No abstract

Based on our preclinical data showing a potential accelerating effect of acetylsalicylic acid (ASA) in combination with fluoxetine in an animal model of depression, we examined the effect of ASA augmentation therapy on selective reuptake inhibitors (SSRI) in major depressed non-responder patients. Twenty-four non-responder patients having received at least 4 weeks of an adequate SSRI treatment were included in a pilot open-label study. Participants were treated openly during 4 weeks with 160 mg/day ASA in addition to their current antidepressant treatment. The combination SSRI-ASA was associated with a response rate of 52.4%. Remission was achieved in 43% of the total sample and 82% of the responder sample. In the responder group, a significant improvement was observed within week 1 (mean Hamilton Depression Rating Scale-21 items at day 0=29.3+/-4.5, at day 7=14.0+/-4.1; P<0.0001) and remained sustained until day 28. Despite limitations due to the open nature of this study, our preliminary results confirm our preclinical findings and are in favour of an accelerating effect of ASA in combination with SSRIs in the treatment of major depression. Potential physiological and biochemical mechanisms may involve an anti-inflammatory and/or neurotrophic effect.

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic–pituitary–adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

Epidemiological studies clearly indicate that posttraumatic stress disorder (PTSD) is becoming a major health concern worldwide even if still poorly recognized and not well treated. PTSD commonly co-occurs with other psychiatric disorders, and several symptoms overlap with major depressive disorders, anxiety disorders and substance abuse; this may contribute to diagnostic confusion and underdiagnosis. This anxiety disorder provokes significant occupational, psychiatric, medical and psychosocial disability, and its consequences are enormously costly, not only to the survivors and their families, but also to the health care system and society. Work impairment associated with PTSD is very similar to the amount of work impairment associated with major depression. The pathophysiology of PTSD is multifactorial and involves dysregulation of the serotonergic as well as the noradrenergic system. A rational therapeutic approach should normalize the specific psychobiological alterations associated with PTSD. This can be achieved through the use of antidepressant drugs, mainly of those that potentiate serotonergic mechanisms. Recent double-blind placebo-controlled studies report the efficacy of selective serotonin reuptake inhibitors. Several cognitive-behavioral and psychosocial treatments have also been reported to be efficacious and could be considered when treating PTSD patients.