Comparison of the antidepressant effects of venlafaxine and dosulepin in a naturalistic setting.

The relative efficacy of the various classes of antidepressants has not been established. Observational studies in naturalistic settings are important in evaluating treatment outcomes with antidepressants, since controlled clinical trials include only a minority of patients present in clinical practice. This study sought to evaluate in a naturalistic setting the treatment outcomes of dosulepin and venlafaxine for patients with depressive episodes. At the university hospital in Copenhagen, Denmark, between 1998 and early 2001, the first-line treatment for psychiatric inpatients with depression was dosulepin; after that time, venlafaxine was the first-line medication. We compared the treatment outcomes among inpatients during the respective periods. There was no significant difference in the primary outcome parameters between the two groups. A tendency in favour of dosulepin confirmed by a post-hoc analysis suggested that the failure to achieve significant difference was related to a type 2 error. However, missing data and possible confounders related to the different treatment periods weaken the results. This naturalistic study showed a non-significant trend for poorer treatment outcomes (probably because of an underpowered design) after replacing dosulepin with venlafaxine as first-line drug for depression in a naturalistic inpatient setting.

Toxicokinetics of dothiepin: 2 case reports.

In this article, 2 cases of intentional dothiepin intoxication are presented. Both patients survived after receiving appropriate supportive care. The dothiepin and metabolite levels were measured at different times after ingestion. The initial levels of dothiepin were 1900 microg/L in case 1 and 5500 microg/L in case 2. In case 1, a toxicokinetic model was fitted, suggesting a higher peak level, corresponding with the QRS duration and clinical symptoms. In case 2, a combined dothiepin-ethanol intoxication was seen, complicating the interpretation of clinical parameters, such as the QRS duration. In conclusion, the severity of dothiepin intoxication is poorly predicted by plasma levels alone, as time of ingestion can be critical for interpretation. However, especially in combined intoxications, interpretation of the QRS duration may also fail. Therefore, it is important to evaluate the whole range of clinical parameters, QRS duration, clinical symptoms, dothiepin concentration(s), and other possible intoxications.

Site-to-site variability of drug concentrations in skeletal muscle.

The homogeneity of drug concentrations in skeletal muscle was assessed in eight fatal overdoses. Ten to 30 random samples were taken from leg muscle weighing 1,650 to 7,985 g. For cases involving paracetamol the mean muscle-to-blood ratio ranged from 0.1 to 1.1 (n = 4) for amitriptyline 1.1 to 3.6 (n = 3), and for dothiepin 0.8 to 2.1 (n = 2). The coefficient of variance was large for all drugs, ranging from 10.5 (carbamazepine) to 50 (thioridazine). Skeletal muscle is not homogeneous with respect to drug concentrations in fatal overdose cases. Of 16 instances of drug detection in blood 2 (nortriptyline and promethazine) were not detected in muscle. Muscle-to-blood drug ratios varied significantly among cases, possibly influenced by survival time after drug ingestion. Quantitative interpretations of muscle drug levels present significant difficulties. However, skeletal muscle can be used for qualitative corroboration of blood analyses and is a suitable specimen for drug detection where none other is available.

Effect of exposure to dothiepin and northiaden in breast milk on child development.

BACKGROUND: This study looks at the outcome of infants exposed to dothiepin in breast milk in an attempt to guide clinicians on the risk-benefit ratio of breast-feeding when on antidepressants. METHOD: Thirty women, who had had HDRS scores > 15 within the first five years postpartum from the same women's hospital, were assessed with their children 3-5 years postpartum; half had breast-fed while on dothiepin (study group). Thirty-six non-depressed women were also assessed. Rating scales assessed depression, anxiety, self-esteem, personality, social support, marital relationship, child behaviour and temperament. The children were assessed by the McCarthy Scale. RESULTS: Comparisons of the two depressed groups showed no significant differences on any measures except marital conflict and child behaviour, which were the most disturbed in the study group (P < 0.001). Overall cognitive scores for the children did not differ between the groups. Higher levels of dothiepin and northiaden were associated with higher cognitive scores on subscales (P = 0.02). CONCLUSIONS: We are cautiously optimistic about the lack of any negative associations between cognitive development and exposure to dothiepin via breast milk.

Postmortem redistribution and degradation of dothiepin. Human case studies and an animal model.

Two suicides took estimated maximum dothiepin doses of 765 and 1875 mg, respectively. Initial drug levels in nine and 12 blood samples were 0.26-1.85 and 4.08-23.98 mg/L, with highest concentrations in the pulmonary veins. Pulmonary artery concentrations rose markedly over 18 h: 0.32 rising to 0.9, and 6.54 rising to 19.53 mg/L. Peripheral blood concentrations were relatively stable. Concentrations in liver, heart, lung, and skeletal muscle were, for case 1, 4.3, 2.92, 18.6, and 1.1 mg/kg; and, for case 2, 52, 16.8, 73.9, and 8.98 mg/kg. New Zealand white female rabbits (2.4-3.2 kg) given 20 mg dothiepin hydrochloride intravenously were killed with pentobarbital after 1 h. Blood was sampled from the thorax, infra-renal inferior vena cava, and supra-renal inferior vena cava at 0, 1/2, 1, 4, 8, 12, and 24 h postmortem in paired animals. Liver, heart, lung, and skeletal muscle were sampled at 0 and 24 h. Mean dothiepin levels in thoracic blood rose from 0.43 mg/L at time 0 to 1.73 at 8 h and then fell to 0.61 at 12 h, likely reflecting initial redistribution from the lungs (63.4 mg/kg at time 0 and 27.3 mg/kg at 24 h) followed by putrefaction-associated bacterial degradation. Falls in blood drug levels associated with putrefaction were not seen in the human cases. Interpretation of postmortem dothiepin blood concentrations is complicated by pronounced interindividual variations in in vivo pharmacokinetics, the postmortem redistribution phenomenon, and variable drug degradation by bacteria.

Successful physostigmine treatment of acute dothiepin intoxication.

We report on a severe intoxication with the tricyclic antidepressant dothiepin. A treatment with a continuous infusion of physostigmine was successful and improved the ventricular arrhythmia. Dothiepin and its active metabolites were determined in plasma and urine by HPLC.

The excretion of dothiepin and its primary metabolites in breast milk.

1. The excretion of dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide into breast milk was studied in eight women. Exposure to drug was measured in five of their infants, and possible drug-related effects were assessed in all eight infants. 2. Using pre-feed milk samples mean (+/- s.e. mean) milk:plasma (M:P) ratios were 0.78 +/- 0.12, 0.85 +/- 0.16, 1.18 +/- 0.29 and 1.86 +/- 0.29 for dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide, respectively. In post-feed milk samples, the mean M:P ratio for dothiepin (1.59 +/- 0.32) was significantly greater (P less than 0.05) but M:P ratios for the metabolites were similar. 3. Mean total calculated infant daily doses, (in dothiepin equivalents and as a percent of the maternal dose) were 0.58% for dothiepin, 0.23% for nordothiepin, 2.47% for dothiepin-S-oxide, and 1.17% for nordothiepin-S-oxide. 4. Plasma samples were obtained from five infants. In one, both dothiepin and nordothiepin were below their minimum quantifiable levels (2 micrograms l-1) while in four others both dothiepin-S-oxide and nordothiepin-S-oxide were below their minimum quantifiable levels (10 micrograms l-1). No adverse effects were found in any of the eight infants. 5. Use of dothiepin by depressed mothers is unlikely to be a significant hazard to their breast-feeding infants.

Disposition of dothiepin after overdose: effects of repeated-dose activated charcoal.

Although the tricyclic antidepressant dothiepin is often encountered in deliberate self-poisonings, there are no published studies of its disposition in overdose. In the present study, we have documented the plasma disposition of dothiepin and its major metabolites in eight overdose patients. All had high initial levels of dothiepin (819-3,851 micrograms/L), dothiepin-S-oxide (655-2,162 micrograms/L), nordothiepin (88-422 micrograms/L), and nordothiepin-S-oxide (176-530 micrograms/L) that were considerably above steady-state therapeutic concentrations. In three patients who received treatment with repeated-dose activated charcoal, dothiepin half-lives were 10.6, 12.5, and 13.1 h compared with the literature range of 18.5-24 h. All patients survived and none experienced any significant cardiovascular event despite exhibiting clinical signs of tricyclic antidepressant overdose. We suggest that repeated-dose activated charcoal treatment may decrease the dothiepin half-life after overdose.

Pharmacokinetics and adverse effects of single doses of dothiepin in young and elderly subjects.

1. The pharmacokinetics and side-effects of Dothiepin (DOT) were studied for four days after administration of a single oral dose of 75 mg to young adult and elderly subjects. 2. In the elderly DOT is absorbed, distributed and eliminated with half-lives about the same as in young adults but it is cleared less efficiently. 3. This difference of clearance in the elderly, after single-dose administration, is not reflected in increased incidence of side-effects.

Dothiepin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness.

Dothiepin is a tricyclic antidepressant that is structurally related to amitriptyline. It appears that the antidepressant activity of dothiepin is mediated through facilitation of noradrenergic neurotransmission by uptake inhibition and possibly also by enhancement of serotoninergic neurotransmission. The overall therapeutic efficacy of dothiepin is very similar to that of amitriptyline. In addition, dothiepin appears to be comparable to imipramine, doxepin, maprotiline, mianserin, fluoxetine, fluvoxamine and trazodone. Dry mouth is the most commonly reported side effect of therapeutic doses but the incidence of this and other anticholinergic side effects is less among patients treated with dothiepin than with amitriptyline. However, the sedative/anxiolytic activity of dothiepin is similar to that of amitriptyline. Dothiepin has not been associated with cardiotoxicity at therapeutic doses. Thus, many years of extensive clinical use have shown that dothiepin is now an established and effective antidepressant in both inpatients and outpatients with depressive symptoms of varying severity and coexisting anxiety. Its therapeutic equivalence to other tricyclics ensures its place as a treatment alternative in these disorders.