Antidepressant prescribing patterns and adverse events following introduction of a National Prescribing Indicator to monitor dosulepin usage in Wales.

AIMS: Limiting use of the antidepressant dosulepin has been encouraged due to associated risks of toxicity. In April 2011, the All Wales Medicines Strategy Group introduced a National Prescribing Indicator (NPI) to monitor dosulepin usage. The aim of this study was to investigate antidepressant prescribing patterns, and selected adverse events in patients prescribed dosulepin following introduction of the NPI. METHODS: An e-cohort study was conducted. Adult patients receiving regular dosulepin prescriptions between October 2010 and March 2011 were included. Characteristics of patients who were continued on dosulepin, were switched to an alternative antidepressant or whose dosulepin was discontinued following introduction of the NPI were compared. RESULTS: In total, 4121 patients were included. Of these, 1947 (47%) continued dosulepin, 1487 (36%) were switched and 692 (17%) discontinued. Of the 692 who discontinued, 92% did not receive a prescription for another antidepressant during the follow-up period. Patients whose dosulepin was discontinued were older and were less commonly coprescribed benzodiazepines. During follow-up, recorded incidence of selected adverse events was low across all groups and no significant difference was observed. CONCLUSION: Over half of patients had discontinued dosulepin at the end of the period when the NPI was in place. Further interventions may have been required to have a greater impact on prescribing. This study provides some reassurance that dosulepin discontinuation can be a successful strategy, and that the risk of the adverse events investigated was unlikely to have been greater in those who had dosulepin discontinued than in those in whom dosulepin had been continued.

A change in the trend in dosulepin usage following the introduction of a prescribing indicator but not after two national safety warnings.

WHAT IS KNOWN AND OBJECTIVE: The tricyclic antidepressant dosulepin has been associated with an increased risk of toxicity in overdose compared with other antidepressants. In the UK, the MHRA and NICE have issued advice on the prescribing of dosulepin, and a National Prescribing Indicator (NPI) to monitor usage was introduced in Wales in 2011. The aim of this study was to assess whether trends in dosulepin usage in Wales and NE England changed following the two pieces of safety guidance and the introduction of the National Prescribing Indicator in Wales. METHODS: Primary care dosulepin usage in the 12 months prior to and following MHRA safety advice (in 2007), NICE guideline CG90 (in 2009) and the introduction of the NPI (in 2011) was obtained. Usage was measured using defined daily doses (DDDs) per 1000 prescribing units (PUs). The trends in the 12 months prior to and following the introduction of prescribing advice and the NPI were compared using an autoregressive integrated moving average (ARIMA) model. RESULTS AND DISCUSSION: In Wales, the trend in dosulepin usage did not change significantly prior to and following the MHRA advice: -0·18 and -0·43 DDDs/1000PUs per month, respectively (P = 0·07), or prior to and following NICE CG90: -0·30 and -0·49 DDDs/1000PUs per month, respectively (P = 0·35). In the 12 months prior to and following the introduction of the NPI, the trend was -0·45 and -0·98 DDDs/1000PUs per month, respectively (P = 0·001). In NE England, the trend did not alter significantly following the NICE advice or the introduction of the NPI in Wales. WHAT IS NEW AND CONCLUSION: The trend in dosulepin usage in Wales altered significantly following the introduction of the NPI, but not after the other prescribing advice. This association, coupled with the absence of a significant change in NE England over the same period, provided some evidence of the effectiveness of the NPI in prompting a change in prescribing behaviour in Wales.

Hyponatraemia and confusion in a 70-year-old female when bupropion was added to dothiepin and escitalopram.

OBJECTIVE: Hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a well-recorded adverse event observed in elderly patients on antidepressant treatment. Bupropion is an antidepressant agent usually reserved as an augmentation strategy for treatment-resistant depression. While hyponatraemia is not a documented side effect of bupropion, there are a few cases outside of Australia reported in the literature. We report on a case of hyponatraemia observed on bupropion initiation in a 70-year-old female patient with treatment-resistant depression. We present a discussion of the possible mechanism of action for the hyponatraemia observed in our case and prior reported cases. CONCLUSIONS: Our case and review of the available literature highlights the dangers of polypharmacy in the management of treatment-resistant depression. Our findings suggest that the association of hyponatraemia with bupropion in our and subsequent cases was likely the result of medication interaction and not a direct side effect of bupropion. Where bupropion is being used as an augmenting agent in the treatment of depression we would suggest checking of serum sodium prior to commencement of bupropion, and monitoring thereafter. This is especially important in elderly patients where other risk factors for hyponatraemia are likely to be present.

"Lipid rescue" for tricyclic antidepressant cardiotoxicity.

BACKGROUND: Tricyclic antidepressant (TCA) toxicity results predominantly from myocardial sodium-channel blockade. Subsequent ventricular dysrhythmias, myocardial depression, and hypotension cause cardiovascular collapse. Animal studies have demonstrated the effectiveness of intravenous lipid-emulsion in treating TCA cardiotoxicity. CASE REPORT: We report a case of dothiepin (tricyclic antidepressant) overdose causing refractory cardiovascular collapse, which seemed to be successfully reversed with lipid-emulsion therapy (Intralipid(®); Fresenius, Cheshire, UK). CONCLUSIONS: Lipid emulsions are a potentially novel therapy for reversing cardiotoxicity seen in TCA overdose. Research is required into the role of lipid emulsion in the management of poisoning by oral lipophilic agents.

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.

Abuse of dosulepin to induce mania.

BACKGROUND: Tricyclic antidepressants sometimes trigger mania in bipolar patients, but little is known about their potential for abuse in this regard. CASE DESCRIPTION: We describe a man with bipolar disorder and alcohol dependency who abused dosulepin repeatedly in order to induce manic episodes. This caused serious problems for treatment and long-term outcome. We mention two further cases in which dosulepin or clomipramine was used deliberately to induce bipolar mania. CONCLUSIONS: Tricyclic antidepressants can be abused to induce mood elevation in bipolar patients. This should be considered in cases of treatment-resistant mania.

Dothiepin hydrochloride: treatment efficacy and safety.

Dothiepin, a thio analogue of amitriptyline, has been used extensively in Europe during the past 15 years. It is a safe and effective agent for the treatment of major depressive disorder. Although the onset of action is comparable to that of other tricyclic antidepressants, dothiepin may cause fewer intolerable side effects and have less cardiotoxicity than these other compounds. In addition, dothiepin reduces the anxiety associated with some major depressive episodes. These features suggest that dothiepin may be particularly helpful for treating anxious depressed patients and patients who have underlying cardiac disease or who are elderly.

A double-blind study of the efficacy and safety of dothiepin hydrochloride in the treatment of major depressive disorder.

In a 6-week double-blind parallel treatment study, dothiepin and amitriptyline were compared to placebo in the treatment of 33 depressed outpatients. Dothiepin and amitriptyline were equally effective in alleviating the symptoms of depressive illness, and both were significantly superior to placebo. The overall incidence of side effects and the frequency and severity of blurred vision, dry mouth, and drowsiness were significantly less with dothiepin than with amitriptyline. Dothiepin also produced fewer CNS and cardiovascular effects. There were no clinically important changes in laboratory parameters. Dothiepin thus was found to be an effective antidepressant drug associated with fewer side effects than amitriptyline in the treatment of depressed outpatients.

An overview of seventeen years of experience with dothiepin in the treatment of depression in Europe.

The European clinical experience with dothiepin since 1962 indicates that it is efficacious in the treatment of depression (neurotic, psychotic, and with concomitant anxiety) in dose of 75-200 mg/day. The side effects profile is similar to the tricyclic antidepressant drugs with significantly less anticholinergic side effects and cardiotoxicity then amitriptyline. The result of the current ongoing clinical trails in the United States with several hundred patients will more precisely define the efficacy, dosage and side effect profile of dothiepin.

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.

The tolerability of dothiepin: a review of clinical studies between 1963 and 1990 in over 13,000 depressed patients.

1. A total of 13,834 depressed patients were exposed to dothiepin most frequently at a dose of 150 mg/day and over 6 weeks, in 116 clinical studies between 1963 and 1990. 2. Overall, 2,066 (15%) patients were withdrawn prematurely from dothiepin for a variety of reasons, the most commonly specified reason being due to drug-related events in 500 (4%) patients. 3. In the remaining 11,768 patients, there were 9,312 reports of unwanted events most typically associated with the pharmacological effects of a tricyclic antidepressant although no serious sequelae were reported. 4. This review indicates that the incidence of serious adverse events associated with dothiepin at therapeutic doses is very low.

Effects of dothiepin on delayed conduction produced by ventricular arrhythmia in the canine heart after myocardial infarction.

1. In order to clarify the arrhythmogenic effects of antidepressants, the authors examined the effects of dothiepin and amitriptyline on the ventricular activation time (VAT), effective refractory periods(ERP) and incidence of arrhythmias induced by programmed electrical stimulation(PES) in the dog heart in situ after myocardial infarction. 2. Myocardial infarction was produced by two-stage ligation of the left anterior descending coronary artery. Seven days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and normal zones to apply an electrical stimulation or record ventricular activation. An electrical stimulation with coupling interval 250 or 180 ms was applied on the ventricular surface, and AT was measured. 3. Dothiepin at doses of 1-3 mg/kg increased the heart rate. The VAT of coupling interval 180 ms in the infarcted zone was increased by the administration of 3 mg/kg dosulepin. Dothiepin at 3 mg/kg increased the incidence of ventricular arrhythmias induced by PES. 4. Amitriptyline, at doses of 1-3 mg/kg, significantly increased the heart rate. Amitriptyline increased the VAT dose- and frequency-dependently(2,3 mg/kg zone), and prolonged the ERP and QT c interval. Amitriptyline at doses of 1-3 mg/kg increased the incidence of ventricular arrhythmias by PES. 5. These results indicate that dothiepin, 1-3 mg/kg, has lesser effects on cardiac delayed conduction produced by ventricular arrhythmia than amitriptyline.

Depression in general practice: a comparison of flupenthixol dihydrochloride and dothiepin hydrochloride.

A single-blind, parallel group, general practice study was carried out in 153 patients with mild to moderate depression to compare the efficacy and tolerability of flupenthixol dihydrochloride and dothiepin hydrochloride. Patients were allocated at random to receive single daily doses of either 1 mg flupenthixol in the morning or 75 mg dothiepin in the evening, and this dose could be doubled at the end of 2 weeks in the event of inadequate response. Assessments were made on entry and after 1, 2, 4 and 6 weeks of treatment using the Hamilton Depression Rating Scale, a 4-point severity scale and an unwanted symptoms checklist. The results showed that both treatments significantly improved the patients' condition over 6 weeks, and there was a significant difference in favour of flupenthixol at end-point. Both drugs were well tolerated, although persistence of anticholinergic side-effects in the dothiepin group resulted in a trend favouring flupenthixol. One patient in the flupenthixol group attempted suicide by overdose but made a complete recovery.

A single-blind comparative study of once daily dothiepin ("Prothiaden") and divided daily doses of amitriptyline.

Forty-eight patients took part in a single-blind clinical trial comparing a once daily dose of dothiepin (75 mg) and 25 mg 3-times a day of amitriptyline. The results showed that dothiepin caused a greater improvement than amitriptyline after 4 weeks of treatment as judged by depression scores, total scores and global assessments. The incidence of side-effects was less with dothiepin and in those patients who actually reported side-effects the severity was much less with dothiepin than with amitriptyline.

The treatment of mixed affective disorders in general practice: a comparison of trazodone and dothiepin.

The efficacy and tolerance of trazodone in the treatment of mixed affective disorder was compared with that of dothiepin in a double-blind, parallel group study in 228 general practice patients at 10 centres. After satisfying entry criteria, patients were randomized to receive either 150 mg trazodone at night, or 75 mg dothiepin at night for a 6-week period. Efficacy was assessed using the Hamilton Rating Scales for Depression and Anxiety. Significant improvements were observed in the condition of patients in each of the two treatment groups during the 6-week treatment period (p = 0.0001), with no statistically significant difference between the groups. There were no marked differences between the two treatment groups in the type of side-effects reported in response to open questioning, although a higher percentage of symptoms in the trazodone group were mild compared to the dothiepin group, and a lower percentage were severe. The incidence side-effects recorded by means of a checklist of common psychotropic side-effects was similar for the two treatment groups: dry mouth and drowsiness were the most frequent. A slightly higher proportion of patients withdrew from the dothiepin group, and of those who withdrew a higher percentage was due to side-effects than in the trazodone group.

A double-blind, randomized, 26-week study comparing the cognitive and psychomotor effects and efficacy of 75 mg (37.5 mg b.i.d.) venlafaxine and 75 mg (25 mg mane, 50 mg nocte) dothiepin in elderly patients with moderate major depression being treated in general practice.

To investigate the efficacy and cognitive and psychomotor effects of venlafaxine and dothiepin in elderly patients with moderate major depression. A prospective, randomized, double-blind, parallel-group, active comparator controlled study was conducted. Eighty-eight patients (aged > or = 60 years) were enrolled. Each patient received either venlafaxine (immediate release formulation) 37.5 mg twice per day or dothiepin 25 mg mane followed by 50 mg nocte for 26 weeks. Efficacy was assessed with the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. A psychometric test battery to assess cognitive function, activities of daily living and sleep consisted of Critical Flicker Fusion (CFF), Short-term Memory--Kim's Game, Cognitive Failures Questionnaire, Milford Epworth Sleepiness Scale, Leeds Sleep Evaluation Questionnaire, and an Accident Scoring Questionnaire. Quality of Life Questionnaires (Short Form 36 and Quality of Life in Depression Scale) were also administered. Venlafaxine significantly (p < 0.05) raised CFF scores compared to baseline but had no effect on any other measure. Dothiepin significantly (p < 0.05) lowered CFF threshold, and increased ratings of both sedation and difficulty in waking. The results showed that venlafaxine at doses of 37.5 mg b.i.d. in elderly depressed patients is free from disruptive effects on cognitive function and psychomotor performance.

Effects of 5 weeks of administration of fluoxetine and dothiepin in normal volunteers on sleep, daytime sedation, psychomotor performance and mood.

This was a placebo-controlled, double-blind randomized crossover study of long-term (5 weeks) administration of fluoxetine (20 mg/day) and dothiepin (75 mg/day for 1 week followed by 150 mg/day for 4 weeks) in 12 healthy male volunteers. Subjects were studied on day 10 and day 36 of treatment, with tests of nocturnal sleep, driving performance, continuous electroencephalogram (EEG), sleep during scheduled naps, computerized visual attention tasks, saccadic eye movement measurement and visual analogue ratings of mood. Both drugs had a marked suppressive effect on nocturnal rapid eye movement (REM) sleep; these effects were less at 36 days than at 10 days, and fluoxetine decreased and dothiepin increased REM in daytime naps. Sleep fragmentation after fluoxetine is similar to that reported in the literature. We found no sleep-promoting effects of dothiepin, in contrast to our previous single-dose study, and no subjective sleep effects of either drug. Subjects were less sleepy after both antidepressants than placebo at 5 weeks measured by sleep latencies and EEG. Saccadic eye movement measures were significantly faster after 5 weeks of fluoxetine than after 5 weeks of placebo. Reaction times to a peripheral stimulus during computerized tracking task were shorter after 10 days of dothiepin compared with placebo. Driving performance, visual attention and mood ratings showed no treatment effects. Subjective health reports during each 5 weeks of treatment were similar in number for the two drugs but showed a different profile of side-effects.

Antidepressants and galactorrhoea.

Several antidepressants have been reported to produce hyperprolactinaemia, with or without galactorrhoea. We report a case of galactorrhoea associated with dothiepin and discuss the effects of a subsequent change in antidepressants.

A double-blind, placebo-controlled comparison of sertraline and dothiepin in the treatment of major depression in general practice.

In a double-blind multi-centre study of general practice patients with DSM-III-R major depressive disorder, sertraline (50 or 100 mg/day) was compared with dothiepin (75 or 150 mg/day) and with placebo. There were 83, 96 and 90 patients evaluated in the respective treatment groups; treatment lasted 6 weeks. Patients were assessed on the MADRS, CGI, and Leeds Self-rating Scales. Statistically significant differences (p < 0.05) between sertraline and placebo were found on MADRS and CGI but not the Leeds Scales. In the mild subgroup analyses, there were no significant differences between sertraline and placebo. However, clear significant differences (p < 0.05) between sertraline and placebo were present in the severe subgroup. Dothiepin failed to achieve a statistically significant difference from placebo on any analyses. Seventy-six per cent of patients were treated with 50 mg sertraline and 81% of patients received 150 mg dothiepin. Both sertraline and dothiepin were generally well tolerated; the most frequent side effects with sertraline were nausea, dizziness and headache; with dothiepin the most frequent side effects were dry mouth, somnolence and headache.