The discovery of imipramine created a ‘founder effect’ that still
influences antidepressant drug development. The key pharmaco-
logical action of imipramine is believed to be blockade of the
membrane transporters that terminate the actions of noradren-
aline and serotonin (5-hydroxytryptamine, 5-HT) released into
the synaptic cleft at central monoamine synapses. Many currently
used antidepressants have been designed to achieve these effects
more potently and selectively. However, blockade of transporters
can be detected immediately after drug administration, whereas
the therapeutic effect of antidepressant treatment requires a
number of weeks to become clinically important.1This apparent
discrepancy has stimulated an abundance of experimental work
over the past three decades that has focused on the neuro-
biological effects of repeated antidepressant treatment. Secondary
pharmacological effects whose time course requires repeated
administration are numerous, and seem natural candidates to
explain how antidepressants produce their therapeutic effects.
Such theories have emphasised the potential therapeutic
importance of downstream neuroadaptive changes for anti-
depressant drug action, including downregulation of subsets of
post-synaptic 5-HT and noradrenergic receptors as well as
desensitisation of autoreceptors located on 5-HT and noradren-
aline cell bodies.1More recently attention has shifted to anti-
consequent changes in gene expression. This is associated with
increased production of neurotropic factors resulting ultimately
in changes in synaptic plasticity and neurogenesis.2
downstream effects of established antidepressants are taken to
provide alternative molecular targets for potential new anti-
Although of great potential interest, purely neurochemical
theories of antidepressant action cannot explain how these
pharmacological mechanisms lead to the remission of clinical
symptoms in a depressed person. When it is discussed at all, it
ofsecond messengers and
is generally assumed that the primary psychological action of
antidepressants is to elevate mood and that improvement in the
various symptom domains is, broadly, a secondary consequence
of this effect. This view, however, appears incomplete because
antidepressant drugs do not reliably elevate mood in non-
depressed people and the psychostimulant drugs that can produce
such mood elevation do not appear to be clinically useful anti-
depressants.3Hence, the mechanisms by which the neurochemical
and neural changes induced by antidepressant drugs are translated
into clinically meaningful effects in depression are still broadly
unknown. This review summarises evidence for a cognitive
neuropsychological hypothesis of antidepressant drug action
which aims to integrate what we know about the neurochemistry
and psychology of depression and its treatment and provide an
alternative explanation for the therapeutic delay in antidepressant
Cognitive neuropsychological hypothesis
of antidepressant drug action
We propose the hypothesis that, at a neuropsychological level,
antidepressants work by remediating negative affective biases in
depression and anxiety and that these actions occur relatively
quickly following drug administration. Such changes in bias are
probably not accessible to subjective state, but the effects of
processing emotional and social stimuli in a more positive manner
would be expected to lead to gradual changes in social reinforce-
ment, behaviour and mood over time and experience of these
cues. As illustrated in Fig. 1, this view suggests that the critical
time lag in antidepressant drug action does not result from a delay
in relevant neuropharmacological actions, but is imposed between
the effects of antidepressants on emotional processing and the
subsequent effects on mood. In other words, changes in affective
Why do antidepressants take so long to work?
A cognitive neuropsychological model
of antidepressant drug action
Catherine J. Harmer, Guy M. Goodwin and Philip J. Cowen
The neuropharmacological actions of antidepressants are
well characterised but our understanding of how these
changes translate into improved mood are still emerging.
To investigate whether actions of antidepressant drugs on
emotional processing are a mediating factor in the effects of
these drugs in depression.
We examined key published findings that explored the
effects of antidepressants on behavioural and functional
magnetic resonance imaging (fMRI) measures of emotional
Negative emotional bias has been reliably associated with
depression. Converging results suggest that antidepressants
modulate emotional processing and increase positive
emotional processing much earlier than effects on mood.
These changes in emotional processing are associated with
neural modulation in limbic and prefrontal circuitry.
Antidepressants may work in a manner consistent with
cognitive theories of depression. Antidepressants do not act
as direct mood enhancers but rather change the relative
balance of positive to negative emotional processing,
providing a platform for subsequent cognitive and
Declaration of interest
G.M.G. and P.J.C. have been members of advisory boards of
pharmaceutical companies marketing antidepressants. C.J.H.
has acted as a paid consultant for Lundbeck and Merck
Sharp & Dohme and is on the advisory board of P1vital.
The British Journal of Psychiatry (2009)
195, 102–108. doi: 10.1192/bjp.bp.108.051193
Harmer et al
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