Multi-dimensional relationships among dementia, depression and prescribed drugs in England and Wales hospitals.

BACKGROUND: Dementia is a group of symptoms that largely affects older people. The majority of patients face behavioural and psychological symptoms (BPSD) during the course of their illness. Alzheimer's disease (AD) and vascular dementia (VaD) are two of the most prevalent types of dementia. Available medications provide symptomatic benefits and provide relief from BPSD and associated health issues. However, it is unclear how specific dementia, antidepressant, antipsychotic, antianxiety, and mood stabiliser drugs, used in the treatment of depression and dementia subtypes are prescribed in hospital admission, during hospital stay, and at the time of discharge. To address this, we apply multi-dimensional data analytical approaches to understand drug prescribing practices within hospitals in England and Wales. METHODS: We made use of the UK National Audit of Dementia (NAD) dataset and pre-processed the dataset. We evaluated the pairwise Pearson correlation of the dataset and selected key data features which are highly correlated with dementia subtypes. After that, we selected drug prescribing behaviours (e.g. specific medications at the time of admission, during the hospital stay, and upon discharge), drugs and disorders. Then to shed light on the relations across multiple features or dimensions, we carried out multiple regression analyses, considering the number of dementia, antidepressant, antipsychotic, antianxiety, mood stabiliser, and antiepileptic/anticonvulsant drug prescriptions as dependent variables, and the prescription of other drugs, number of patients with dementia subtypes (AD/VaD), and depression as independent variables. RESULTS: In terms of antidepressant drugs prescribed in hospital admission, during stay and discharge, the number of sertraline and venlafaxine prescriptions were associated with the number of VaD patients whilst the number of mirtazapine prescriptions was associated with frontotemporal dementia patients. During admission, the number of lamotrigine prescriptions was associated with frontotemporal dementia patients, and with the number of valproate and dosulepin prescriptions. During discharge, the number of mirtazapine prescriptions was associated with the number of donepezil prescriptions in conjunction with frontotemporal dementia patients. Finally, the number of prescriptions of donepezil/memantine at admission, during hospital stay and at discharge exhibited positive association with AD patients. CONCLUSION: Our analyses reveal a complex, multifaceted set of interactions among prescribed drug types, dementia subtypes, and depression.

Suspected antidepressant-induced switch to mania in unipolar depression: a first-person narrative.

BACKGROUND: Antidepressant-induced switch to mania has not been thoroughly characterized in bipolar disorder and is even less well understood in unipolar depression. METHOD AND RESULTS: I describe, as a first-person narrative, my own experience of psychotic mania, which was suspected to have been induced by the tricyclic antidepressant, dosulepin. I have had a 16-year history of depression and was receiving sertraline 50 mg od when I was prescribed, off licence, dosulepin 25 mg 1-2 nocte for insomnia. Within days, I developed mild hypomanic symptoms and returned to my GP, who discontinued dosulepin but continued treatment with sertraline. I was also referred for psychiatric assessment. Two months later, I was detained under Section II of the Mental Health Act 1983 and admitted to hospital with psychotic manic symptoms. CONCLUSION: More understanding of antidepressant-induced switch to mania is needed in unipolar depression. My case study highlights the need for prompt specialist care for patients with depression reporting even mild, sub-threshold symptoms of mania.

A comparative study of non-fatal self-poisoning with antidepressants relative to prescribing in three centres in England.

BACKGROUND: Antidepressants are used frequently in non-fatal self-poisoning. There are national guidelines for prescribing antidepressants. There have been few investigations of how non-fatal self-poisoning with antidepressants varies in relation to prescribing and to patient characteristics. METHODS: A comparative study of the use of specific antidepressants (amitriptyline and dosulepin (tricyclics), citalopram, fluoxetine, paroxetine and sertraline (selective serotonin reuptake inhibitors) and venlafaxine (serotonin norepinephrine reuptake inhibitor)) for non-fatal self-poisoning (episode-based), relative to prescribing, in three centres in England, 2004 to 2006. RESULTS: There was marked variation between centres in the ratio of rates of self-poisoning to prescribing for specific antidepressants. Higher rates of self-poisoning relative to prescribing for all antidepressants combined, and for venlafaxine, were found in the centre with greater proportions of patients with a history of self-harm and/or previous psychiatric treatment. Within each centre, higher rates of self-poisoning relative to prescribing were found for citalopram and fluoxetine than amitriptyline. However, rates of self-poisoning relative to prescribing for either amitriptyline or dosulepin were also similar to sertraline, which is of concern given the known toxicity of tricyclics. LIMITATIONS: An ecological study, where prescriptions were for all indications and not specifically for the patients who self-poisoned. CONCLUSIONS: Marked differences found in ratios of self-poisoning with antidepressants to levels of prescribing, in three centres in England, are likely to reflect differences in both prescribing practices (despite clear national guidance) and patient characteristics. Risk of overdose and toxicity should be considered when local prescribing policy and clinical practice relating to antidepressants are under review.

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.

QT dispersion estimated from 80 body surface potential map leads and from standard 12-leads ECG in psychiatric patients treated with dosulepin.

The aim of the study was to detect changes of the QT dispersion (QTd) due to cardiotoxicity of tricyclic antidepressant dosulepin. Electrocardiographic and body surface potential mapping (BSPM) recordings were obtained using Cardiag 112.2 diagnostic system from 27 psychiatric outpatients treated with prophylactic doses of dosulepin and compared to those obtained from 37 healthy volunteers. From these recordings the QTd and the dispersion of heart rate-corrected QT interval QTc were evaluated. These parameters were estimated both from 80 BSPM leads and from 12 standard ECG leads. Acquired data were statistically correlated by Spearman rank order correlation coefficient with dosulepin plasma levels. The average QTd evaluated from BSPM leads (+/-SD) in the dosulepin group was significantly higher [70 (+/-21) ms] than that in the control group [34 (+/-12) ms] (P< 0.001). Moreover, the correlation between QTd and the dosulepin plasma level was statistically significant as well (P< 0.001) with the value of correlation coefficient 0.7871. The QTd evaluated from standard 12 ECG leads was increased in dosulepin group as well [46 (+/-18) ms vs. 28 (+/-10) ms - P< 0.05] but we have not found any significant correlation of the QTd with the dosulepin plasma level. According to the above-mentioned results we can conclude that the QTd estimated from BSPM leads (but not that estimated from 12-lead ECG) could be used as a marker of the dosulepin effect on the myocardium.

QT dispersion and electrical heart field morphology in patients treated with dosulepin.

The aim of the study was to detect the changes of QT dispersion (QTd) due to cardiotoxicity of tricyclic antidepressant dosulepin. Electrocardiographic and vectorcardiographic recordings were obtained using Cardiag 112.2 diagnostic system from 28 psychiatric outpatients treated with prophylactic doses of dosulepin and compared to those obtained from 37 healthy volunteers. From these recordings following parameters were evaluated: QTd, spatial QRS-STT angle and amplitude of T-wave. The acquired data were correlated with the dosulepin plasma levels using Spearman's rank order correlation test. The average QTd (+/-S.D.) in the dosulepin group was significantly higher (70+/-21 ms) than that in the control group (34+/-12 ms) (P<0.001). Moreover, the correlation between QTd and the dosulepin plasma levels was highly significant (r = 0.7871, P<0.001). Similar results were obtained when QTc dispersion was used. On the contrary, the QRS-STT space angle did not correlate with the dosulepin plasma levels. Furthermore, the T-wave amplitude was not significantly correlated to the QT-interval. Thus we can conclude that the QT dispersion could be used as a simple marker of the dosulepin effect on the myocardium.

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.

Antidepressants and the risk of suicidal behaviors.

CONTEXT: The relation between use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), and suicidal ideation and behaviors has received considerable public attention recently. The use of such drugs among teenagers has been of particular concern. OBJECTIVE: To estimate the relative risks (RRs) of nonfatal suicidal behavior in patients starting treatment with 1 of 3 antidepressant drugs compared with patients starting treatment with dothiepin. DESIGN AND SETTING: Matched case-control study of patients treated in UK general practices using the UK General Practice Research Database for 1993-1999. PARTICIPANTS: The base population included 159,810 users of the 4 antidepressant drugs. Participants could have used only 1 of these antidepressants and had to have received at least 1 prescription for the study antidepressant within 90 days before their index date (the date of suicidal behavior or ideation for cases and the same date for matched controls). MAIN OUTCOME MEASURES: Frequency of first-time exposure to amitriptyline, fluoxetine, paroxetine, and dothiepin of patients with a recorded diagnosis of first-time nonfatal suicidal behavior or suicide compared with comparable patients who did not exhibit suicidal behavior. RESULTS: After controlling for age, sex, calendar time, and time from first antidepressant prescription to the onset of suicidal behavior, the relative risks for newly diagnosed nonfatal suicidal behavior in 555 cases and 2062 controls were 0.83 (95% confidence interval, [CI] 0.61-1.13) for amitriptyline, 1.16 (95% CI, 0.90-1.50) for fluoxetine, and 1.29 (95% CI, 0.97-1.70) for paroxetine compared with those using dothiepin. The RR for suicidal behavior among patients first prescribed an antidepressant within 1 to 9 days before their index date was 4.07 (95% CI, 2.89-5.74) compared with patients who were first prescribed an antidepressant 90 days or more before their index date. Time since first antidepressant prescription was not, however, a confounder of the relation between specific antidepressants and suicidal behavior since its relation to suicidal behavior was not materially different among users of the 4 study drugs. Similarly for fatal suicide, the RR among patients who were first prescribed an antidepressant within 1 to 9 days before their index date was 38.0 (95% CI, 6.2-231) compared with those who were first prescribed an antidepressant 90 days or more before their index date. There were no significant associations between the use of a particular study antidepressant and the risk of suicide. CONCLUSIONS: The risk of suicidal behavior after starting antidepressant treatment is similar among users of amitriptyline, fluoxetine, and paroxetine compared with the risk among users of dothiepin. The risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days. A possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression. Based on limited information, we also conclude that there is no substantial difference in effect of the 4 drugs on people aged 10 to 19 years.

Length of therapy with selective serotonin reuptake inhibitors and tricyclic antidepressants in Australia.

OBJECTIVE: To investigate the proportion of patients starting on either selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) who continued treatment for a period consistent with recommended guidelines for major depression, that is at least 6 months. METHOD: Cohort study using a national dispensing claims database involving patients eligible for social security entitlements in Australia. Two 'new user' cohorts were established of patients who were supplied a prescription for either an SSRI (6026) or a TCA (4158) in the first week of April 2000 and who had not received a prescription for any antidepressant in the preceding three months. The main outcome measure was the proportion of patients who were still having any SSRI or TCA prescription, respectively, dispensed between 6 and 8 months after initiation. Additionally, for patients starting on either a leading SSRI (sertraline) or TCA (dothiepin), the proportions of those that remained on these drugs or had changed to other antidepressants were determined. The dispensing data are not linked to reason for prescribing in the national dataset. RESULTS: 2267 SSRI 'new users' (38%) were still receiving SSRIs 6-8 months later, compared with 1269 (31%) of the 4158 TCA 'new users' (p < 0.001). The difference between the groups occurred early, by the 2-4 month time interval. 1038 (41%) of patients starting on the individual SSRI and 385 (38%) of patients starting on the individual TCA were receiving some type of antidepressant therapy at 6-8 months, with no significant difference (p = 0.6) in the proportions that had changed to another antidepressant. CONCLUSIONS: In 2000, only 40% of patients started on an antidepressant continued to be prescribed some antidepressant therapy 6-8 months later. Patients were more likely to continue on SSRIs as a class than on TCAs and the difference in continuation between these two classes occurred within the first 2 months of therapy. However, patients starting on an individual SSRI or TCA were equally likely to change to another antidepressant.

Electrocardiographic dose-dependent changes in prophylactic doses of dosulepine, lithium and citalopram.

Tricyclic antidepressant drugs dosulepine (TCA), serotonin selective reuptake inhibitor (SSRI) and prophylactic agent with antidepressant effect lithium carbonicum (Li) have different cardiovascular side-effects. We compared them in the prophylactic therapy of periodic affective disorder in remission with TCA, SSRI and Li. Our previous papers confirmed the most prominent effects of heart electric field parameters in TCA patients (Slavícek et al., 1998). In the present work we studied for the first time the dose-dependent changes of ECG, body surface potential maps (BSPM - parameter DIAM 30, 40) in 43 TCA dosulepine, 40 SSRI citalopram and 30 Li outpatients (Hamilton scale: HAMDL10; age 40+/-5 years; treated for depressive disorders or bipolar disorders). The daily doses of dosulepine were 50-250 mg, citalopram 20-80 mg, Li plasma levels 0.66+/-0.08 meq/l. The electrocardiogram (ECG), vectorcardiogram (VCG), and BSPM were measured and calculated by the Cardiag 112.1 diagnostic system. The results have shown a relation between the dose of dosulepine and extremum (maximum and minimum) of depolarization isoarea map in dosulepine, but not in citalopram patients. The repolarization BSPM changes were most pronounced in SSRI patients. Lithium in long-term prophylaxy (1-22 years) caused only minimal ECG BSPM changes. The present results correspond with our previous observations.

Plasma levels of dosulepine and heart electric field.

Antidepressants, particularly tricyclic (TCA) antidepressants, may have cardiotoxic effects, such as cardiac arrhythmias, especially in patients with cardiovascular diseases. For most of TCA, no exact correlation between dosage, plasma levels and changes of ECG parameters of standard ECG has been found. So far, no relationship between dosulepine plasma levels and heart electric field parameters has been studied. We selected 18 female outpatient subjects diagnosed with recurrent depressive disorders, currently in the remission phase (HAMD < 10), without any cardiovascular disease. Patients were treated with daily dosulepine doses of 25-125 mg for 4-8 weeks. 30 heart electric field parameters were analyzed by Cardiag 128.1 diagnostic system as part of BSPM (Body Surface Potential Mapping). Acquired data were correlated with dosulepine plasma levels by means of Spearman's rank order correlation test. Four ECG parameters showed a significant correlation with dosulepine plasma levels: QRS axis deviation in frontal plane (p=0.01), DIAM 40 max (p<0.05), QRS-STT angle in transversal and left sagittal plane (p<0.05). The demonstrated changes confirmed dosulepine influence on the early myocardium depolarization phase and the correlation of this effect with dosulepine dose (its plasma concentration). The higher the dosulepine level, the more marked are the changes of the QRS-STT angle in transversal and sagittal planes and the changes in the QRS axis deviation in frontal plane. Repeatedly recorded changes in the heart electric field were dosulepine-specific and dependent on its plasma levels.

Burning mouth syndrome and vulvodynia coexisting in the same patient: a case report.

The 'dynias' are a group of chronic focal pain syndromes with a predilection for the orocervical and urogenital regions. This is a case report of stomatodynia (burning mouth syndrome) and vulvodynia coexisting in a middle-aged woman. The dynias are an enigma in terms of aetiology, which is multifactorial, making clinical investigations difficult and often requiring liaison with other specialties.

Chronic facial pain: a multidisciplinary problem.

Atypical facial pain is an unrecognised and unhelpful diagnosis but one which describes chronic pains that do not fit the present classification system. Due to the site of the pain, patients may seek and, indeed, receive treatment from dental practitioners and specialists, but the pain is often unresponsive and may have more in common with unexplained medical symptoms affecting other areas of the body, than with other dental symptoms. This review suggests a need for a diagnostic category of "chronic facial pain", which demands a multidisciplinary approach to diagnosis and management.

Effect of dothiepin on gastric ulceration mediated by lipid derived eicosanoids.

Dothiepin, a tricyclic antidepressant, significantly inhibited the development of gastric ulcers induced by alcohol, aspirin, indomethacin and Shay's pyloric ligation. Antisecretory studies in pyloric ligated rats revealed that the drug at a dose of 100 mg/kg significantly reduced total acidity, gastric output and protein content. In another set of experiments, dothiepin significantly reduced gastric output, total acidity and protein content in pyloric ligated rats which received 50% alcohol (v/v) 30 minutes after the administration of dothiepin.

Longitudinal study of the influence of life events and personality status on diagnostic change in three neurotic disorders.

It has been known for many years that diagnosis within the neurotic spectrum of disorders is temporally unstable and also that life events can be major precipitants of change in symptoms. Reasons for this instability could include inherent inadequacy of current diagnostic practice, the influence of life events as an agent of diagnostic shift, and an innate course of disorder with features dependent on the stage at which disorder presents (e.g., development of panic to agoraphobia). These possibilities were examined in a prospective study that was initially a randomised controlled trial. Two hundred ten patients recruited from primary care psychiatric clinics with DSM-III diagnosed dysthymic, generalised anxiety, and panic disorders were randomly allocated to either drug treatment (mainly antidepressants), cognitive-behaviour therapy, or self-help therapy over a 2 year period, irrespective of original diagnosis. Life events were recorded by using a standard procedure over the period 6 months before starting treatment and at five occasions over 2 years; 181 (86%) of the patients had follow-up data and 76% maintained compliance with the original treatment allocated over the 2 years; and 155 of the 181 patients (86%) had at least one diagnostic change in this period. There was no difference in the number of diagnostic changes between the three original diagnostic groups, but dysthymic disorder changed more frequently to major depressive episode than did GAD or panic disorder (20; 11; 12) (%) and panic disorder changed more frequently to agoraphobia (with or without panic) than did dysthymia or GAD (18; 8; 6) (%). There was no relationship between loss events and depressive diagnoses or between addition events and anxiety diagnoses, but greater numbers of conflict events were associated with diagnostic change. More life events were associated with the flamboyant and dependent personality disorders, reinforcing other evidence that many life events are internally generated by personality characteristics and cannot be regarded as truly independent.

Compliance with antidepressant medication in the treatment of major depressive disorder in primary care: a randomized comparison of fluoxetine and a tricyclic antidepressant.

OBJECTIVE: Many claims have been made for superior compliance with selective serotonin reuptake inhibitors (SSRIs) compared with tricyclic antidepressants, but to date meta-analyses have not confirmed reduced dropouts in randomized controlled trials. The authors used a randomized study design to evaluate differential compliance with antidepressant medications in a primary care setting. METHOD: A total of 152 patients treated in 10 primary care practices in the United Kingdom were included in a randomized, open-label, parallel-group study of fluoxetine and dothiepin at therapeutic doses for 12 weeks. Compliance was assessed by using pill count, patient questionnaires, and the Medication Event Monitoring System. RESULTS: The level of compliance with fluoxetine was numerically higher than the level of compliance with dothiepin on all three primary outcome measures, although the differences were not significant. In a secondary analysis using data from the Medication Event Monitoring System, both a survival analysis for length of time without a gap in medicine taking and a derived compliance index showed a significant advantage to fluoxetine. Patients in the fluoxetine group reported superior response on the health transition scale of the 36-item Short-Form Health Survey Questionnaire and numerically greater improvement on the Hamilton Depression Rating Scale. In both treatment arms patients with a superior compliance index were more likely to have improved in Hamilton depression scale scores by the last study visit. CONCLUSIONS: This study supports recent meta-analyses of SSRIs versus tricyclic antidepressants in finding no significant differences in crude indices of compliance between fluoxetine and dothiepin, despite marked differences in side effect profile and dose regimen. However, both a survival analysis and a new measure that takes account of prolonged periods of noncompliance distinguished between the treatments and was associated with improvement in both groups.