Literature week 7
The cognitive neuropsychological model of antidepressant response – Annabel EL Walsh
and Catherine J Harmer
http://proxy-ub.rug.nl/login?url=https://www.sciencedirect.com/science/article/pii/S2352250X14000402
It has been hypothesised that, at a neuropsychological level, the direct action of antidepressants is to
remediate negative biases in affective processing and that these actions occur early in treatment
prior to an improvement in mood. Here we discuss the latest evidence for the cognitive
neuropsychological model of antidepressant response as well as the clinical applications and
limitations of the model. The majority of research has been conducted using antidepressants
predominantly affecting serotonin or noradrenaline activity. Future research must focus on
replicating these effects in larger samples with antidepressants influencing different
neurotransmitter systems, such as dopamine and glutamate.
1. Introduction
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and is associated
with substantial disability. Among outpatients starting first-line antidepressant treatment for MDD,
approximately only half will respond and only one third will achieve remission. Therefore, the
development of more broadly effective or patient-specific treatment strategies should be a priority.
The acute neuropharmacological actions of antidepressants are now well characterised, with the
majority acting to enhance either serotonin (5-HT) and/or noradrenaline (NA) neurotransmission.
This review summarises recent evidence for the cognitive neuropsychological model of
antidepressant response, which, through the integration of the neuropharmacology and cognitive
psychology of MDD, could provide the missing link between the acute neuropharmacological actions
of antidepressants and mood improvement.
2. The cognitive neuropsychological model of antidepressant response
It has been hypothesised that, at a neuropsychological level, the direct action of antidepressants is to
remediate negative biases in affective processing, that is, the tendency to extract negative rather
than positive affective information from a variety of social and affectively valenced stimuli, and that
these actions occur early in treatment prior to an improvement in mood. The importance of such
negative affective biases in the aetiology and maintenance of MDD has long been known and they
are believed to critically fuel the low mood and negative views about oneself, the world and the
future observed in MDD.
2.1. The role of negative affective biases in depression
Numerous studies have shown that both MDD patients and those at high risk for MDD reliably
display negative biases in both emotional and reward processing across a range of cognitive domains.
MDD patients tend to perceive ambiguous information as negative, preferentially attend to negative
affective information and better recall negative information.
, Such negative affective biases in MDD have been shown to be associated with aberrant activity in
limbic and striatal circuitry involved in the initial appraisal and memory of affective stimuli. MDD
patients have also been shown to display aberrant responses to reward, punishment and
performance feedback. For example, MDD patients display blunted responsiveness to both
anticipated reward and actual reward outcomes but respond catastrophically to negative
performance feedback. This results in a failure to adjust performance following positive or negative
feedback in order to maximise reward or minimise the risk of further error, respectively, as measured
by trial-bytrial adjustment of reaction time (RT).
Negative affective biases have been found to be associated with relapse and exhibited by individuals
at high risk of MDD by virtue of high neuroticism and family or personal history of MDD. Low reward
sensitivity has also been found to predict the subsequent development of MDD symptoms one year
after testing. Therefore, negative affective biases appear to play a role in the vulnerability to and
aetiology of MDD rather than simply being a secondary consequence of low mood.
2.2. The effects of antidepressants on affective processing
Subchronic (7 day) antidepressant treatment has been found to increase processing of positive
affective information in healthy volunteers. Even a single administration of citalopram] or reboxetine
has been found to be sufficient to increase the recognition of happy facial expressions. A single
administration of reboxetine has also been shown to restore the normal balance of positive to
negative processing in facial expression recognition and the recall of self-descriptive words in MDD
patients in the absence of any changes in subjective mood.
It appears that whilst SNRIs can enhance reward processing, SSRIs actually diminish neural processing
of both aversive and rewarding stimuli resulting in a general dampening of all negative and positive
affective experiences, similar to the effect of dopamine receptor antagonists.
2.3. Can the model explain the delayed onset of clinical effect and symptomatic relief?
It appears that acute antidepressant treatment can indeed produce early changes in affective
processing prior to a subjective improvement in mood. It is argued that such changes are not
consciously accessible and require interaction with the social environment prior to the improvement
in mood, hence a subjective delay in response to antidepressants. A positive correlation exists
between negative affective bias and impairments in mood recovery following a negative mood
induction. Furthermore, the magnitude of the initial effect of citalopram on negative emotional
memory biases predicts later resilience to negative mood induction. Such a process might involve re-
learning a range of emotional associations, which fits well with the observation that antidepressants
also promote synaptic plasticity, hippocampal neurogenesis and learning in animal models.
The requirement for changes in negative affective biases and interaction with the social environment
may help to explain some of the variance in clinical response to antidepressant treatment. Treatment
resistant MDD patients may have highly entrenched, long-standing negative affective biases that are
resistant to change or highly adverse social environments that cannot support an improvement in
mood even with remediation of the negative affective biases.
A reduction in the preoccupation with negative information would certainly improve mood, reduce
social withdrawal and increase the availability of information processing resources for other cognitive
tasks, such as episodic memory that is often impaired in MDD.
The cognitive neuropsychological model of antidepressant response – Annabel EL Walsh
and Catherine J Harmer
http://proxy-ub.rug.nl/login?url=https://www.sciencedirect.com/science/article/pii/S2352250X14000402
It has been hypothesised that, at a neuropsychological level, the direct action of antidepressants is to
remediate negative biases in affective processing and that these actions occur early in treatment
prior to an improvement in mood. Here we discuss the latest evidence for the cognitive
neuropsychological model of antidepressant response as well as the clinical applications and
limitations of the model. The majority of research has been conducted using antidepressants
predominantly affecting serotonin or noradrenaline activity. Future research must focus on
replicating these effects in larger samples with antidepressants influencing different
neurotransmitter systems, such as dopamine and glutamate.
1. Introduction
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and is associated
with substantial disability. Among outpatients starting first-line antidepressant treatment for MDD,
approximately only half will respond and only one third will achieve remission. Therefore, the
development of more broadly effective or patient-specific treatment strategies should be a priority.
The acute neuropharmacological actions of antidepressants are now well characterised, with the
majority acting to enhance either serotonin (5-HT) and/or noradrenaline (NA) neurotransmission.
This review summarises recent evidence for the cognitive neuropsychological model of
antidepressant response, which, through the integration of the neuropharmacology and cognitive
psychology of MDD, could provide the missing link between the acute neuropharmacological actions
of antidepressants and mood improvement.
2. The cognitive neuropsychological model of antidepressant response
It has been hypothesised that, at a neuropsychological level, the direct action of antidepressants is to
remediate negative biases in affective processing, that is, the tendency to extract negative rather
than positive affective information from a variety of social and affectively valenced stimuli, and that
these actions occur early in treatment prior to an improvement in mood. The importance of such
negative affective biases in the aetiology and maintenance of MDD has long been known and they
are believed to critically fuel the low mood and negative views about oneself, the world and the
future observed in MDD.
2.1. The role of negative affective biases in depression
Numerous studies have shown that both MDD patients and those at high risk for MDD reliably
display negative biases in both emotional and reward processing across a range of cognitive domains.
MDD patients tend to perceive ambiguous information as negative, preferentially attend to negative
affective information and better recall negative information.
, Such negative affective biases in MDD have been shown to be associated with aberrant activity in
limbic and striatal circuitry involved in the initial appraisal and memory of affective stimuli. MDD
patients have also been shown to display aberrant responses to reward, punishment and
performance feedback. For example, MDD patients display blunted responsiveness to both
anticipated reward and actual reward outcomes but respond catastrophically to negative
performance feedback. This results in a failure to adjust performance following positive or negative
feedback in order to maximise reward or minimise the risk of further error, respectively, as measured
by trial-bytrial adjustment of reaction time (RT).
Negative affective biases have been found to be associated with relapse and exhibited by individuals
at high risk of MDD by virtue of high neuroticism and family or personal history of MDD. Low reward
sensitivity has also been found to predict the subsequent development of MDD symptoms one year
after testing. Therefore, negative affective biases appear to play a role in the vulnerability to and
aetiology of MDD rather than simply being a secondary consequence of low mood.
2.2. The effects of antidepressants on affective processing
Subchronic (7 day) antidepressant treatment has been found to increase processing of positive
affective information in healthy volunteers. Even a single administration of citalopram] or reboxetine
has been found to be sufficient to increase the recognition of happy facial expressions. A single
administration of reboxetine has also been shown to restore the normal balance of positive to
negative processing in facial expression recognition and the recall of self-descriptive words in MDD
patients in the absence of any changes in subjective mood.
It appears that whilst SNRIs can enhance reward processing, SSRIs actually diminish neural processing
of both aversive and rewarding stimuli resulting in a general dampening of all negative and positive
affective experiences, similar to the effect of dopamine receptor antagonists.
2.3. Can the model explain the delayed onset of clinical effect and symptomatic relief?
It appears that acute antidepressant treatment can indeed produce early changes in affective
processing prior to a subjective improvement in mood. It is argued that such changes are not
consciously accessible and require interaction with the social environment prior to the improvement
in mood, hence a subjective delay in response to antidepressants. A positive correlation exists
between negative affective bias and impairments in mood recovery following a negative mood
induction. Furthermore, the magnitude of the initial effect of citalopram on negative emotional
memory biases predicts later resilience to negative mood induction. Such a process might involve re-
learning a range of emotional associations, which fits well with the observation that antidepressants
also promote synaptic plasticity, hippocampal neurogenesis and learning in animal models.
The requirement for changes in negative affective biases and interaction with the social environment
may help to explain some of the variance in clinical response to antidepressant treatment. Treatment
resistant MDD patients may have highly entrenched, long-standing negative affective biases that are
resistant to change or highly adverse social environments that cannot support an improvement in
mood even with remediation of the negative affective biases.
A reduction in the preoccupation with negative information would certainly improve mood, reduce
social withdrawal and increase the availability of information processing resources for other cognitive
tasks, such as episodic memory that is often impaired in MDD.
