Most currently available antidepressants target monoamine neurotransmitter function. However, a purely neurotransmitter-based explanation for antidepressant drug action is challenged by the delayed ...clinical onset of most agents and the need to explain how neurochemical changes reverse the many different symptoms of depression. Novel approaches to understanding of antidepressant drug action include a focus on early changes in emotional and social processing and the role of neural plasticity. In this Review, we discuss the ways in which these two different theories reflect different or complementary approaches, and how they might be integrated to offer novel solutions for people with depression. We consider the predictions made by these mechanistic approaches for the stratification and development of new therapeutics for depression, and the next steps that need to be made to facilitate this translation of science to the clinic.
Rationale
There is now compelling evidence for a link between enteric microbiota and brain function. The ingestion of probiotics modulates the processing of information that is strongly linked to ...anxiety and depression, and influences the neuroendocrine stress response. We have recently demonstrated that prebiotics (soluble fibres that augment the growth of indigenous microbiota) have significant neurobiological effects in rats, but their action in humans has not been reported.
Objectives
The present study explored the effects of two prebiotics on the secretion of the stress hormone, cortisol and emotional processing in healthy volunteers.
Methods
Forty-five healthy volunteers received one of two prebiotics (fructooligosaccharides, FOS, or Bimuno®-galactooligosaccharides, B-GOS) or a placebo (maltodextrin) daily for 3 weeks. The salivary cortisol awakening response was sampled before and after prebiotic/placebo administration. On the final day of treatment, participants completed a computerised task battery assessing the processing of emotionally salient information.
Results
The salivary cortisol awakening response was significantly lower after B-GOS intake compared with placebo. Participants also showed decreased attentional vigilance to negative versus positive information in a dot-probe task after B-GOS compared to placebo intake. No effects were found after the administration of FOS.
Conclusion
The suppression of the neuroendocrine stress response and the increase in the processing of positive versus negative attentional vigilance in subjects supplemented with B-GOS are consistent with previous findings of endocrine and anxiolytic effects of microbiota proliferation. Further studies are therefore needed to test the utility of B-GOS supplementation in the treatment of stress-related disorders.
Depression is a leading cause of disability worldwide and improving its treatment is a core research priority for future programmes. A change in the view of psychological and biological processes, ...from seeing them as separate to complementing one another, has introduced new perspectives on pathological mechanisms of depression and treatment mode of action. This review presents a theoretical model that incorporated this novel approach, the cognitive neuropsychological hypothesis of antidepressant action. This model proposes that antidepressant treatments decrease the negative bias in the processing of emotionally salient information early in the course of antidepressant treatment, which leads to the clinically significant mood improvement later in treatment. The paper discusses the role of negative affective biases in the development of depression and response to antidepressant treatments. It also discusses whether the model can be applied to other antidepressant interventions and its potential translational value, including treatment choice, prediction of response and drug development.
There is growing interest in the effects of antidepressant drug treatment on measures of emotional processing. Such actions may help us understand the role of monoamines in emotional dysfunction in ...depression and how antidepressant drug treatments work. Recent studies suggest that decreasing central serotonin function with tryptophan depletion can reinstate negative biases in recovered depressed patients, even at doses insufficient to induce changes in mood. Conversely, antidepressant drug administration increases the processing of positive emotional information in healthy volunteers and acutely depressed patients early in treatment. This increase in positive bias may provide a platform for subsequent cognitive restructuring and learning which contributes to the evolution of symptom change in depression. Functional neuroimaging studies suggest that these early antidepressant effects involve fronto-limbic and extra-striate circuitry suggestive of actions on both the initial appraisal and attentional processing of affective stimuli. This approach may therefore provide a framework for linking psychological and biological processes in emotional disorders and their treatment. Antidepressants may not directly modulate mood and anxiety but rather allow a different perspective for our ongoing evaluation of our self, the world and the future.
Background Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of ...motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans. Methods We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment. Results Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key “punishment” areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect. Conclusions Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment.
Background Abnormalities in the neural representation of rewarding and aversive stimuli have been well-described in patients with acute depression, and we previously found abnormal neural responses ...to rewarding and aversive sight and taste stimuli in recovered depressed patients. The aim of the present study was to determine whether similar abnormalities might be present in young people at increased familial risk of depression but with no personal history of mood disorder. Methods We therefore used functional magnetic resonance imaging to examine the neural responses to pleasant and aversive sights and tastes in 25 young people (16–21 years of age) with a biological parent with depression and 25 age- and gender-matched control subjects. Results We found that, relative to the control subjects, participants with a parental history of depression showed diminished responses in the orbitofrontal cortex to rewarding stimuli, whereas activations to aversive stimuli were increased in the lateral orbitofrontal cortex and insula. In anterior cingulate cortex the at-risk group showed blunted neural responses to both rewarding and aversive stimuli. Conclusions Our findings suggest that young people at increased familial risk of depression have altered neural representation of reward and punishment, particularly in cortical regions linked to the use of positive and negative feedback to guide adaptive behavior.
Antidepressants are licensed for use in depressive disorders, but non-response and poor adherence to treatment affect a considerable number of patients. Pre-clinical and clinical evidence suggest ...that statins can augment the effects of antidepressants. However, the acceptability and tolerability of combining statins with antidepressants are unclear, and their add-on efficacy has only been shown in small, short-term clinical trials. Observational data can provide complementary information about treatment effects on larger samples over longer follow-ups. In this study, we therefore assessed the real-world acceptability, tolerability, and efficacy of concomitant antidepressant and statin treatment in depression.
We conducted a population-based cohort study investigating QResearch primary care research database, which comprises the anonymised electronic healthcare records of 35 + million patients over 1574 English general practices. Patients aged 18-100 years, registered between January 1998 and August 2020, diagnosed with a new episode of depression, and commencing an antidepressant were included. Using a between-subject design, we identified two study groups: antidepressant + statin versus antidepressant-only prescriptions. Outcomes of interest included the following: antidepressant treatment discontinuations due to any cause (acceptability) and due to any adverse event (tolerability) and effects on depressive symptoms (efficacy) measured as response, remission, and change in depression score on the Patient Health Questionnaire-9. All outcomes were assessed at 2, 6, and 12 months using multivariable regression analyses, adjusted for relevant confounders, to calculate adjusted odds ratios (aORs) or mean differences (aMDs) with 99% confidence intervals (99% CIs).
Compared to antidepressant-only (N 626,335), antidepressant + statin (N 46,482) was associated with higher antidepressant treatment acceptability (aOR
0.88, 99% CI 0.85 to 0.91; aOR
0.81, 99% CI 0.79 to 0.84; aOR
0.78, 99% CI 0.75 to 0.81) and tolerability (aOR
0.92, 99% CI 0.87 to 0.98; aOR
0.94, 99% CI 0.89 to 0.99, though not long term aOR
1.02, 99% CI 0.97 to 1.06). Efficacy did not differ between groups (range aOR
1.00 and 1.02 for response and remission, range aOR
- 0.01 and - 0.02 for change in depression score).
On real-world data, there is a positive correlation between antidepressant treatment adherence and statin use, partly explained by fewer dropouts due to adverse events. The main limitation of our study is its observational design, which restricts the potential to make causal inferences.
The fact that selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in some patients supports the notion that serotonin plays a role in the mode of action of antidepressant ...drugs. However, neither the way in which serotonin may alleviate depressed mood nor the reason why several weeks needs to elapse before the full antidepressant effect of treatment is expressed is known. Here, we propose a neuropsychological theory of SSRI antidepressant action based on the ability of SSRIs to produce positive biases in the processing of emotional information. Both behavioural and neuroimaging studies show that SSRI administration produces positive biases in attention, appraisal and memory from the earliest stages of treatment, well before the time that clinical improvement in mood becomes apparent. We suggest that the delay in the clinical effect of SSRIs can be explained by the time needed for this positive bias in implicit emotional processing to become apparent at a subjective, conscious level. This process is likely to involve the re-learning of emotional associations in a new, more positive emotional environment. This suggests intriguing links between the effect of SSRIs to promote synaptic plasticity and neurogenesis, and their ability to remediate negative emotional biases in depressed patients.
PDF
