is very unlikely that a true difference was present and not detected. There were fewer adverse reactions to trimipramine.

Trimipramine-induced neuroleptic malignant syndrome after transient psychogenic polydipsia in one patient.

A case of neuroleptic malignant syndrome (NMS) was induced by the antidepressant trimipramine in a 47-year-old woman with obsessive compulsive disorder and major depression. NMS symptoms were associated with a brief episode of polydipsia, and both conditions may have had dopaminergic dysfunction as a common etiology. The patient improved with bromocriptine and dantrolene.

Plasma levels and therapeutic response with trimipramine treatment of endogenous depression.

In a 6-week, double-blind study involving 34 endogenously depressed patients, plasma trimipramine levels of two dosage groups, 75-mg/day and 150-mg/day, were compared with regard to clinical efficacy as determined by scores on the Hamilton Rating Scale for Depression, the Clinical Global Impressions scale, and the Zung Self-Rating Depression Scale. Both dosage levels of trimipramine produced prompt, consistent, and progressive antidepressant effects. No correlation between plasma levels and clinical efficacy was found.

Combined use of tricyclic antidepressants and monoamine oxidase inhibitors.

Combined treatment with tricyclic antidepressants and MAO inhibitors has been an area of some controversy. The efficacy of the combination approach is not established; the only controlled trail showed trimipramine alone to be superior to an MAOI alone and to the combination of trimipramine with an MAOI in treating depressed outpatients not selected for a history of treatment refractoriness. The safety of the combination varies according to the specific drugs used; tranylcypromine and clomipramine are not recommended, and recent pharmacologic studies suggest that specific serotonin reuptake inhibitors are dangerous in combination with MAOIs. Further controlled clinical studies are clearly needed before combined therapy can be recommended for routine clinical use.

A comparative trial of the antidepressant, anxiolytic, and cardiovascular effects of trimipramine and doxepin in depressed hospitalized patients.

After a 1-week placebo washout, 25 depressed hospitalized patients were treated for 4 weeks with trimipramine or doxepin in a fixed equivalent dosage schedule ending in 150 mg h.s. The study used a parallel group double-blind design. Comparisons over time revealed that both drugs improved patients' overall well-being as indicated by the rating scales studied. Significant (p less than .05) differences between the treatments favored trimipramine over doxepin: the Hamilton scale diurnal variation cluster at Week 1 and the sleep disturbance factor at Week 4; the Clinical Global Impressions improvement index at Week 1; and the Anxiety Status Inventory somatic symptoms cluster at Week 4. No differences in blood pressure, heart rate, PVCs, or PACs were observed in any of the comparisons. The total number of side effects reported was greater in the doxepin-treated patients.

Trimipramine and maprotiline: antidepressant, anxiolytic, and cardiotoxic comparison.

A 5-week placebo washout comparison of trimipramine 150 mg/day and maprotiline 150 mg/day was carried out in 15 male and 24 female patients with unipolar major affective disorder. There were no significant differences between the two groups in age, sex, weight, height, or vital signs. Both groups showed significant improvement over time, with no difference between the groups on the Severity and Improvement factors of the Clinical Global Impression scale, on the total and factor subscales of the Hamilton Depression Rating Scale, and on the Anxiety Status Inventory. The maprotiline group showed a greater increase in weight over the study period than did the trimipramine group. There was a significant lowering of systolic blood pressure in the trimipramine group only and a significant and linear increase in pulse rate by Week 3 in the maprotiline group. Analysis of ECG showed that the atrial rates were significantly increased in the maprotiline group (p less than .002) but not in the trimipramine group. Trimipramine had significantly fewer anticholinergic, neurologic, and cardiovascular adverse effects than maprotiline.

Antidepressant efficacy and cardiac safety of trimipramine in patients with mild heart disease.

The antidepressant efficacy and cardiac safety of trimipramine were evaluated in 22 depressed patients with mild heart disease (New York Heart Association class I, II, or III) who received doses of 50 to 200 mg/day for 28 days. Efficacy was evidenced by a significant decrease from baseline in Hamilton Rating Scale for Depression scores. The only significant change from baseline in electrocardiographic, Holter monitor, myocardial function, or vital sign evaluations was a transient prolongation of the mean QRS interval. None of the adverse reactions involved the cardiovascular system. The results demonstrate that trimipramine is effective in the treatment of depression and is not likely to produce serious or harmful cardiovascular side effects in patients with mild heart disease.

Increased trimipramine plasma levels during fluvoxamine comedication.

A depressive patient, a non-responder to trimipramine (TRI), was comedicated first with citalopram (CIT) and then with fluvoxamine (FLUV). Both the TRI-CIT and TRI-FLUV combination treatments led to a worsening of the depressive state and to the appearance of panic attacks. The addition of FLUV to TRI resulted in a twofold increase of the plasma levels of TRI and to a slight increase of its N-demethylated and 2-hydroxylated metabolites. These results suggest that the interaction between FLUV and TRI occurred at the level of cytochrome P-450IID6 and cytochrome P-450meph in this patient, phenotyped as an extensive metabolizer of both dextromethorphan and mephenytoin. The adverse effects were possibly due to (a) a pharmacokinetic interaction between CIT and FLUV with TRI and/or (b) alterations in serotonergic and/or dopaminergic neurotransmission.

Trimipramine--an atypical neuroleptic?

Trimipramine and clozapine show some similarities in their receptor binding profiles. Since both have the same affinity for the D2 receptor and since the affinity for this receptor correlates closely with the antipsychotic potency of a drug, an antipsychotic efficacy of trimipramine in acute schizophrenia could be expected. Therefore 28 schizophrenic patients in an acute phase were treated with trimipramine up to 400 mg/d in an open clinical trial. For the whole group of patients the BPRS total score changed from 58 +/- 5 before treatment to 46 +/- 18 at the last rating (p less than 0.05). According to our clinical judgement the patients were divided into three subgroups. Thirteen patients showed a good remission under trimipramine so that they could be discharged on a trimipramine maintenance treatment. They improved on the BPRS from 58 +/- 6 before treatment to 32 +/- 8 at endpoint. Six patients deteriorated during the first week of treatment and had to be withdrawn from the study. Nine patients showed insufficient improvement or became worse after an initial improvement. The observed side-effects (dry mouth, sedation, sweating, increased appetite, constipation, tremor, vertigo) are well known under trimipramine and were therefore expected. Beyond these, one patient developed a cardiac insufficiency. No clinical relevant extrapyramidal side-effects occurred. Since the improvement of florid psychotic symptoms seems to be markedly higher under trimipramine than the one reported under placebo, our results indicate that trimipramine may have an antipsychotic potency.

Nocturnal gastric secretion following treatment with trimipramine (Surmontil).

The study was conducted double blind in 12 healthy volunteers, average age 30 years (23-48). On separate days they were allocated at random to either two tablets of Trimipramine, 25 mg each, or two tablets of Placebo, one and a half hours before introduction of a Levine tube into the stomach. The volunteers had on the day of starting the experiment performed their normal duties, and consumed the last meal, the dinner, at 5 pm. The gastric juice was collected continuously in half hour samples from 11 pm until 7 am the next morning. The average recovery was 87% in 4 tested experiments. The volume of gastric juice was 448 ml/8 h for the series receiving Placebo compared to 418 ml/8 h for those treated with Trimipramine (Table 1). During the first half hour a relative high volume was aspirated, whereas in the following 3 half hours portions the volume decreased to a fairly stable level of about 15-23 ml. A significant lower volume was observed in the Trimipramine treated series in some of the morning portions. A significant lower concentration and output of HCl was found during the middle of the night and in some morning portions in the subjects given Trimipramine. Similarly the concentration and output of pepsin were lower in the Trimipramine series than in the Placebo treated subjects.

Seizures after single-agent overdose with pharmaceutical drugs: analysis of cases reported to a poison center.

CONTEXT: Seizures during intoxications with pharmaceuticals are a well-known complication. However, only a few studies report on drugs commonly involved and calculate the seizure potential of these drugs. OBJECTIVES: To identify the pharmaceutical drugs most commonly associated with seizures after single-agent overdose, the seizure potential of these pharmaceuticals, the age-distribution of the cases with seizures and the ingested doses. METHODS: A retrospective review of acute single-agent exposures to pharmaceuticals reported to the Swiss Toxicological Information Centre (STIC) between January 1997 and December 2010 was conducted. Exposures which resulted in at least one seizure were identified. The seizure potential of a pharmaceutical was calculated by dividing the number of cases with seizures by the number of all cases recorded with that pharmaceutical. Data were analyzed using descriptive statistics. RESULTS: We identified 15,441 single-agent exposures. Seizures occurred in 313 cases. The most prevalent pharmaceuticals were mefenamic acid (51 of the 313 cases), citalopram (34), trimipramine (27), venlafaxine (23), tramadol (15), diphenhydramine (14), amitriptyline (12), carbamazepine (11), maprotiline (10), and quetiapine (10). Antidepressants were involved in 136 cases. Drugs with a high seizure potential were bupropion (31.6%, seizures in 6 of 19 cases, 95% CI: 15.4-50.0%), maprotiline (17.5%, 10/57, 95% CI: 9.8-29.4%), venlafaxine (13.7%, 23/168, 95% CI: 9.3-19.7%), citalopram (13.1%, 34/259, 95% CI: 9.5-17.8%), and mefenamic acid (10.9%, 51/470, 95% CI: 8.4-14.0%). In adolescents (15-19y/o) 23.9% (95% CI: 17.6-31.7%) of the cases involving mefenamic acid resulted in seizures, but only 5.7% (95% CI: 3.3-9.7%) in adults (≥ 20y/o; p < 0.001). For citalopram these numbers were 22.0% (95% CI: 12.8-35.2%) and 10.9% (95% CI: 7.1-16.4%), respectively (p = 0.058). The probability of seizures with mefenamic acid, citalopram, trimipramine, and venlafaxine increased as the ingested dose increased. CONCLUSIONS: Antidepressants were frequently associated with seizures in overdose, but other pharmaceuticals, as mefenamic acid, were also associated with seizures in a considerable number of cases. Bupropion was the pharmaceutical with the highest seizure potential even if overdose with bupropion was uncommon in our sample. Adolescents might be more susceptible to seizures after mefenamic acid overdose than adults. "Part of this work is already published as a conference abstract for the XXXIV International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 27-30 May 2014, Brussels, Belgium." Abstract 8, Clin Toxicol 2014;52(4):298.