Effect of Sertraline, Dosulepin, and Venlafaxine on Non-BDNF Neurotrophins in Patients With Depression: A Cohort Study.

BACKGROUND: The neurotrophic hypothesis of depression has been mostly studied with a focus on brain-derived neurotrophic factor (BDNF) leading to lack of data on non-BDNF neurotrophins (NTs). The aim of this study was to evaluate the effect of antidepressant drugs on changes in serum nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). METHODS: A prospective cohort study was conducted on 105 patients with depression who were subgrouped to the group 1 (mild and moderate depression without somatic syndrome treated with sertraline), group 2 (mild and moderate depression with somatic syndrome treated with dosulepin), and group 3 (severe depression without psychotic symptoms treated with venlafaxine). At baseline, the severity of depression (Montgomery-Asberg Depression Rating Scale [MADRS]), serum NGF, NT-3, and NT-4 were estimated. Thirty-five healthy volunteers were recruited as controls for a baseline comparison of NTs. All patients were followed up after 6 weeks to evaluate the changes in NT levels and correlate it with the change in MADRS scores. RESULTS: At baseline, NT levels were significantly lower in patients with depression in comparison with healthy control. In group 1, serum NGF, NT-3, and NT-4 level were found to increase significantly after treatment, whereas changes in groups 2 and 3 were statistically not significant. Montgomery-Asberg Depression Rating Scale score and serum NGF at baseline had an inverse relation (r = -0.648), whereas the change in MADRS score in sertraline group had a positive correlation (r = 0.86) with the change of serum NGF. CONCLUSIONS: Monotherapy with sertraline increased the level of non-BDNF NTs; however, treatment with dosulepin and venlafaxine did not produce any significant changes in patients with depression.

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.

Evaluation of efficacy and tolerability of dothiepin hydrochloride in the management of major depression in patients suffering from rheumatoid arthritis.

Several studies have shown that 20 to 66.2% of patients with rheumatoid arthritis have associated psychiatric comorbidity especially depression. Dothiepin hydrochloride is a well-established and effective antidepressant in patients with depressive symptoms of varying severity and co-existing anxiety. To document the efficacy and tolerability of dothiepin hydrochloride in the management of major depressive disorder (MDD) in rheumatoid arthritis patients a phase IV, open, single arm, prospective study was initiated with dothiepin hydrochloride in the dose of 75 mg/day, duration of therapy was 6 weeks. Twenty-five rheumatoid arthritis patients suffering from co-morbid MDD completed the 6-week dothiepin hydrochoride treatment and were considered for final analysis. There was significant reduction (p < 0.05) in mean HAM-D scores at week 2 (13.92 +/- 5.45), week 4 (9.28 +/- 4.13) and week 6 (5.72 +/- 3.26) compared to baseline (21.64 +/- 5.93). There was significant reduction (p < 0.05) in mean HAM-A scores at week 2 (6.52 +/- 3.34), week 4 (4.0 +/- 2.25) and week 6 (2.76 +/- 1.59) compared to baseline (10.68 +/- 3.68). The global impression of efficacy at the end of 6 weeks of dothiepin hydrochloride treatment was rated by the clinician (psychiatrist) as marked and moderate improvement in 20 (80%) and 5 patients (20%) respectively. Only 2 patients reported dry mouth as an adverse event in the study. The overall assessment of tolerability at the end of 6 weeks of dothiepin hydrochloride treatment was rated by the clinician (psychiatrist) as good and fair in 19 (76%) and 6 patients (24%) respectively. Dothiepin hydrochloride was found to be an effective and well-tolerated drug in the management of MDD and anxiety in patients suffering from rheumatoid arthritis.

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.

Misdiagnosis of antidepressant discontinuation symptoms.

OBJECTIVE: To demonstrate that when antidepressants are switched, discontinuation symptoms from the first antidepressant may be misdiagnosed as adverse effects of the second antidepressant. METHOD: Single case report. RESULTS: A female patient was switched from paroxetine to dothiepin due to lack of efficacy. Over the next week she developed physical symptoms which she and her doctor regarded as side effects of dothiepin. It was decided to change the dothiepin and a second opinion was obtained regarding a suitable alternative. At that point it was realized that her symptoms represented a paroxetine discontinuation syndrome. The patient was reassured and continued dothiepin. The discontinuation symptoms resolved over the next 3 weeks and her depression subsequently remitted. CONCLUSION: Increased professional awareness of discontinuation symptoms is necessary to prevent misdiagnosis and inappropriate treatment.

The effects of dothiepin on subjects with rheumatoid arthritis and depression.

BACKGROUND: The relative importance of direct analgesic and antidepressant effects of antidepressant drugs in rheumatoid arthritis (RA) is not clear. METHOD: Forty-eight female out-patients with RA, with depression and/or anxiety, were entered into a double-blind, placebo-controlled study of dothiepin in doses up to 150 mg daily to assess the effects on mood [Hospital Anxiety and Depression (HAD) scale and Hamilton Rating Scale (HRS) for Depression], pain [visual analogue scale (VAS)] and disability [Health Assessment Questionnaire (HAQ)]. RESULTS: Repeated measures multivariate analysis of variance revealed that treatment had a significant effect on pain (F(d.f. 1,39) =5.7, P=0.02). There were further interaction effects between treatment and time on pain (F(d. f. 3,117) =3.3, P=0.03), disability (F(d.f. 3,117)=4.2, P=0.008) and duration of early morning stiffness (F(d.f. 3,117) =3.3, P=0.03). Depression (HRS) was considerably reduced in both the dothiepin and placebo groups, and there was no significant difference between groups. Post hoc analyses using analysis of covariance revealed that, in the dothiepin group, pain was significantly reduced by week 4 and remained so at week 12. Disability scores and duration of early morning stiffness were consistently lower in the dothiepin group, although differences failed to reach statistical significance at any follow-up assessment. In the group as a whole, reductions in pain were highly significantly correlated with reductions in HAD depression (r =0.63, P<0.0005), HAD anxiety (r=0.46, P=0.001) and HRS depression (r=0.37, P=0.01). CONCLUSION: Dothiepin is effective in relieving pain, disability and reducing the duration of early morning stiffness in out-patients with RA. Although there is a general association between pain reduction and improved anxiety and depression, the analgesic effect of dothiepin is independent of its antidepressant effect. Individual variation is considerable and further research should try to identify mechanisms of interaction between the antidepressant and analgesic effects of treatment in different patient groups.

Nightmares and hallucinations after long-term intake of tramadol combined with antidepressants.

Tramadol is a weak opioid with effects on adrenergic and serotonergic neurotransmission that is used to treat cancer pain and chronic non malignant pain. This drug was initiated in association with paroxetine and dosulepine hydrochloride in a tetraparetic patient with chronic pain. Fifty-six days after initiation of the treatment the patient presented hallucinations that only stopped after the withdrawal of psycho-active drugs and tramadol. The case report questions the long term use of pain killers combined with psycho-active drugs in chronic non malignant pain, especially if pain is under control.

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.

Dothiepin versus doxepin in major depression: results of a multicenter, placebo-controlled trial. Prothiaden Collaborative Study Group.

BACKGROUND: The tricyclic antidepressant dothiepin is well established in Europe, but clinical experience with the drug in the United States is limited. METHOD: In a 10-week, multicenter, randomized, double-blind, placebo-controlled study in the United States, the efficacy and tolerability of dothiepin and doxepin (both administered as a 150-mg nightly dose) were compared in 579 outpatients with major depression. RESULTS: Patients in both active treatment groups showed significant improvements in depressive symptoms, associated anxiety, and sleep parameters compared with the placebo-treated group. The adverse effect profile of dothiepin was superior to that of doxepin, particularly with respect to drowsiness, weight gain, and increased appetite. CONCLUSION: These results confirm that dothiepin is useful when a tricyclic agent is indicated for the treatment of depression.

Management of depression in real-life settings: knowledge gained from large-scale clinical trials.

This paper reports the results of two studies of depressed patients, evaluating the efficacy and toleration of the selective serotonin reuptake inhibitor (SSRI) sertraline in a general practice setting in the UK. In the first of these studies, 308 patients, with a DSM-III-R diagnosis of major depressive episode, were treated for 6 weeks with either sertraline 50-100 mg/day or the tricyclic antidepressant dothiepin 75-150 mg/day, or placebo. Seventy-six per cent of sertraline-treated patients were maintained on the lower dose (50 mg/day), whereas 81% of dothiepin-treated patients required the higher dose (150 mg/day). Sertraline-treated patients demonstrated a significant improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) severity scores compared with placebo-treated patients, while dothiepin-treated patients did not show significant improvement compared with placebo. The active drugs were well tolerated, and there were no significant differences in adverse events between the groups. The second study, "Sertraline in General Practice, A Multicenter Assessment", or SIGMA, was a large, multicentre trial with a cohort of 3396 patients recruited to receive 6 weeks of treatment. Patients started on sertraline 50 mg/day, and for 59% of patients this was the final dose; less than 10% of patients reached final doses of more than 100 mg/day. A 50% or greater reduction in MADRS scores was seen in 69% of patients across a wide range of severity of symptoms at baseline, and 87% of patients demonstrated excellent or good toleration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term outcome of facial pain treatment.

The long-term outcome of facial pain treatment is largely unknown. This study reports the results of a 4-yr review which indicated that conservative treatments including drug therapy and counselling are effective for 70% of patients. Refractory pain was associated with a long complex history of pain, a preoccupation with physical symptoms and poor psychosocial adjustment.

How long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin. Old Age Depression Interest Group.

Of 219 elderly patients with a major depressive disorder (meeting RDC), 69 recovered sufficiently and consented to enter a two-year double-blind placebo-controlled trial of dothiepin. Survival analysis revealed that dothiepin reduced the relative risk of relapse by two and a half times. Past but not current serious physical illness was also associated with a favourable outcome, whereas a prolonged index depressive illness trebled the relative risk of relapse. In the light of previous research on prognosis it is suggested that elderly persons who recover from a major depressive illness should continue with antidepressant medication for at least two years, if not indefinitely.

The role of the practice nurse in the management of depression in general practice: treatment adherence to antidepressant medication.

This pilot study demonstrated the feasibility of providing practice nurse support as an adjunct to standard general practitioner treatment to patients with depressive disorders prescribed antidepressant medication. With respect to the measures used and pilot study objectives identified, there were no statistically significant differences between the study groups in treatment adherence to the prescription of antidepressant medication or in the incidence and severity of adverse events to medication. Large-scale randomized controlled trials are in progress to assess the effectiveness of practice nurse interventions in the management of depressive illness in general practice.

Dexamethasone suppression test and response to antidepressants in depressed mentally handicapped subjects.

Nineteen mentally handicapped subjects who were referred to the service with clinically significant depression were assessed with a view to determining the value of the dexamethasone suppression test (DST) in clinical diagnosis and in predicting response to antidepressant treatment. They were assessed initially and then 3 months after they had been treated with a tricyclic antidepressant. It was found that a significant proportion had an abnormal DST response which reversed after recovery in some but not in others. Non-reversal was more likely to occur in the more severely handicapped patients. It was concluded that DST was of little value as a diagnostic tool for the detection of depression in mentally handicapped subjects.

Effect of dothiepin on nociceptive response in diabetic rats.

In alloxan-diabetic rats of 4 wk duration with blood glucose levels of about 300 mg/100 ml, the tail flick reaction time (TFRT) to thermal stimuli was significantly elevated (P less than 0.25), indicating hypoalgesia. Intraperitoneal dothiepin, injections of 25 mg & 50 mg/kg body weight per day did not significantly alter the TFRT, either in control or in diabetic rats, following either acute (one dose), or short term (once a day for five days) administration. It is concluded that at least in the dosage schedule used herein, dothiepin does not influence hypoalgesia of diabetic neuropathy.

The general neurotic syndrome: a coaxial diagnosis of anxiety, depression and personality disorder.

The validity of the general neurotic syndrome, a combination of anxiety, depression and dependent personality disorder, was examined in a 2-year study of outpatients with dysthymic, panic and generalized anxiety disorder diagnosed using a structured interview schedule. The general neurotic syndrome, found in a third of the patients, was associated with greater mental disorder and a significantly worse outcome than patients without the syndrome. It did not, however, predict response to treatment. Further analysis revealed that the general neurotic syndrome was a better predictor of short- and long-term outcome than any other variable apart from initial psychopathology score. It is argued that the syndrome may represent a personality diathesis that makes the individual more vulnerable to both anxiety and depressive symptoms.

Cognitive behaviour therapy in chronic fatigue syndrome.

Fifty patients fulfilling operational criteria for the chronic fatigue syndrome (CFS), and who had been ill for a mean of five years, were offered cognitive behaviour therapy in an open trial. Those fulfilling operational criteria for depressive illness were also offered tricyclic antidepressants. The rationale was that a distinction be drawn between factors that precipitate the illness and those that perpetuate it. Among the latter are cognitive factors such as the belief that physical symptoms always imply tissue damage, and behavioural factors such as persistent avoidance of activities associated with an increase in symptoms. Therapy led to substantial improvements in overall disability, fatigue, somatic and psychiatric symptoms. The principal problems encountered were a high refusal rate and difficulties in treating affective disorders. Outcome depended more on the strength of the initial attribution of symptoms to exclusively physical causes, and was not influenced by length of illness. These results suggest that current views on both treatment and prognosis in CFS are unnecessarily pessimistic. It is also suggested that advice currently offered to chronic patients, to avoid physical and mental activity, is counterproductive.