Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol--a double-blind multicenter trial.

BACKGROUND: Patients with delusional depression are difficult to treat. The atypical antidepressant trimipramine was effective in a previous 4-week open label pilot study in patients with this disorder. The major neurobiological effect of trimipramine is the inhibition of the hypothalamic-pituitary-adrenocortical (HPA) system. In delusional depression HPA overactivity is more distinct than in other subtypes of depression. HPA suppression is thought to contribute to the action of trimipramine. METHODS: In a double-blind, randomized, placebo controlled multicenter trial we compared the effects of trimipramine monotherapy versus a combination of amitriptyline and haloperidol. Dosage was increased stepwise from 100mg up to 400mg trimipramine and from 100mg up to 200mg amitriptyline combined with 2mg up to 7.5mg haloperidol. The average dose of trimipramine was higher than that of amitriptyline throughout the trial. During sixth week mean dosage (+/-standard deviation) were 356.1+/-61.2mg trimipramine, 184.0+/-23.6 mg amitriptyline and 6.3+/-1.8 mg haloperidol. During six weeks psychometric assessments were performed weekly. For HPA monitoring a dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed before active medication and at the end of treatment. Additionally tolerability was monitored by ECG, EEG assessment of extrapyramidal symptoms and akathisia, clinical laboratory routine and recording of blood pressure and heart rate. Adverse events were documented. RESULTS: 94 patients were enclosed into the study. The per protocol sample consisted of 33 patients of the trimipramine group and of 24 patients of the amitriptyline/haloperidol group. The decrease of the Hamilton depression (HAMD) score (24 items) showed non-inferiority of trimipramine compared to amitriptyline/haloperidol. Twenty-eight patients (84.84%) in the trimipramine arm and 17 patients (70.83%) in the amitriptyline/haloperidol arm were responders (HAMD

Receptor occupancy of mirtazapine determined by PET in healthy volunteers.

RATIONALE: Molecular tools are needed for assessing anti-depressant actions by positron emission tomography (PET) in the living human brain. OBJECTIVES: This study determined whether [(11)C]mirtazapine is an appropriate molecular tool for use with PET to estimate the magnitude of neuroreceptor occupancy produced by daily intake of mirtazapine. METHODS: This study used a randomised, double-blind, placebo-controlled, parallel-group, within-subject design. Eighteen healthy volunteers were PET-scanned twice with [(11)C]mirtazapine; once under baseline condition and again after receiving either placebo or mirtazapine (7.5 or 15 mg) for 5 days. We determined kinetic parameters of [(11)C]mirtazapine in brain regions by the simplified reference region method and used binding potential values to calculate receptor occupancy produced by mirtazapine. RESULTS: Serum concentrations of mirtazapine ranged from 33 to 56 nmol/l after five daily doses of 7.5 mg mirtazapine and were between 41 and 74 nmol/l after 15 mg mirtazapine. Placebo treatment failed to alter the binding potential of [(11)C]mirtazapine from baseline values, whereas daily intake of mirtazapine markedly decreased the binding potential in cortex, amygdala and hippocampus. Receptor occupancy ranged from 74 to 96% in high-binding regions of the brain after five daily doses of 7.5 mg or 15 mg mirtazapine, whereas 17-48% occupancy occurred in low-binding regions. CONCLUSIONS: [(11)C]Mirtazapine together with PET can determine the degree of receptor occupancy produced by daily doses of mirtazapine in regions of the living human brain.

Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultrahigh activity.

OBJECTIVE: The tricyclic antidepressant trimipramine is one of the drugs with the most pronounced differences in pharmacokinetics caused by the CYP2D6 genetic polymorphism. However, the effect of CYP2D6 genotype on steady state kinetics and on bioavailability has not been studied so far. In addition, we were interested in trimipramine pharmacokinetics in genetically defined ultra rapid metabolizers. METHODS: We studied intravenous and multiple dose oral application of 50 mg trimipramine in five, seven, and three healthy volunteers with CYP2D6 genotypes predicting deficient, highly active and ultrarapid metabolism. The latter group included carriers of one wild-type and one duplication allele. Trimipramine and desmethyltrimipramine concentrations were measured by HPLC over a time interval of 72 h after intravenous and after one oral application. RESULTS: Both bioavailability and systemic clearance significantly depended on CYP2D6 genotype with a linear gene dose relationship. Mean bioavailability was 44, 16 and 12% in carriers of zero, two and three active genes of CYP2D6, respectively, and the corresponding data for systemic clearance were 12.0, 24.2, and 30.3 l/h. Consequently, the mean total oral clearances were 27.3, 151, and 253 l/h in poor, extensive and ultrarapid metabolizers. CONCLUSIONS: High bioavailability combined with low systemic clearance of trimipramine in poor metabolizers of CYP2D6 substrates results in a very high exposure to trimipramine with the risk of adverse drug reactions. On the other hand, the extremely high systemic and presystemic elimination may result in sub-therapeutic drug concentrations in carriers of CYP2D6 gene duplications with a high risk of poor therapeutic response.

Antipsychotic efficacy of the antidepressant trimipramine: a randomized, double-blind comparison with the phenothiazine perazine.

BACKGROUND: The tricyclic antidepressant trimipramine exhibits several features (e. g., dopaminergic effect, molecular structure similar to a neuroleptic, receptor-binding profile similar to clozapine) that suggest its potential as an antipsychotic medication. The aim of the study was to investigate the antipsychotic potential of trimipramine in a controlled clinical trial comparing its antipsychotic efficacy with that of a neuroleptic. METHOD: In a German multi-center, randomized, double-blind trial, the antipsychotic efficacy of trimipramine was compared with that of the phenothiazine neuroleptic perazine, using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions (CGI). Antidepressant efficacy of both agents was measured by use of the Bech-Rafaelsen Melancholia Scale (BRMES). Ninety-five patients with acute schizophrenia (DSM-III-R) and a BPRS total score > 40 at baseline were treated with either 300-400 mg trimipramine or 450-600 mg perazine for 5 weeks. RESULTS: Therapeutic equivalence of both treatments (in the dosages used) could not be demonstrated (change in BPRS total score, per-protocol [PP] analysis, one-sided equivalence testing). However, intention-to-treat (ITT) as well as PP analysis showed a statistically significant decrease in the BPRS total scores in both treatment groups (PP: trimipramine, 56.5 +/- 9.8 to 44.1 +/- 17.9; perazine, 56.4 +/- 10.8 to 37.9 +/- 12.9). Significant decreases in all BPRS and PANSS subscores as well as CGI results and response rate support the antipsychotic efficacy of trimipramine. The BRMES total scores significantly decreased in both treatment groups without showing a significant difference between the two agents. Trimipramine was better tolerated than perazine and did not elicit extrapyramidal symptoms. CONCLUSION: Trimipramine failed to exhibit therapeutic equivalence to perazine in the dosages used. However, there was evidence of a substantial antipsychotic effect of trimipramine. It may be a useful medication if depressive symptoms in psychotic patients require antidepressant treatment or if other antipsychotics cannot be administered.

Clinical outcome after trimipramine in patients with delusional depression - a pilot study.

The treatment of delusional depression is a major challenge in psychopharmacology. Hypothalamic-pituitary-adrenocortical (HPA) overdrive may contribute, via increased dopaminergic activity, to the pathophysiology of the disorder. Trimipramine appears to be an interesting potential candidate, since it is an atypical antidepressant that is known to inhibit HPA activity. In a four-week open trial we investigated its effects in 15 inpatients with delusional depression. The dosage was increased within 7 days up to 300 - 400 mg/d and was then maintained for three weeks. Psychometric assessments and safety monitoring were conducted weekly. Assessment of the HPA activity was achieved by a combined dexamethasone suppression/corticotropin-releasing hormone stimulation (Dex/CRH) test before and after four weeks of treatment. Therapeutic response was defined as a decrease in the HAMD-score of at least 50 %. Eight out of 13 completers were rated as responders. Therapeutic response was associated with L, D-trimipramine concentrations higher than 160 ng/ml. Intent-to-treat analysis showed significant improvement in psychometric variables. Despite the high dosage, the substance was generally well tolerated, with the exception of one patient who suffered from a hypotensive reaction. Mean +/- SD concentration of L-trimipramine and D-trimipramine were 138 +/- 61 ng/ml and 119 +/- 50 ng/ml at a final dose of 346 +/- 50 mg/d. The ACTH and cortisol area under the curve in the Dex/CRH tests decreased significantly, reflecting a decrease of activity in the HPA system. We suggest that the clinical use of high-dose trimipramine in delusional depression seems to be a promising treatment strategy.

Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study.

In recent years, sedating antidepressants have been increasingly used to treat primary insomnia. Up to now, only one open pilot study with trimipramine and one double-blind placebo-controlled study with doxepin have provided scientific support for this approach in treating primary insomnia. In order to test the hypothesis that sedating antidepressants are useful in the treatment of primary insomnia, the effect of trimipramine on objectively and subjectively measured parameters of sleep was investigated in a double-blind placebo- and lormetazepam-controlled study in a sample of 55 patients with primary insomnia attending outpatient sleep-disorder clinics. Trimipramine was selected since it has shown positive effects on sleep continuity with a lack of REM sleep suppression in studies on depressed patients and in one pilot study on patients with primary insomnia. Trimipramine at an average dose of 100 mg over a period of 4 weeks significantly enhanced sleep efficiency, but not total sleep time (which had been the primary target variable) compared to placebo as measured by polysomnography. Changes in objective sleep parameters were paralleled by changes in subjective sleep parameters. Trimipramine did not suppress REM sleep. Lormetazepam decreased wake time and sleep stage 3 and increased REM sleep compared to placebo. After switching trimipramine to placebo, sleep parameters returned to baseline. There was no evidence of any rebound effect from trimipramine. Side effects from trimipramine were only marginal. This first double-blind placebo-controlled study with trimipramine suggests its efficacy in the treatment of primary insomnia. However, due to the large intra- and interindividual variance in the parameters of interest before and during treatment a larger sample size would have been necessary to strengthen the validity of our findings.

[Delusional depression as differential dementia of the Alzheimer type diagnosis]. / Wahnhafte Depression als Differenzialdiagnose der Demenz vom Alzheimer-Typ.

For several years, a 68-year-old patient had been treated for a dementia of Alzheimer's type and finally admitted to a closed gerontopsychiatric nursing home. According to information from his relatives, he first developed psychotic symptoms 3 years prior to admission in our psychiatric department. Several months later, he developed a lack of drive, lack of interests, and reduced emotional reaction. After a standard diagnostic work-up (psychiatric, neurological, and general medical examination, CSF examination, laboratory analyses, cranial computerized tomography), we began electroconvulsive therapy (ECT) with a working hypothesis of major depression with psychotic symptoms. The ECT was able to ameliorate rapidly the psychiatric status of the patient. After 10 weeks of inpatient treatment, he could be discharged from the hospital and was able to take up his usual professional activities on a voluntary basis. This article describes the need for an early differential diagnosis of dementias. Standardized and differential diagnoses of dementias are necessary for an antidementive therapy as well as for the detection of potentially curable diseases.

Seizures associated with therapeutic doses of venlafaxine and trimipramine.

OBJECTIVE: To report a patient having a first-time seizure after receiving venlafaxine and trimipramine for depression. CASE SUMMARY: A 25-year-old white woman with chronic depression was treated with venlafaxine 150 mg/d and trimipramine 50 mg/d. Eleven days after increase of the trimipramine dosage to 100 mg/d, she was hospitalized because of seizures suggesting a secondary generalized grand-mal episode. The electroencephalogram showed a pathologic pattern with several generalized epileptiform discharges. Because of suspected drug-induced seizures, both antidepressants were stopped. After antidepressant drug cessation, the patient was symptom free and had no further seizure episodes within the following 12 months of follow-up. No other potential cause for the seizure episode could be identified. DISCUSSION: Both venlafaxine and trimipramine have been associated with seizures, mainly after overdose. Venlafaxine-associated seizures at therapeutic doses have not been reported in the literature. We hypothesize that a pharmacodynamic or pharmacokinetic drug interaction between venlafaxine and trimipramine involving the CYP2D6 isoenzyme may have played a role in inducing the seizures. CONCLUSIONS: Clinicians should be aware of the proepileptogenic effect of venlafaxine and trimipramine at therapeutic doses and that this combination may eventually increase the risk of seizures.

Trimipramine and maprotiline plasma levels during combined treatment with moclobemide in therapy-resistant depression.

In an open pilot study of 21 therapy-resistant depressive inpatients, plasma levels of antidepressants were determined during treatment with a combination of moclobemide/ trimipramine (n = 15) and moclobemide/maprotiline (n = 6). After combined administration of trimipramine and moclobemide (MCB), a significant increase in the plasma level of trimipramine (39%) was observed. After combination of maprotiline with moclobemide, maprotiline levels were increased (25%, n.s.). The results show that moclobemide, as an inhibitor of isoenzymes of the cytochrome P 450 oxidase, can cause increases in the plasma levels of tricyclic and tetracyclic antidepressants. No correlation between the serum level of the antidepressants and treatment outcome was found in this open study.

[Depressive stupor--malignant neuroleptic syndrome--serotonin syndrome. A case contribution to a difficult differential diagnosis]. / Depressiver Stupor--malignes neuroleptisches Syndrom--Serotoninsyndrom. Ein kasuistischer Beitrag zu einer schwierigen Differentialdiagnose.

Depressive stupor and malignant neuroleptic syndrome are very well-known problems in clinical psychiatry. The serotonin syndrome, however, a potentially life-threatening side effect of treatment with serotonergic substances, has been included in the clinical differential diagnosis increasingly often in the last few years. The development of new serotonin selective antidepressants and selective reversible inhibitors of monoamine oxidase A has led to the use of more and more substances that can cause these life-threatening complications if they are taken in too high doses or together with other drugs. We present a 61 year old depressed female impatient who developed an abortive malignant neuroleptic syndrome while being treated for depressive stupor. We discuss a possible relation between serotonin syndrome and a highly dosed combination therapy with moclobemide. Owing to the importance of both syndromes, we consider drug monitoring absolutely necessary for patients who are being treated with new antidepressants, and especially for those who develop neurological and psychiatric complications when such preparations are given in combination with other drugs.

[Sleep disorders--what can be done when hypnotics no longer help? Overview and case report]. / Schlafstörungen--Was tun, wenn Schlafmittel nicht mehr helfen? Ubersicht und Fallvorstellung.

We report on the case of a 45-year old female with chronic insomnia and refractory to hypnotics, who also has a - polygraphically documented - tolerance to the imidazopyridine "zolpidem". We discuss the main differential diagnosis and demonstrate a therapeutic regimen which allows a step-by-step replacement of hypnotics by sedative antidepressants. This interval replacement treatment reduces on the one hand the risk of developing a severe withdrawal syndrome. On the other hand the replacement by sedative antidepressants improves insomnia and insomnia-associated depressive symptoms. Finally, the clinical implications and rationale of a therapeutic approach with sedative antidepressants in chronic insomnia are discussed.

Sleep deprivation and bright light as potential augmenters of antidepressant drug treatment--neurobiological and psychometric assessment of course.

The present study was designed to investigate the clinical efficacy of trimipramine with adjunct sleep deprivation (SD) or bright light (BL) and to evaluate psychometric and neurobiological variables that might be of predictive value for treatment response. We used (1) the combined dexamethasone-corticotropin releasing hormone test (DEX-CRH test) to characterize alterations of the hypothalamic-pituitary-adrenal (HPA) system; (2) polysomnography to evaluate sleep disturbances; and (3) a standardized test battery to assess cognitive psychomotor functions after study initiation and after 5 weeks of treatment. The overall response rate (> or = 50% decrease in score on Hamilton Rating Scale for Depression [HRS]) was 55% (N = 42). The response rate in the group with trimipramine monotherapy (N = 14) was 79%, whereas in the groups with adjunct SD (N = 14) and BL (N = 14), respectively, it was only 43%. All three groups showed significant improvement at the end of the third week of treatment. Neither of the adjunct treatments hastened the onset of antidepressant action as measured by HRS. A significantly higher proportion of nonresponders than responders (p < .05) had HPA dysregulation, disturbed rapid eye movement (REM) sleep (REM latency, REM% first third of night) and decreased non-REM sleep (% stage 2). The non-responders showed significantly more corticotropin (ACTH) secretion after CRH stimulation in the DEX-CRH test than the responders and a less rapid normalization of the neuroendocrine dysregulation (cortisol secretion) (p < .01). In addition, REM latency was significantly shorter in the BL group than in the monotherapy group and estimated duration of illness significantly longer in the SD group than in the monotherapy group. REM latency, percentage of REM sleep during the first third of the total sleep period, percentage of non-REM sleep stage 2 and ACTH release after a DEX-CRH challenge predicted response across all three treatment groups. The neurobiological symptoms were unevenly distributed, among the three groups, thus creating heterogeneity in these measures. This heterogeneity may have contributed to the different treatment response rates as defined by psychopathology (HRS). In contrast, the neuropsychological tests and some of the sleep-EEG investigations revealed different response patterns for different groups: The onset of improvement in simple cognitive functions and in sleep continuity was earlier in the adjunct treatment groups. This study underlines the need for a multidimensional approach including use of neurobiological and neuropsychological measures to identify the therapeutic profiles of different treatment strategies and predictors of outcome.

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.

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.

Trimipramine: acute and lasting effects on sleep in healthy and major depressive subjects.

The acute effects of trimipramine on sleep EEG patterns were investigated in six depressed inpatients and six healthy volunteers. The effects of long-term administration were then assessed in depressed patients after 4 weeks of treatment. Sedative effects of the drug were more pronounced in healthy subjects while sleep parameters of depressed patients seemed less sensitive to the drug. Chronic effects tended to correct most of the sleep disturbances seen in depressed subjects with respect to the natural organization of sleep. The major sleep effect of trimipramine concerned REM latency which was lengthened in both groups, independently of the treatment protocol.

Influence of quinidine on the pharmacokinetics of trimipramine and on its effect on the waking EEG of healthy volunteers. A pilot study on two subjects.

The pharmacokinetics and pharmacodynamics (waking EEG) of 75 mg trimipramine taken orally were determined in two healthy volunteers on two separate occasions, once without and once after comedication with 2 x 50 mg quinidine. Quinidine, a potent cytochrome P-450IID6 inhibitor, is used as a pharmacological tool to mimic a lack of this enzyme in man. In this study, it markedly altered the pharmacokinetics of trimipramine, almost doubling its plasma half-life and decreasing its apparent clearance and volume of distribution. These results strongly suggest that trimipramine is a substrate of cytochrome P-450IID6. These modifications of trimipramine metabolism were accompanied by measurable changes in some EEG variables, most notably with regard to the relative power in the alpha and theta bands, which showed higher and longer-lasting effects of trimipramine. Since cytochrome P-450IID6 is deficient in 5-10% of Caucasian subjects, this may have consequences in trimipramine-treated subjects, especially with regard to the effects of the drug on the EEG.

Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression.

Human corticotropin releasing hormone (h-CRH) was administered to 14 patients with major depression, after premedication with an overnight dose of 1.5 mg dexamethasone. Cortisol response, expressed as area under the time course curve (AUC), was significantly higher in the 14 patients than in a group of 13 age-matched control subjects (9.4 +/- 7.6 ng x min x 1,000/ml vs. 3.1 +/- 3.6 ng x min x 1,000/ml). Corresponding AUC values for plasma adrenocorticotropic hormone (ACTH) were also significantly higher in patients than in control subjects (4.9 +/- 1.4 pg x min x 1,000/ml vs. 2.6 +/- 0.9 pg x min x 1,000/ml). After patients were treated with trimipramine (200 mg/day) for 6 weeks, the combined dexamethasone/h-CRH test was repeated. At that time, depression scores were significantly improved and the patients' cortisol response pattern became indistinguishable from that of controls. While plasma cortisol output normalized during treatment with trimipramine, ACTH release remained exaggerated. The combined dexamethasone/h-CRH challenge test may be of particular value in the detection of state-dependent changes of pituitary-adrenocortical neuroregulation.

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.

High-dose trimipramine in acute schizophrenia. Preliminary results of an open trial.

Trimipramine and clozapine show some similarities in receptor-binding profiles. Both have the same dissociation constant for D2-receptors and marked binding potencies for H1-receptors and muscarinic acetylcholine receptors. Based on these similarities an antipsychotic efficacy of trimipramine might be postulated. To generate hypotheses 15 schizophrenic patients with a BPRS total score of at least 50 were treated with trimipramine up to 400 mg per day. Four patients deteriorated under this treatment and had to be withdrawn from the study between the 4th and the 10th day. One patient stopped participating after the 15th day due to lack of improvement. These drop-outs showed a mean impairment in BPRS total score from 56 at baseline to 66 at endpoint. Ten patients were treated for 4 to 5 weeks successfully and improved on the BPRS from 57 at baseline to 31 at endpoint. High-dose trimipramine was tolerated well. In schizophrenic patients the expected sedative effect was small. One patient developed a modest parkinsonism, no acute dystonia was seen.