Three antidepressants (amitriptyline,dothiepin, fluoxetine), with and without alcohol,compared with placebo on tests of psychomotor ability related to car driving

Eight female volunteers received acute doses of amitriptyline 50 mg (AMI), dothiepin 50 mg (DOT), fluoxetine 40 mg (FLU) or placebo both with and without a ‘social’ dose of alcohol (ALC) equivalent to 0·5 g/kg body weight absolute alcohol. Performance on a variety of tests of psychomotor ability and cognitive function (critical flicker fusion, choice reaction time, tracking, Maddox Wing and simulated car steering) were performed at 1·5 and 4 hours following treatment. AMI and DOT both with and without ALC impaired performance on a range of tests at either or both 1·5 and 4 hours, although the effects of AMI and AMI + ALC were more widespread and severe than those found with either DOT or DOT + ALC. FLU and FLU + ALC showed no evidence of impairment on any test at either the 1·5 or the 4 hours assessments. The results suggest that there are differences between the experimental substances, at the doses used, in their intrinsic potential for impairing aspects of psychomotor performance and cognitive function.     

The effects of fluoxetine and dothiepin on cognitive function in depressed patients in general practice

The objective of this study was to assess whether there are any differences between fluoxetine and dothiepin on cognitive function of patients with major depression (DSMIII‐R). A randomized, double‐blind, parallel group design, 6 week trial in patients in general practice was employed where patients were randomly allocated to one of two treatment groups, i.e. fluoxetine 20 mg mane or dothiepin 75 mg nocte (increasing to 150 mg in the 2nd week). Eighty‐four depressed patients aged 18–70 (mean 43·8) years were admitted to the study. Cognitive function was assessed by a valid battery of tests before and during treatment. The severity of depression was assessed using the Hamilton Depression Rating Scale (HAMD) at the start and end of the study. Both treatments were similarly efficacious in reducing the HAMD and performance tended to improve with both drugs during treatment. There were significant differences between the drugs on the critical flicker fusion task where the fluoxetine group performed significantly better than the dothiepin group (p<0·05). The fluoxetine group also had better scores on a mental arithmetic task. No significant differences were observed in the adverse event profiles. The results of this study show that fluoxetine and dothiepin cannot be differentiated in terms of efficacy manifest by changes in the HAMD, but do possess different profiles of action on the battery of cognitive tests. Copyright © 1999 John Wiley & Sons, Ltd.     

The Effect of Paroxetine and Dothiepin on Subjective Sleep in Depressed Patients

Paroxetine improve the quality of sleep and the ease of waking up on subjective measures of sleep (the LSEQ). Dothiepin in contrast improved the ease of getting to sleep, but caused a reduced quality of sleep and a ‘hangover’ effect the next morning. © 1997 John Wiley & Sons, Ltd.     

Plasma and breast milk concentrations of dothiepin and northiaden in lactating women

Plasma and breast-milk concentrations of dothiepin and its metabolite northiaden were measured in 20 lactating women receiving the drug for post-partum depression. Samples were collected at steady-state and both compounds quantitated by HPLC. Doses of dothiepin varied from 75 mg/day to 225 mg/day. Accordingly a wide range of plasma and breast-milk concentrations of dothiepin and northiaden were determined. Most determinations were made for women receiving 150 mg/day. At this dose mean (± SD) plasma concentrations of dothiepin and northiaden were 56(±27)m?g/l and 72(±79)m?g/l respectively while breast-milk concentrations were 95(±71) m?g/l and 40(±29) m?g/l for dothiepin and northiaden respectively. The data reflect the well recognised inter-individual variability in plasma concentrations for subjects receiving the same oral dose. Similar variability was noted in breast-milk concentrations at all doses of dothiepin. Dothiepin passes into the breast-milk of lactating women receiving the drug for post-partum depression. In this respect the drug is similar to other tricyclic antidepressants. The inter-individual variability of results recorded here suggest the need to determine drug concentrations on an individual basis before reaching a decision about breastfeeding. Perceived side effects in the infant are clear criteria for cessation of breastfeeding; high levels of drug in breastmilk where the infant is unaffected, warrant monitoring in view of our inadequate knowledge regarding long term effects of these drugs.     

Decreased 5-HT2 but not 5-HT1 receptor binding in cortex of rat after chronic administration of dothiepin. Application of the Woolf plot to analysis of binding parameters

Prolonged administration of the antidepressant drug, dothiepin hydrochloride (30 mg/kg orally twice daily for 24 days), resulted in a significant decrease in the population of serotonin2 (5-HT2) binding sites in the frontal cortex of rats whereas serotonin1 (5-HT1) binding sites remained unaltered. No significant differences in affinity constants for either ligand-binding site interaction were observed. Analyses of the binding parameters was performed using linear transformation methods of the specific binding isotherms according to Scatchard (1949) [Ann. N.Y. Acad. Sci. 51: 660-672] or Woolf (see Haldane, 1957: Nature 179: 832). The resulting parameter estimates generated in each analysis were compared. Although both methods demonstrated the decreased Bmax for 5-HT2 binding sites with no change in 5-HT1 sites after prolonged administration of dothiepin, Woolf analyses gave reliably better estimates of the binding parameters as judged by examination of the respective correlation coefficients for best fit linear regression lines.     

High dose tertiary amine tricyclic antidepressants in the treatment of severe refractory depression: The central role of plasma concentration estimations

The relationships between dosage, plasma concentration, antidepressant response and toxicity were investigated in 24 highly selected patients with severe, refractory major depression who were prescribed amitriptyline, clompramine or dothiepin at high dosage (150–525 mg/day), usually in combination with lithium or other psychotropics. of serious adverse effects 83 per cent were encountered when tricyclic antidepressant (TCA) plasma concentrations exceeded 400 mcg/1. Therapeutic drug monitoring of high dose TCAs is useful in minimizing the risk of toxicity and in revealing poor compliance, undertreatment and pharmacokinetic interactions which can mitigate against drug efficacy. The value of carbamazepine in the management of refractory depression in the context of unipolar affective disorder is put into question.     

Pharmacology of cyanodothiepin (BTS 56 424), a selective 5-hydroxytryptamine reuptake inhibitor

The pharmacological profile and antidepressant potential of cyanodothiepin (BTS 56 424) have been compared to those of dothiepin, cianopramine, and imipramine. Rat brain synaptosomes and human platelets were used to measure the effects of drugs on radiolabeled monoamine uptake in vitro. The 2-nitrile substitution converted the actions of dothiepin from nonselective inhibition of 5-hydroxytryptamine (5-HT) and noradrenaline uptake to those of cyanodothiepin, a potent and very selective 5-HT uptake inhibitor (Ki = 4.8 and 597 nM vs. 5-HT and noradrenaline uptake, respectively; rat brain synaptosomes). Nitrile substitution similarly conferred in vitro 5-HT selectivity on cianopramine (Ki = 0.71 and 15 nM vs. 5-HT and noradrenaline) compared to imipramine. The selectivity of cyanodothiepin as a 5-HT reuptake inhibitor was maintained in vivo in a variety of rodent models. Cianopramine was a more potent but less selective 5-HT reuptake inhibitor than cyanodothiepin in these paradigms. In monoamine-depletor based tests for antidepressant activity, cyanodothiepin was weakly active compared to cianopramine and imipramine; cyanodothiepin was active in the Porsolt test for antidepressants. Compared to cianopramine, cyanodothiepin showed weaker affinity for muscarinic cholinergic and 5-HT2 receptors in vitro and in vivo, and for α1-adrenergic, dopamine (D1 and D2) receptors in vitro. Cyanodothiepin was less sedative than cianopramine and was also a weaker enhancer of drug-induced loss of righting reflex in mice. Overall, cyanodothiepin is a potent and selective 5-HT reuptake inhibitor which exhibits antidepressant potential and probably possesses a lower propensity to induce side effects associated with tricyclic antidepressants. © 1993 Wiley-Liss, Inc.     

Actigraphy can measure antidepressant-induced daytime sedation in healthy volunteers

Actigraphy is the continuous measurement of the motor component of behaviour. A change in behaviour will result in a change in activity. Drugs that are behaviourally toxic will cause changes in activity which can be measured using an actigraph. It is hypothesized that a reduction in daytime activity is a measure of sedation. A study was conducted comparing actigraphy with valid, reliable psychometric tests which are sensitive to the behaviourally toxic effects of psychoactive drugs. The study was designed to investigate whether actigraphy could accurately measure the daytime sedation associated with tricyclic antidepressants. The effects of fluvoxamine and dothiepin on behavioural activity and psychomotor abilities, in 12 healthy male volunteers, was investigated in a placebo-controlled, double-blind, crossover study. Subjects completed a battery of psychometric tests prior to dosing then at 1, 2, 3, 4 and 6 h post dose. Actigraphy showed that dothiepin caused daytime sedation, defined as a reduction in activity and this result was confirmed by the results from the psychometrics which showed that dothiepin impaired cognitive and psychomotor performance in the majority of the tests. These results show that actigraphy is capable of accurately measuring daytime sedation. © 1997 John Wiley & Sons, Ltd.     

Citalopram Compared to Dothiepin and Placebo: Effects on Cognitive Function and Psychomotor Performance

Three doses of citalopram (10, 20 and 40 mg), and placebo were administered to healthy volunteers for periods of 8 days each. Dothiepin 75 mg was given as an acute dose on days 1 and 8 only, with placebo dothiepin on days 2–7. Subjects were tested on days 1 and 8 of the dosing periods on a battery of psychometric tests. The results showed that citalopram at all doses had no detrimental effects on psychomotor performance. The effect of citalopram on critical flicker fusion (CFF) was to raise thresholds. This indicates an improvement in CNS function, i.e. an elevation of cognitive processing ability, with no evidence of an arousing or alerting effect. The effects were apparent after both acute and sub-chronic dosing. These data are in contrast to those collected for dothiepin, which showed significant impairment of cognitive and psychomotor function on most of the measures employed. The most frequent adverse events reported for citalopram were drowsiness, nausea and headache, with the nausea appearing to be dose dependent. The main adverse events reported for dothiepin were drowsiness, sleepiness and dizziness. The rates of adverse events for all active treatments were not statistically significantly different to placebo. It is concluded that citalopram is relatively free from behavioural toxicity and so represents a significant improvement over the older antidepressant agents such as dothiepin. © 1997 by John Wiley & Sons, Ltd.     

The effects of acute doses of dothiepin (25, 50, and 75 mg) versus placebo on psychomotor performance and cognitive function

Sixteen healthy volunteers received dothiepin 25 mg, 50 mg, 75 mg and placebo in a double-blind crossover study. Each subject received the four treatments once, with a 6-day washout period between test days. On each occasion psychomotor performance and cognitive function were measured 30 min before dosing and 1, 2, 4, 6 and 8 h after drug administration. The test battery comprised: Critical Flicker Fusion, Choice Reaction Time, Continuous Tracking and Short Term Memory. Subjective ratings of sedation were measured using Line Analogue Rating Scales. Dothiepin at the subtherapeutic dose of 75 mg was shown to produce statistically significant impairment (p<0·05) on several of the variables investigated. These included CFF at the 2- and 4-h test points, TRT at the 2-h test point and LARS at the 2- and 4-h test points. Lower doses also produced impairment of cognitive function and psychomotor performance as measured by the present test battery. © 1997 John Wiley & Sons, Ltd.