‘It's the way that you look at it’—a cognitive neuropsychological account of SSRI action in depression

Abstract

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.

Increased neural response to social rejection in major depression

“…Previous studies have shown MDD patients to exhibit hyperactivation in the amygdala to negative emotional and threatening stimuli (Harmer & Cowen, 2013). Being socially ostracized leads to significant discomfort, and individuals fear exclusion and rejection.…”

A non-reward attractor theory of depression

“…It is well established that not receiving expected reward, or receiving unpleasant stimuli or events, can produce depression (Beck, 2008;Drevets, 2007;Eshel and Roiser, 2010;Harmer and Cowen, 2013;Price and Drevets, 2012;Pryce et al, 2011). More formally, in terms of learning theory, the omission or termination of a reward can give rise to sadness or depression, depending on the magnitude of the reward that is lost, if there is no action that can be taken to restore the reward (Rolls, 2013b(Rolls, , 2014a.…”

Reward Processing in Motivational and Affective Disorders

“…However, the precise mechanism by which this occurs is critical to treatment strategies: while either impairment might lead to similar behavioral deficits, exactly which impairment a patient has carries implications for their treatment. At present, serotonin-targeting treatments are the first-line antidepressant method, but do not seem to alleviate depressive symptoms in many patients (Harmer and Cowen, 2013). After failed SSRI treatment, dopamine-targeting treatments can be attempted (Rush et al, 2006;Trivedi et al, 2006).…”

“…It is true that we already have elegant emotional/cognitive accounts of depression (Harmer and Cowen, 2013), and there are many putative biological explanations of disruption and restoration at cellular (Castrén and Rantamäki, 2010) and molecular (Berman et al) levels. However, pharmacological level explanations often lose sight of the multidimensional nature of the depressive phenotype; and emotional or high-level explanations are difficult to relate directly back to the neurobiology.…”