Olanzapine / fluoxetine combination for treatment resistant depression : efficacy and clinical utility

Antidepressant monotherapy is a first-line treatment for depression; however, not all sufferers will adequately respond to treatment. When treating a patient with treatment-resistant depression, the clinician needs to consider all factors which may contribute to an inadequate response to an antidepressant. These include accuracy of diagnosis and medication adherence, as well as the patient’s personality, lifestyle, life events and social circumstances. If it is determined that treatment resistance is due to failure of efficacy of antidepressant monotherapy, then an augmentation strategy using an atypical antipsychotic may be considered. Treatment using olanzapine/fluoxetine combination (OFC) is one of many options. Four randomized, acute-phase trials have suggested OFC is useful for reducing Montgomery–Åsberg Depression Rating Scale scores after inadequate response to antidepressant monotherapy. OFC has been useful at doses of olanzapine/fluoxetine 6/25, 6/50, 12/25 and 12/50 mg/day, with 1/5 mg/day suggested to be an ineffective dose. Treatment with OFC has been associated with some side effects, including weight gain and the metabolic syndrome, somnolence, dry mouth, increased appetite and headache. Treatment decisions therefore need to be made to balance the risks and benefits.

Metyrapone and fluoxetine suppress enduring behavioral but not cardiac effects of subchronic stress in rats

In humans, chronic stressors have long been recognized as potential causes for cardiac dysregulation. Despite this, the underlying mechanistic links responsible for this association are still poorly understood. The purpose of this study was to determine whether exposure to a paradigm of subchronic stress can provoke enduring changes on the heart rate of experimental rats and, if so, to reveal the autonomic and neural mechanisms that mediate these effects. The study was conducted on adult male Sprague-Dawley rats instrumented for telemetric recording of heart rate and locomotor activity. Animals were submitted to a subchronic stress protocol, consisting of a 1-h foot shock session on five consecutive days. Heart rate and locomotor activity were recorded continuously for 3 days before and for 6 days after the subchronic stress period. Subchronic foot shock produced significant and enduring reduction in heart rate both during the dark/active [Δ= −23 ± 3 beats per minute (bpm)] and light/inactive (Δ= −20 ± 3 bpm) phases of the circadian cycle, and a reduction in locomotor activity during the dark/active phase [Δ= −54 ± 6 counts per hour (cph)]. The bradycardic effect of subchronic stress was not related to a reduced locomotion. Selective sympathetic (atenolol) and vagal (methyl-scopolamine) blockades were performed to reveal which autonomic component was responsible for this effect. We found that the fall in heart rate persisted after subchronic stress in animals treated with atenolol (active phase Δ= −16 ± 3 bpm, inactive phase Δ= −19 ± 2 bpm), whereas vagal blockade with scopolamine transiently prevented this effect, suggesting that the bradycardia following subchronic stress was predominantly vagally mediated. Fluoxetine (selective serotonin reuptake inhibitor) and metyrapone (inhibitor of corticosterone synthesis) treatments did not affect heart rate changes but prevented the reduction in locomotion. We conclude that subchronic stress exposure in rats reduces heart rate via a rebound in vagal activation and that this effect is serotonin- and corticosterone-independent.

The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): study protocol for a randomised control trial.

The aim of the Youth Depression Alleviation-Combined Treatment (YoDA-C) study is to determine whether antidepressant medication should be started as a first-line treatment for youth depression delivered concurrently with psychotherapy. Doubts about the use of medication have been raised by meta-analyses in which the efficacy and safety of antidepressants in young people have been questioned, and subsequent treatment guidelines for youth depression have provided only qualified support.

A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes.

Evidence of the antidepressant efficacy of lamotrigine is increasing, although there are no placebo-controlled trials of lamotrigine augmentation in depression. The aim of this study was to assess if augmentation with lamotrigine was superior to placebo in patients who were receiving fluoxetine for resistant major depressive episodes.

Fluoxetine and hemostatic function: a pilot study.

Isolated case reports have appeared implicating fluoxetine as a cause of impaired hemostatic function. The authors attempted to investigate this phenomenon.

Fluoxetine treatment of acral lick dermatitis in dogs: a placebo-controlled randomized double blind trial.

The aim of the study was to assess the efficacy and tolerability of fluoxetine treatment of acral lick dermatitis (ALD) in dogs and to investigate ALD as an animal model of obsessive-compulsive disorder (OCD). Sixty-three dogs with ALD were treated with fluoxetine 20 mg daily, or placebo, for 6 weeks. In the fluoxetine group, owners rated both appearance of the lesion (t = 10.2, df = 29, P < 0.0001) and licking behavior (t = 10.2, df = 29, P < 0.0001) as significantly improved by the end of the trial. Veterinarian-rated pre- and post-treatment photographs showed statistically significant improvement in the fluoxetine group (mean = 2.55). There were no significant changes in the placebo group as rated by owners and veterinarians. These results demonstrate the efficacy of fluoxetine in the treatment of ALD and lend further support to ALD as an animal model of OCD.

Fluoxetine for maintenance of remission and to improve quality of life in patients with Crohn's disease: a pilot randomized placebo-controlled trial.

BACKGROUND AND AIMS: Previous studies have shown that antidepressants reduce inflammation in animal models of colitis. The present trial aimed to examine whether fluoxetine added to standard therapy for Crohn's disease [CD] maintained remission, improved quality of life [QoL] and/or mental health in people with CD as compared to placebo. METHODS: A parallel randomized double-blind placebo controlled trial was conducted. Participants with clinically established CD, with quiescent or only mild disease, were randomly assigned to receive either fluoxetine 20 mg daily or placebo, and followed for 12 months. Participants provided blood and stool samples and completed mental health and QoL questionnaires. Immune functions were assessed by stimulated cytokine secretion [CD3/CD28 stimulation] and flow cytometry for cell type. Linear mixed-effects models were used to compare groups. RESULTS: Of the 26 participants, 14 were randomized to receive fluoxetine and 12 to placebo. Overall, 14 [54%] participants were male. The mean age was 37.4 [SD=13.2] years. Fluoxetine had no effect on inflammatory bowel disease activity measured using either the Crohn's Disease Activity Index [F(3, 27.5)=0.064, p=0.978] or faecal calprotectin [F(3, 32.5)=1.08, p=0.371], but did have modest effects on immune function. There was no effect of fluoxetine on physical, psychological, social or environmental QoL, anxiety or depressive symptoms as compared to placebo [all p>0.05]. CONCLUSIONS: In this small pilot clinical trial, fluoxetine was not superior to placebo in maintaining remission or improving QoL. [ID: ACTRN12612001067864.].

Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction

Background: Contact hypersensitivity (CS) reaction in the skin is T-cell mediated immune reaction which plays a major role in the pathogenesis and chronicity of various inflammatory skin disorders and, like other delayed-type hypersensitivity (DTH) reactions, affords immunity against tumor cells and microbes. CS response is a self-limiting reaction, and interleukin (IL)-10 is considered to be a natural suppressant of cutaneous inflammatory response. Recently, it has been demonstrated that major depression is related to activation of the inflammatory response and elevation of some parameters of cell-mediated immunity. It has been suggested that such activation of the immune system may play a role in etiology of depression. If this immunoactivation is involved in etiology of depression, one would expect that antidepressant agents may have negative immunoregulatory effects. To the best of our knowledge, the effect of antidepressants on contact hypersensitivity has not been studied.

Methods: The aim of the present study was to establish the effect of prolonged desipramine or fluoxetine treatment on CS reaction to picryl chloride.

Results: Antidepressants significantly suppressed CS reaction, fluoxetine by 53% whereas desipramine by 47% compared to positive control. Moreover, desipramine and fluoxetine decreased relative weight of auxillary lymph nodes. Desipramine decreased also relative weight of inguinal lymph nodes and spleens whereas desipramine and fluoxetine increased production of IL-10 in comparison to positive control.

Conclusion: The observed effect of antidepressant drugs on CS reaction is consistent with the hypothesis that T-cell mediated immunity is targeted by antidepressants.

Duloxetine: a review.

A developing concept is that antidepressant strategies which combine multiple mechanisms of action may have advantages over agents with single mechanisms. Duloxetine is a novel potent dual reuptake inhibitor of noradrenaline and serotonin. The antidepressant efficacy of duloxetine is reviewed in three trials. Results that emerge confirm the acute efficacy of the agent in major depressive disorder. In particular, remission rates in the comparative trials are higher with duloxetine than with either paroxetine or fluoxetine. Duloxetine appears to have specific efficacy in patients with somatic symptoms and there is some clinical evidence of analgesic properties. Modest weight loss was consistently described in the three acute trials and modest weight gain was seen in an open label follow-up study. Duloxetine was well-tolerated in all three trials with similar patterns of adverse events. No significant safety issues emerged from these trials.