Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

The neurobiology of depression and antidepressant action

Paul Willner a,∗ , Jørgen Scheel-Krüger b , Catherine Belzung c
a
Department of Psychology, Swansea University, Singleton Park, Swansea SA2 8PP, UK
b
Center of Functionally Integrative Neuroscience, University of Aarhus, Denmark
c
INSERM 930 and University Francois-Rabelais, Tours, France

a r t i c l e i n f o a b s t r a c t

Article history: We present a comprehensive overview of the neurobiology of unipolar major depression and antide-
Received 24 April 2012 pressant drug action, integrating data from affective neuroscience, neuro- and psychopharmacology,
Received in revised form neuroendocrinology, neuroanatomy, and molecular biology. We suggest that the problem of depression
26 November 2012
comprises three sub-problems: first episodes in people with low vulnerability (‘simple’ depressions),
Accepted 10 December 2012
which are strongly stress-dependent; an increase in vulnerability and autonomy from stress that devel-
ops over episodes of depression (kindling); and factors that confer vulnerability to a first episode (a
Keywords:
depressive diathesis). We describe key processes in the onset of a ‘simple’ depression and show that
Unipolar major depression
Antidepressant drugs
kindling and depressive diatheses reproduce many of the neurobiological features of depression. We
Affective neuroscience also review the neurobiological mechanisms of antidepressant drug action, and show that resistance to
Hippocampus antidepressant treatment is associated with genetic and other factors that are largely similar to those
Amygdala implicated in vulnerability to depression. We discuss the implications of these conclusions for the under-
Ventromedial prefrontal cortex standing and treatment of depression, and make some strategic recommendations for future research.
Anterior cingulate cortex
Nucleus accumbens © 2012 Elsevier Ltd. All rights reserved.
Caudate nucleus
Habenula
Stress
Treatment resistance

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2332
2. Different mechanisms for depression and antidepressant action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2333
3. The psychobiology of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2334
3.1. The diathesis/stress model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2334
3.1.1. Diathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2334
3.1.2. Stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2335
3.1.3. Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2335
3.2. Effects of stress on the HPA axis and hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2335
3.2.1. Neurotoxic effects of stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2336
3.2.2. Morphological consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2337
3.3. Frontal brain circuitry underlying the symptoms of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2337
3.4. What drives the changes? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2338
3.4.1. Anhedonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2339
3.5. Mechanisms mediating affective information-processing biases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2339
3.5.1. Amygdala and nucleus accumbens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2339
3.5.2. The habenula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2340
3.6. Failure to cope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2340
3.6.1. Stimulus appraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2340
3.6.2. Learned helplessness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2341

∗ Corresponding author.
E-mail address: p.willner@swansea.ac.uk (P. Willner).

0149-7634/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.neubiorev.2012.12.007
2332 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371

3.7. Rumination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2341

3.7.1. Rumination and recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2342
3.8. Basal ganglia involvement in coping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2342
3.9. Summary: stress and depression in conditions of low vulnerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2343
3.10. Vulnerability to depression: 1. Kindling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2343
3.11. Vulnerability to depression: 2. Predisposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2344
3.11.1. Animal models of vulnerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2345
3.11.2. The vulnerability brain and the depressed brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2345
4. Mechanisms of antidepressant action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2345
4.1. Potentiation of monoamine transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2345
4.2. Post-transductional mechanisms of antidepressant action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2346
4.3. Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2348
4.3.1. The pathway from synapse to neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2348
4.3.2. Functional significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2349
4.4. HPA axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2349
4.5. Why are antidepressants slow to act? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2350
4.6. Treatment implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2350
4.7. Treatment resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2352
4.7.1. Pharmacokinetics, misdiagnosis and comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2352
4.7.2. Parallels with vulnerability to depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2353
4.8. Approaches to the treatment of resistant depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2354
4.8.1. New targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2355
5. Conclusions and research implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2356
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2358

1. Introduction an absolute or relative deficiency of monoamines at functionally

important receptor sites in the brain”, with the corollary that
Depression is the commonest psychiatric disorder. It is the most antidepressants work by correcting these deficiencies) has pro-
disabling medical condition, in terms of years lost to disability, and vided the major neurobiological account of depression. Indeed,
it is projected that by 2030 depression will be the foremost con- until recently, it was the only significant hypothesis, and while its
tributor to the worldwide burden of disease (WHO, 2008). In this predominance has been to some extent eclipsed by newer con-
review, we focus on unipolar major depressive disorder, which is cepts over the past decade, it remains the case that the monoamine
defined in DSM-IV (American Psychiatric Association, 1994), as a hypothesis has provided the only significant theoretical frame-
condition characterized by the presence of loss of pleasure or inter- work for antidepressant drug development, proving stubbornly
est in usually pleasurable activities (anhedonia), together with an resistant to the numerous and very expensive attempts by the phar-
array of other features, including anergia, changes in sleep and maceutical industry to break out of the monoamine straitjacket
appetite, sadness, and suicidal ideation. Presentations of unipo- with drugs that act through novel mechanisms. As summarized
lar major depressive disorder (which we shall refer to as simply in Fig. 1, newer antidepressants differ from the older drugs in
‘depression’) can be very variable, but this fact has not featured decreasing the incidence of unwanted side effects and/or narrow-
prominently in the literature that we shall review. ing the neurochemical target, rather than by introducing novel
Depression is characterized by a profoundly negative view of mechanisms of action. However, improvements in both antide-
the world, oneself and the future (Beck, 1967), and this nega- pressant response rates and the slow onset of clinical effect,
tive world-view has been related to negative biases in attention, requiring several weeks of chronic treatment to achieve the full
interpretation and memory (Mathews and MacLeod, 2005). Specif- effect, have been minimal. Tolerability has improved, but dif-
ically, studies of cognitive processing in depression have reported ferences in efficacy are small and difficult to demonstrate, and
increased elaboration of negative information, difficulties disen- there is little evidence that the newer antidepressants are more
gaging from negative material, and deficits in cognitive control efficacious than the older antidepressants. Indeed, one of the old-
when processing negative information, which inter alia explain est antidepressants, the tricyclic clomipramine, remains among
why depressed people experience a high level of negative auto- the most efficacious, alongside the serotonin-noradrenaline reup-
matic thoughts and pathological rumination (Gotlib and Joormann, take inhibitor (SNRI) venlafaxine, the selective serotonin reuptake
2010). Depressed people are particularly vulnerable to negative inhibitors (SSRIs) sertraline and escitalopram, and the atypical
psychological feedback, which has a disproportionately disruptive antidepressant mirtazepine (Montgomery et al., 2007; Cipriani
effect on subsequent performance (Elliott et al., 1996). In addition to et al., 2009). Antidepressants have consistently shown only moder-
an increased response to aversive events, depression is also char- ate response rates, with around 30–40% of patients being classified
acterized by a decreased response to anticipated (McFarland and as non-responders, and the latency of clinical onset remains stub-
Klein, 2008) or actual (Pizzagalli et al., 2008; Chase et al., 2010) bornly long (Trivedi et al., 2006; Holtzheimer and Mayberg, 2011).
rewards, and this provides a cognitive explanation of the core While antidepressant efficacy has been claimed for a number of
symptom of depression, anhedonia. These two complementary non-monoaminergic drugs that are marketed for other indications,
biases, increased negativity and decreased positivity, are central and the failure of some novel agents may to some extent involve
to much of the recent neurobiological literature on depression, increased regulatory requirements, the relative lack of progress
because they play directly into two of the major experimental over the past 50 years is remarkable (Blier, 2010; Baghai et al.,
methodologies, functional neuroimaging and animal models of 2011).
depression. In this paper we present a comprehensive overview of the neu-
Since its introduction almost 50 years ago, the monoamine robiology of unipolar major depression and antidepressant drug
hypothesis (“some, if not all, depressions are associated with action, integrating data from affective neuroscience, neuro- and
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371 2333

Fig. 1. Antidepressant drug development: new wine in old bottles. The figure summarizes the ways in which the five major newer classes of antidepressant drugs represent
refinements of the mechanisms introduced in the original drug classes, the tricyclic antidepressants and monoamine oxidase inhibitors.

psychopharmacology, neuroendocrinology, neuroanatomy, and
molecular biology, and from preclinical and clinical research. In so
doing, we develop a framework for understanding the neurobiology
of depression, which also provides a basis for understanding the
limited success of research in antidepressant drug development.
In Section 3, we first provide a detailed account of a ‘basic’ psy-
chobiology of depression, which centres on the effects of stress on
neurobiological and psychological functioning in individuals who
have a low predisposition to become depressed. We next consider
the mechanisms that underlie various vulnerabilities to depression,
and review evidence that these reflect changes in brain function
that resemble effects of stress, with the result that depression is
more easily precipitated and less stress-dependent. In Section 4,
we review recent research on the mechanisms of antidepressant
action which demonstrates that antidepressants essentially coun-
teract and repair the effects of stress. We also show that the factors
implicated in resistance to antidepressant treatment largely reca-
pitulate the factors involved in vulnerability to depression, and
argue that antidepressants are ineffective under these conditions
in the neural bases of depression and antidepressant action, and
the action of antidepressants cannot accurately be described as
reversing and normalizing the processes that are dysfunctional in
the depressed brain.
The clearest evidence that the brain of an antidepressant-treated
patient is not in a normal state comes from studies in which
antidepressant effects are blocked by acute drug treatments. An
example is shown in Fig. 2. In this study, after depressed patients
had been successfully treated with SSRIs, they were administered a
low dose of the dopamine (DA) D2 receptor blocker sulpiride. This
caused a profound return of depressed mood in the treated patients,
Depressed mood
6.0
5.0
VAS rating

because stress is of minor importance. In Section 5, we discuss the 4.0

implications of these conclusions for the understanding and treat-
ment of depression, and make some strategic recommendations for 3.0
future research. But first (Section 2), we explain why it is necessary
Con-Plac
to give separate consideration to the analyses of depression and 2.0
Con-Sul
antidepressant action.
Dep-Plac
1.0
Dep-Sul
2. Different mechanisms for depression and antidepressant
action 0.0
0 1 2 3 4 5 6 7
A feature of the monoamine hypothesis of depression that has Time (h)
gone largely unremarked is that it proposes a single mechanism for
both depression and antidepressant drugs: depression results from Fig. 2. A demonstration that the antidepressant-treated brain is not in a ‘normal’
state. Volunteers (Con) or depressed patients who had recovered following SSRI
a decreased functioning in NA and/or 5HT which antidepressants
treatment (Dep) were administered acutely either placebo (Plac) or a low dose of
increase back to normal. The same symmetry is seen in most of the the DA D2 receptor blocker sulpiride (Sul). Sulpiride caused a return of severely
more recent hypotheses that will be discussed below. However, the depressed mood in the patients but not in controls.
assumption of symmetry is incorrect. There are many differences Adapted from Willner et al. (2005).
2334 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
but if anything, slightly improved mood in a non-depressed non-
antidepressant-treated control group (Willner et al., 2005). Exactly
the same effect is seen in studies of serotonin (5HT) or noradren-
aline (NA) depletion. Consumption of a mixture of dietary amino
acids that omits tryptophan, the precursor of 5HT, leads rapidly to
a 70–80% decrease in plasma levels of tryptophan, and a consequent
decrease in brain 5HT levels; and the tyrosine hydroxylase inhibitor
alpha-methyl-para-tyrosine (AMPT) causes a selective depletion
of the catecholamines DA and NA. Tryptophan depletion causes a
severe reinstatement of symptoms in the majority of patients in
remission following successful treatment of depression with SSRIs
(Delgado et al., 1990, 1999). Similarly, AMPT precipitates a similar
relapse in depressed patients successfully treated with NA reuptake
inhibitors (NRIs) (Delgado et al., 1993; Miller et al., 1996). However,
neither of these manipulations has major effects on mood in people
who are not depressed or at high-risk for depression (Ruhé et al.,
2007).
Similar findings have been reported in animal studies. Both
5HT depletion and NA depletion block the action of SSRIs and
NRIs, respectively, in animal models of depression. However, as
in the clinical situation, while reversing the effects of antidepres-
sants, neither manipulation produces a depressive phenotype in
untreated animals (Lucki and O’Leary, 2004; Cryan et al., 2004;
Yalcin et al., 2008). Chronic mild stress (CMS) is a well-validated
animal model of depression, based on the loss of responsiveness
to rewards by animals subjected to a varying schedule of minor
stressor (Willner et al., 1987; Willner, 1997a). In a large scale
transcriptomic study in mice, CMS induced a molecular shift in cor-
ticolimbic brain areas that was only partly reversed by fluoxetine:
for example, fluoxetine failed to block over a quarter of the changes
in the amygdala and cingulate cortex, and almost three quarters of
the changes in the hippocampus, even though the behaviour of the
mice had returned to normal after treatment (Surget et al., 2009).
It is evident that antidepressants do not normalize brain
activity: mood and behaviour are restored to normal, but the
antidepressant-treated brain is in a different state from the non-
depressed brain. This is also evidenced by the high rate of relapse if
antidepressants are too-rapidly withdrawn following remission of
symptoms (Kaymaz et al., 2008). Therefore it is necessary to exam-
ine separately the neurobiology of depression and the mechanisms
of antidepressant action, rather than conflating these two issues.
3. The psychobiology of depression
3.1. The diathesis/stress model
Individuals within the population vary greatly in their vulnera-
bility to psychiatric disorders, including depression. This variation
is usually understood within a diathesis/stress model that considers
separately issues of vulnerability (the diathesis) and precipitation
(the stress) (Monroe and Simons, 1991). Two features of this model
are critical for our present analysis: as the diathesis increases,
the level of stress needed to precipitate an episode of depression
decreases, and the occurrence of an episode of depression itself
increases the diathesis for future episodes.
3.1.1. Diathesis
We consider first the nature of the depressive diathesis. A pre-
disposition (or diathesis) to become depressed may arise in a
variety of ways, and at different stages of the life cycle. For example,
a number of genetic diatheses have been identified, with a heri-
tability ranging from 31 to 42% (Sullivan et al., 2000; Kendler et al.,
2002, 2006). Some early life experiences are also known to increase
the risk for depression, particularly inadequate emotional contact
with parents (Robertson and Bowlby, 1952; Roy, 1981; Slavich et al.,
2011) or childhood abuse (Kendler et al., 2002, 2006; Widom et al.,
2007). Therefore, interactions between multiple risk genes and
early environment seem to explain a large part of the variability
(Krishnan and Nestler, 2008; Caspi et al., 2010), and much of the
diathesis for depression is laid down in early childhood.
The mechanisms by which these early experiences increase the
risk of depression (and other psychiatric disorders) include not only
biological processes (discussed below) but also psychological and
psychosocial constructs that convert transient traumatic experi-
ences into long-term vulnerabilities. For example, loss of a parent
or a poor quality of parental care leads to low self-esteem and emo-
tional instability (e.g. Akiskal, 1984; Avagianou and Zafiropoulou,
2008; Parsons et al., 2010), and may decrease the ability to form
close relationships, and so dilute the quality of social support avail-
able in later life (e.g. Schoenfelder et al., 2011). There is evidence
that distinct but substantially overlapping neural networks sub-
serve depression and insecure attachment (Galynker et al., 2011).
Even high levels of emotions after romantic love and sexual activi-
ties may increase the risk for later depression in young adolescent
girls, as a result of immature and inefficient social coping after fail-
ures at this young age (Davila et al., 2009). Early life experiences
also determine characteristic styles of processing information in
relation to the self. For example, the negative thinking that charac-
terizes the depressed person is thought to reflect the activation of
a negative ‘cognitive schema’, learned through adverse childhood
experiences such as rejection, criticism, or living with a depressed
parent (Beck, 1967). Although depressive cognitions are to a large
extent state-dependent and their role as vulnerabilities has been
questioned, there is now good evidence for the existence of cog-
nitive diatheses for depression (Alloy et al., 1999; Mathews and
MacLeod, 2005; Roiser et al., 2012), which may only be apparent
when a depressive schema is activated: for example, girls at risk
for depression because their mothers were recurrently depressed
attended selectively to negative facial expressions when subjected
to a depressive mood induction procedure, but not otherwise
(Joormann et al., 2007).
Personality factors, which are moderately heritable, but also
reflect early experience, interact with both cognitive and social
factors in the etiology of depression (Compass et al., 2004). Much
of the influence of both genetics and early traumatic events on
chronic depressive symptomatology is mediated through the per-
sonality factor of neuroticism (Kendler and Gardner, 2011), which
is one of the strongest risk factors for depression (Enns and Cox,
1997; Christensen and Kessing, 2006). Early-onset depression in
particular (first episode before the age of 30), is characterized by
a higher level of neuroticism and a higher prevalence of comorbid
personality disorders, but lower exposure to stressful life events
prior to onset, relative to individuals experiencing a later first
episode (Bukh et al., 2011). Like depression, a high level of neuroti-
cism is also associated with a negative information-processing bias
(Chan et al., 2007). High levels of negative emotionality (a construct
closely related to neuroticism) has been shown to lead, in young
people, to the formation of dysfunctional attitudes and other cog-
nitive vulnerabilities (Lakdawalla and Hankin, 2008; Joiner et al.,
2005), while low levels of positive emotionality (pleasure capac-
ity) increase vulnerability to depression by reducing social support
(Wetter and Hankin, 2009). Neurotic individuals at high genetic
risk for major depression also have an elevated tendency to inter-
act with others in ways that generate stress, and they bear some
responsibility for the stressful life events that they encounter
(Hammen, 2006; Kendler et al., 2006).
Personality factors and in particular, the personality styles
labelled ‘sociotropy’ and ‘autonomy’, may also account for much
of the variability in the symptomatology of depression, includ-
ing the clinical presentations of autonomous (or ‘endogenous’)
and reactive depression. Autonomous people obtain pleasure from
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
‘doing’ and reaching goals. They have autonomous (‘endogenous’)
depressions characterized by interpersonal distance and hostility,
hopelessness/suicidality, feelings of failure, and anhedonia: having
failed in their own terms they lose their motivation, and blaming
themselves for their failure, they minimize the importance of envi-
ronmental precipitants. Socially dependent people rely for their
satisfaction on the approval of others: their depressions are char-
acterized by interpersonal sensitivity, guilt and self-blame, anxiety
and rumination. Their depressions are ‘reactive’: they will show
temporary mood improvements if they receive a strong input of
attention and reassurance; and because relationships with the
outside world are central to them, the events that precipitate
depression are much more obvious, and may be exaggerated in
the attempt to regain love or attention (Beck, 1983; Willner, 1985;
Robins et al., 1997). Contrary to a widespread belief, ‘endogenous’
and ‘reactive’ depressions are distinguished by their presentation
rather than by the presence or absence of precipitants: indeed,
endogenous depression is more stress-sensitive, not less (Harkness
and Monroe, 2006).
3.1.2. Stress
A first episode of depression manifests against the background
of a level of vulnerability that is determined by these genetic and
experiential factors. The precipitant (or stressor) for a depressive
episode could be an internal event, such as a hormonal challenge
or a traumatic head injury. More commonly, the onset of depres-
sion is precipitated by external events. The likelihood of entering a
depressive episode is greatly increased following a major adverse
life event such as bereavement (recent evidence suggests that
interpersonal loss events are particularly powerful precipitants of
depression: Farmer and McGuffin, 2003; Slavich et al., 2010, 2011),
or in relation to an accumulation of chronic minor stresses such
as unemployment, poverty, family disharmony or living with sev-
eral pre-school children (Brown and Harris, 1978; Harkness and
Monroe, 2006). These two types of precipitating events respectively
form the basis of two of the major animal models of depression,
learned helplessness (Seligman, 1975) and CMS (Willner, 1997a).
Bereavement has traditionally precluded a diagnosis of depres-
sion, but this exclusion has been questioned, on the grounds that
bereavement related depression is in all respects similar to other
depressive episodes (Corruble et al., 2011), and it is likely to be
reversed in DSM-V (Zisook et al., 2012).
While the contribution of early life stress to the etiology of the
depression is well established, the role of stress during adulthood
has been debated, because it appears that many instances of depres-
sions are not precipitated by stress. However, there is a simple
resolution of this controversy. It follows from the diathesis/stress
concept that a person who has a weak depressive diathesis would
only succumb to an intense stress, whereas a person with a strong
depressive diathesis may succumb to minor or trivial stresses. For
example, in a large twin study, the odds ration for an association
between severely stressful life events and the onset of a first episode
of depression was four times greater in women with the lowest
level of genetic risk (dizygotic twins whose co-twin had no history
of depression) than in women with the highest level of genetic risk
(monozygotic twins whose co-twin did have a history of depres-
sion) (Kendler et al., 2001). It follows that in a person with a strong
diathesis a precipitating minor stressor (which would not be identi-
fied as a ‘life event’) might be easily overlooked, whereas a person
with a weak diathesis would only succumb to a severe stressor
(Monroe and Harkness, 2005; Harkness and Monroe, 2006).
Furthermore, the relationship between stress and depres-
sion changes over time. Depression is a recurrent condition, in
which each episode increases the probability of a further episode
(Solomon et al., 2000; American Psychiatric Association, 1994).
Indeed, one of the most powerful risk factors for major depression is
2335
a pre-existing chronic minor depression (Fogel et al., 2006). How-
ever, there are many studies demonstrating that the association
between severe stress and depression decreases with each succes-
sive episode, since minor stress episodes may by now be a sufficient
trigger (Dienes et al., 2006; Stroud et al., 2008; Morris et al., 2010;
Slavich et al., 2011). For example, a study of over 2000 women
reported that over the first six episodes of depression the likeli-
hood of an episode occurring in any given month increased 15-fold,
but at the same time, the association with a stressful life event
decreased by 75% (Kendler et al., 2000). So over the course of a
lifetime of depressive episodes, the onset of depression becomes
increasingly autonomous. This effect can be described both neu-
robiologically: an episode of depression sensitizes, or ‘kindles’, the
brain to respond to weaker and weaker precipitants (Post, 1992;
Stroud et al., 2011), and psychologically: the depressed person
relies increasingly on negative modes of information processing
that come to be activated by increasingly minimal cues (Segal et al.,
1996; Monroe et al., 2007). (These two accounts from different
stand-points are entirely compatible with one another.)
Thus, the requirement for strong and identifiable stressors to
precipitate an episode of depression decreases as the depressive
diathesis increases (e.g. several previous episodes of depression and
a high genetic risk). However, in a person with a weak depressive
diathesis (e.g. no history of depression and a low genetic risk) it
is extremely likely that an episode of depression has been precipi-
tated by stress.
3.1.3. Implications
This analysis suggests the heuristic strategy that we have
adopted in the remainder of this review. We propose that a full
understanding of the neurobiology of depression implies a solution
to three separate problems: (1) the mechanisms by which stress
precipitates first episodes of depression in individuals with a weak
depressive diathesis; (2) the kindling process by which depres-
sion becomes increasingly autonomous of stress over repeated
episodes; and (3) the psychological and neurobiological ‘prekin-
dling’ processes by which some individuals acquire a strong
depressive diathesis even prior to their first episode of depression.
We also propose that the first of these problems could be consid-
ered the more fundamental, because a solution to it would provide
a basic model within which to develop solutions to the other two
problems: for example, reports of genetic polymorphisms that con-
fer vulnerability to depression are impossible to interpret without
a model in which to understand what role is played by the cells
in which the gene product is expressed. In the following sections
(Sections 3.2–3.9) we first outline the mechanisms that underly
stress-induced first episodes of depression: we are concerned here
with understanding the impact of stress on particularly vulnera-
ble brain regions, elucidating the neural circuitry that is impacted
by these effects, and relating these neurobiological changes to the
cognitive and behavioural features of depression. We subsequently
consider the ‘kindling’ (Section 3.10) and ‘prekindling’ (Section
3.11) mechanisms that increase vulnerability to depression and
decrease the role of stress.
3.2. Effects of stress on the HPA axis and hippocampus
The major physiological response to stress is an activation
of neuroendocrine systems, most notably, the hypothalamus-
pituitary-adrenal (HPA) axis. In this system, corticotrophin
releasing factor (or hormone: CRF/CRH) is released from the para-
ventricular nucleus of the hypothalamus to stimulate the pituitary
gland to produce adrenocorticotrophic hormone (ACTH), which in
turn stimulates the release of glucocorticoids (cortisol in humans
or corticosterone in rodents) from the adrenal cortex into the blood
circulation, which inter alia exert negative feedback effects on the
2336 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
dlPFC
vmPFC
HPC
Motor
CN
Sensory outputs
inputs NAcc
AMG
PVN
RN
SN
PIT VTA
Ad Co
lHb
Fig. 3. A schematic outline of the affective information-processing brain circuitry
described in the text. The green arrows describe a basic input–output pathway via
the amygdala (AMG) and hippocampus (HPC) on the input side and the nucleus
accumbens (NAcc), substantia nigra (SN) and caudate nucleus (CN) on the output
side. The blue arrows represent the ascending modulation of those structures, as well
as the ventromedial (vm) and dorsolateral (dl) prefrontal cortex (PFC), by the 5HT
projections of the raphe nuclei (RN) and the DA projections of the ventral tegmen-
tal area (VTA), which are themselves modulated by the lateral habenula (lHb). The
red arrows represent descending pathways from the PFC: this part of the diagram
is greatly simplified; in particular, it subsumes the anterior cingulate cortex within
the PFC. The purple arrows show the HPA axis: the paraventricular nucleus of the
hypothalamus (PVN) releases CRF, which stimulates the anterior pituitary (PIT) to
release ACTH, which stimulates the adrenal cortex (AdCo) to release glucocorticoids
that feed back at all levels: the dashed lines show inhibitory and negative feed-
back elements, and the full lines show stimulatory elements, including the positive
feedback to the AMG.
pituitary and hypothalamus that limit the degree of activation of
the HPA axis (de Kloet et al., 2005; Holsboer and Ising, 2010). Emo-
tional stimuli reach the HPA axis via the amygdala and descending
pathways from the forebrain (Fig. 3: purple arrows). The amyg-
dala exerts excitatory control over the hypothalamus to stimulate
the HPA axis, which, via increased cortisol levels, acts in a positive
feedback manner to further stimulate the amygdala (Duvarci and
Pare, 2007). Conversely, the hippocampus exerts inhibitory control
over the HPA axis, such that cortisol stimulation of the hippocam-
pus acts in a negative feedback manner to inhibit the HPA axis.
This negative feedback mechanism is crucial for limiting the activ-
ity of the HPA axis, since without it, the positive feedback loop
via the amygdala would cause the system to run out of control
(Jacobson and Sapolsky, 1991; Herman et al., 1996; Swaab et al.,
2005; Belzung and Billette de Villemeur, 2010). Descending neg-
ative feedback over the HPA axis is also exerted at the level of
the dorsomedial prefrontal cortex (PFC) and the prelimbic cortex
(Ulrich-Lai and Herman, 2009; Jankord and Herman, 2008) so acti-
vation of these areas by emotional self-regulation can also improve
the control over the HPA axis. (This issue is discussed further in
Section 3.6.)
3.2.1. Neurotoxic effects of stress
Chronic exposure to glucocorticoids is neurotoxic, and pre-
clinical studies have shown that hippocampal granule cells are
particularly sensitive to these effects. Prolonged glucocorticoid
exposure leads initially to a loss of glucocorticoid receptors (GR)
in hippocampal granule cells, with a consequent disinhibition of
the HPA axis and a further increase in corticosteroid stimulation
(Raison and Miller, 2003). If further prolonged, the consequences
of the loss of GR-mediated effects for granule cell function, as
well as hyper-stimulation through the activation of other, pri-
marily glutamatergic mechanisms become severe: they include a
hyperactivation of calcium-dependent enzymes leading to the pro-
duction of neurotoxic free radicals, a decrease in glucose transport
into the cell with a consequent loss of energy capacity, and a
decreased production of brain-derived neurotrophic factor (BDNF),
which provides trophic support to cell structure and function.
Through a combination of these effects, prolonged exposure to
stress (Magarinos et al., 1996) or high levels of glucocorticoids
(Woolley et al., 1990) causes atrophy of apical dendrites, and ulti-
mately, granular cell death (Sapolsky, 2000). Exposure to CMS is
sufficient to cause loss of granule cells (Jayatissa et al., 2008, 2010).
Consistent with these structural changes, prolonged exposure to
stress or glucocorticoids impairs hippocampal-dependent mem-
ory processes: spatial memory in animals (Bodnoff et al., 1995;
de Quervain et al., 1998) and verbal declarative memory in peo-
ple (Newcomer et al., 1999; de Quervain et al., 2000). The effect
of stress to decrease BDNF levels is complemented by a report
of decreased BDNF in the hippocampus of suicide victims (Karege
et al., 2005). However the extreme case of hippocampal cell death
has not been observed in post-mortem samples from depressed or
steroid-treated patients (Swaab et al., 2005).
The hippocampal inhibitory control of the HPA axis is exerted
via several multisynaptic pathways projecting from the subiculum
to the paraventricular nucleus of the hypothalamus. The subicu-
lum sends glutamatergic projections to the bed nucleus of the stria
terminalis (Jalabert et al., 2009), the lateral septum, and differ-
ent hypothalamic nuclei, all of which send GABAeric projections
to the paraventricular nucleus (Herman et al., 1995, 2002, 2005;
Cullinan et al., 2008; Belzung and Billette de Villemeur, 2010). All
of these influences are inactivated by chronic stress: changes in the
neuronal activity of all these structures secondary to glucocorti-
coid stimulation of hippocampal neurons were absent in animals
subjected to CMS, and were restored by chronic antidepressant
treatment (Surget et al., 2011).
High circulating levels of glucocorticoids also promote the
release of pro-inflammatory cytokines from macrophages and
microglial cells, which contribute to the desensitization of GR
receptors (Raison et al., 2006) and further stimulate the HPA axis
(Zunszain et al., 2011). There has been much discussion of the
parallels between the anhedonic ‘sickness behaviour’ elicited by
cytokines and depression (Weisler-Frank et al., 2005; Sharpley and
Agnew, 2011), though the value of this parallel may be limited
(Dunn et al., 2005). Elevated levels of cortisol also cause an increase
in the activity of MAO-A, with a consequent decrease in brain lev-
els of NA and 5HT (Slotkin et al., 1998). A neuroimaging study
found increased MAO-A activity throughout the brain of depressed
patients (Meyer et al., 2006; Meyer, 2012), which would explain the
decreased levels of NA and 5HT posited by the monoamine hypoth-
esis of depression, albeit that direct evidence for the existence of
such decreases remains elusive.
A further effect of stress that has been much discussed in the
recent literature is on neurogenesis, the growth and differenti-
ation of new cells, which in the adult brain is confined to two
areas, the subventricular zone, from where new-born cells migrate
into the olfactory bulb, and the dentate gyrus of the hippocam-
pus. Despite their relatively small numbers, there is evidence that
newly generated neurons can affect the functioning of hippocam-
pal circuits: for example, in rodents tested in spatial learning tasks
known to recruit the hippocampus, levels of the immediate early
gene c-Fos are higher in newly generated adult neurons than in
older neurons (Kee et al., 2007). The effect of these cells is ampli-
fied by modulation of GABAergic interneurons: ablation of new
neurons caused an increase in the amplitude of spontaneous ␥-
frequency bursts in the dentate gyrus of the hippocampus, as well
as increased synchronization of dentate neuron firing (Lacefield
et al., 2012). It has frequently been speculated that the role of
neurogenesis in antidepressant action is to support new learn-
ing of more adaptive cognitions and behaviours (e.g. Castrén and
Rantamäki, 2010). This hypothesis receives indirect support from
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
studies showing that suppression of neurogenesis impairs the
learning of a hippocampal-dependent task, context discrimination
(Deng et al., 2010; Tronel et al., 2010, 2012). More direct evidence
comes from a study in which a genetic mutation was used to pre-
vent the programmed death of newly born neurons, leading to
an increase in their number, accompanied by an enhancement of
context-discrimination learning (Sahay et al., 2011). Human neuro-
genesis continues throughout the lifespan (Eriksson et al., 1998) but
decreases as a function of chronological age (Amrein et al., 2011),
and is therefore at a low level in adults. Nevertheless, the number of
newly generated cells in the human hippocampus, while small, may
be sufficient to be of functional significance (Snyder and Cameron,
2012).
Hippocampal neurogenesis is powerfully suppressed by stress
or by prolonged corticosterone exposure (Wong and Herbert, 2004;
Mineur et al., 2007; Samuels and Hen, 2011; Hanson et al., 2011;
Petrik et al., 2012). Such effects have been reported in different
species, including tree shrews (Gould et al., 1997) and higher pri-
mates (Gould et al., 1998; Perera et al., 2011) as well as rodents
(Mineur et al., 2007; Alonso et al., 2004), and are seen follow-
ing both psychosocial (Gould et al., 1997; Czéh et al., 2002) and
physical stressors (Malberg and Duman, 2003; Pham et al., 2003;
Vollmayr et al., 2003). Suppression of neurogenesis has also been
reported in post-mortem samples from elderly depressed patients
(Lucassen et al., 2010). The dynamics of adult neurogenesis are
complex, involving the proliferation of new cells, the formation
of new immature neurons, and the insertion of adult born neu-
rons into a functional network. Stress interferes both with the early
phases of this process (cell proliferation) as well as with neuronal
survival and functionality (Czéh et al., 2001; Mirescu and Gould,
2006; Oomen et al., 2007; Wong and Herbert, 2004). Importantly,
these changes do not occur if chronic stress is predictable, or if
coping with stress is possible: in these situations, neurogenesis is
not suppressed, and may actually be stimulated (Lyons et al., 2010;
Parihar et al., 2011). The mechanisms underlying this important
finding are explored further in Section 3.6.
3.2.2. Morphological consequences
These cellular effects of stress have visible morphological
consequences. Despite some inconsistencies in the literature, meta-
analyses of structural brain imaging studies have reported that
there is a reliable decrease in hippocampal volume in patients suf-
fering from major depression (Campbell et al., 2004; Videbech and
Ravnkilde, 2004), and in rats exposed to CMS (Delgado et al., 2011),
comparable to the effect seen in Cushing’s disease (Sapolsky, 2000).
The effects vary in severity across hippocampal subregions (Cole
et al., 2010; Malykhin et al., 2010) and increase across episodes of
depression (Cole et al., 2010). In patients with late-onset depres-
sion, the decrease in hippocampal volume was correlated with
memory loss (Ballmaier et al., 2008). The major factor in these
volumetric changes, in both preclinical studies of prolonged stress
exposure (Tata and Anderson, 2010) and post-mortem studies of
depressed patients (Czeh and Lucassen, 2007) is thought to be
changes in hippocampal morphology and loss of dendrites, rather
than cell loss. Some clinical studies have failed to observe volumet-
ric changes (McKinnon et al., 2009; MacQueen and Frodl, 2010).
However, given the number and range of molecular processes that
contribute to these effects, and the observation that the propor-
tional loss of synapses is far greater than changes in hippocampal
volume (Tata et al., 2006), it is likely that the functioning of the hip-
pocampus is compromised at levels of damage that are not reflected
in visible morphological changes.
These findings are potentially of considerable importance for
the ‘kindling’ hypothesis discussed above, because the degree of
hippocampal shrinkage is directly proportional to the number and
duration of prior depressive episodes, and to the total duration of
2337
illness (Sheline et al., 2003; Colla et al., 2007; Tata and Anderson,
2010). Hippocampal volume has been observed to decline during
a 3-year prospective study among severely depressed in-patients,
particularly those with a incomplete remission and relapses (Frodl
et al., 2008a), and in one meta-analysis was only significant in
patients who had been depressed for more than 2 years or had more
than one episode of depression (McKinnon et al., 2009). The weight
of this evidence is that the experience of depression increases the
susceptibility of the hippocampus, and after recovery from depres-
sion, patients with a history of recurrent depression continue to
show a decreased hippocampal volume (Neumeister et al., 2005),
consistent with the observation that cognitive impairments also
persist following recovery from a depressive episode (Bhalla et al.,
2006; Preiss et al., 2009).
In short, neurochemical and structural changes observed in
the hippocampus of depressed patients closely resemble those
observed following prolonged exposure to stress or high levels of
circulating glucocorticoids, and the effects of stress leave a ‘scar’ on
the hippocampus that increases the diathesis for depression.
3.3. Frontal brain circuitry underlying the symptoms of
depression
While the hippocampus is the brain area that is most sensitive
to the neurotoxic effects of stress, prolonged exposure to high lev-
els of glucocorticoids can also cause damage in many other brain
regions, particularly the prefrontal cortex (PFC), where neurode-
generative changes include microglial activation (Hinwood et al.,
2011), atrophy of pyramidal neurons (Liu and Aghajanian, 2008),
dendritic retraction (Shansky et al., 2009; McEwen, 2010; Dias-
Ferreira et al., 2009), and reduction of synaptic proteins such as
PSD95, and synapsin I (Li et al., 2010). These changes are associated
with cognitive deficits in PFC-related tasks (Miracle et al., 2006;
Santini et al., 2004). It has also been reported that levels of N-acetyl-
aspartic acid, a marker of neurodegenerative processes, decreased
in the left dorsolateral PFC as a function of the length of depressive
illness (Nery et al., 2009), indicating that, as in the hippocampus,
the effects of stress on the PFC are progressive.
Within the PFC, the most stress-sensitive region is the anterior
cingulate cortex (ACC) (Drevets et al., 2008; Radley et al., 2006;
Mayberg et al., 1997; Holmes and Wellman, 2009; McEwen and
Gianaros, 2010; Hamani et al., 2011; Pizzagalli, 2011; Price and
Drevets, 2010, 2012). A decreased volume of the ACC has also
been reliably observed in imaging studies of depressed patients
(Phillips et al., 2003b; Savitz and Drevets, 2009; van Tol et al., 2010).
Alterations in this area might contribute to the increased vulnera-
bility to recurrence: for example, a history of recurrent depression
is associated with a low level of GABA in the ACC (Bhagwagar
et al., 2008). With the exception of this region, structural imaging
studies of other brain regions in depression are somewhat incon-
sistent, with structural damage, including volume and cell loss,
reported in many regions but not reliably replicated (Phillips et al.,
2003b; Savitz and Drevets, 2009), albeit that consistency in some
regions increases with increased severity or chronicity of depres-
sion (Lorenzetti et al., 2009). In general, however, these changes do
not increase with the duration of depression, or with its recurrence,
as it is the case for the hippocampal- and PFC-related changes. For
example, the amygdala may be enlarged during a first episode of
depression, but this seems not to persist with recurrence (Frodl
et al., 2003; van Eijndhoven et al., 2009). Moreover, there is some
inconsistency between structural and functional imaging studies,
such that volume loss is sometimes associated with increased func-
tional activity. Such effects have frequently been reported in, for
example, the amygdala (Savitz and Drevets, 2009).
In contrast to the relative inconsistency of structural imaging
studies, there is a relatively well-accepted consensus regarding
2338 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
changes in functional activity in frontal brain regions of depressed
patients. This consensus reflects an increasingly well-established
model of the organization of information processing in the fore-
brain. The model recognizes two distinct but interacting systems:
a ventral “affective” circuit involving the amygdala, the anterior
(in rodents, ventral) hippocampus, the ventral striatum, the insu-
lar cortex, the ventral (subgenual) part of the ACC and the ventral
and orbital PFC; and a dorsal “cognitive” circuit, involving the pos-
terior (in rodents, dorsal) hippocampus, the dorsal (pregenual) part
of the ACC and the dorsolateral PFC. [There is some inconsistency in
terminology with respect to the ventral ACC. In this review we use
the terms ventral and subgenual ACC interchangeably to refer to
Brodman’s area 25 and the ventral parts of Brodman’s area 24 and
32 (Phillips et al., 2003a; Mayberg, 2009; Hamani et al., 2011); but
in some papers (e.g. Pizzagalli, 2011; Price and Drevets, 2012), the
ventral ACC is differentiated into anterior (rostral) and posterior
(subgenual) regions. Similarly the term ventromedial PFC refers to
the more frontal Brodman’s area 10 but this term is sometimes
used to connote a larger area including the ventral ACC, which
constitutes a ‘medial prefrontal network’ (Price and Drevets, 2010,
2012). These inconsistencies reflect the limited resolution of many
neuroimaging studies.]
The ventral system is important for the identification of the
emotional significance of a stimulus, the production of affective
states and autonomic regulation related to emotionally signifi-
cant situations, while the dorsal system is important for executive
function, including selective attention, planning, and effortful
regulation of affective states. This understanding is based on a con-
vergence of evidence from animal and human studies, involving
stimulation by emotionally salient stimuli, focal brain lesions, and
functional neuroimaging techniques (Phillips et al., 2003a; Ernst
and Paulus, 2005; Mayberg, 2009; Holtzheimer and Mayberg, 2010,
2011; Hamani et al., 2011).
In the human brain, there is also evidence for lateralization of
emotional information processing, with a greater involvement of
the left hemisphere in appetitive behaviours and of the right hemi-
sphere in avoidance behaviours. This distinction can be related to
the more traditional characterization of a left hemisphere involve-
ment in serial processing, and right hemisphere involvement in
parallel processing, since approach behaviours require precise, cal-
culated sequential strategies, while avoidance behaviours, which
appear under conditions of danger or threat, require an imme-
diate holistic response (Kinsbourne, 1978; Willner, 1985). While
lateralization of function has typically been associated with the
development of language, there is some evidence that lateralized
processing has its origins in non-human species (Sullivan, 2004;
Corballis, 2009).
From these observations it would be predicted that depression
might be associated with decreased functioning in the dorsal “cog-
nitive” circuit, particularly in the left hemisphere, and increased
functioning in the ventral “affective” circuit, particularly the right
hemisphere, and this is what is observed. Indeed, the functional
changes in the depressed brain appear to be exaggerated and pro-
longed versions of those seen during a normal response to aversive
stimuli. Depressed patients have been reliably observed to show
decreased bloodflow, under resting conditions, in the dorsal ACC
and dorsolateral PFC, with greater effects in the left hemisphere
than the right, and increased bloodflow in the amygdala and ven-
tromedial PFC, with greater effects in the right hemisphere than the
left. These two sets of changes are associated with different sets of
symptoms: the decrease in (left) dorsolateral function is associated
with psychomotor retardation, apathy and decreased attentional
capacity, while the increase in (right) ventromedial function is asso-
ciated with increased punishment sensitivity, anxiety, tension and
depressive ruminations (Mayberg et al., 1999; Phillips et al., 2003b;
Savitz and Drevets, 2009; Vago et al., 2011; Elliott et al., 2011;
Mayberg, 2009; Holtzheimer and Mayberg, 2010, 2011; Hamani
et al., 2011; Monkul et al., 2011).
Electrical stimulation of the ACC (deep brain stimulation: DBS),
using stimulation parameters that inhibit activity in the area tar-
getted, has been found to elicit a prolonged recovery in some
treatment-resistant patients: over 50% of patients treated with DBS
showed a greater than 50% improvement in depression scores a
year later (Mayberg, 2009; Hamani et al., 2011). DBS of the medial
PFC has also been reported to elicit antidepressant-like effects in
rats (Hamani et al., 2010). Clinical recovery following DBS of the
ACC was associated with a normalization of functional brain activ-
ity in treatment responders (Mayberg, 2009; Hamani et al., 2011).
Conversely, hyperactivity in this area was reinstated in patients
after recovery from depression following a decrease in either 5HT
or DA and NA activity, brought about by a tryptophan depletion
(Neumeister et al., 2004) or AMPT (Hasler et al., 2008) challenge;
and in remitted depressives, the reactivity of this region to a sad
film clip predicted relapse to depression (Farb et al., 2011). These
findings identify the ACC as a region of particular interest, as will
be discussed further below.
3.4. What drives the changes?
While the functional changes in frontal brain regions associated
with depression and successful treatment have been extensively
described and discussed, there has been less consideration of their
origin. As discussed above, there is evidence of stress-induced
neuropathology in many frontal regions, but this evidence is incon-
sistent across studies, and often inconsistent with the functional
changes. While it is possible that stress-induced neurotoxicity
could account for some of these effects, particularly the hypofunc-
tion of dorsal ACC, a simpler hypothesis is that the changes in the
functioning of frontal brain circuits could be secondary to struc-
tural and functional changes in hippocampal activity, based on the
anatomical interactions between these two structures (Goldman-
Rakic et al., 1984; Jay et al., 1989; Thierry et al., 2000; Taxidis et al.,
2010). Indeed, the hippocampal formation, including the subicu-
lum and the entorhinal cortex, contributes very significantly to the
overall modulatory control and evaluation of the emotional con-
text of information processing by both the dorsal “cognitive” and
ventral “affective” systems. This nodal role reflects the anatomical
organization of the entorhinal cortex (which provides the major
input to the hippocampus), which receives convergent multimodal
and highly processed unimodal sensory inputs and has reciprocal
connections with all the higher-order multimodal association cor-
tex areas, including parietal cortex, temporal cortex and the PFC
(Canto et al., 2008).
A causal relationship between decreased activity in the hip-
pocampus and the decreased dorsolateral PFC activity that is
reliably observed in depressed patients, is suggested by the obser-
vation that decreased hippocampal volume was correlated with
the extent of executive dysfunction, which is known to be depend-
ent on the dorsolateral PFC (Frodl et al., 2006). There are several
anatomical routes that could mediate this relationship. First, there
are direct connections, within the dorsal system, from subiculum
of the hippocampus to dorsal ACC and dorsolateral PFC (Goldman-
Rakic et al., 1984). There are many reports that the connectivity
between these two regions is disturbed in, for example, schizophre-
nia (e.g. Henseler et al., 2010) or Alzheimer’s disease (Goveas
et al., 2011a); by contrast, hippocampal-prefrontal connectivity
increased with severity of depression in a sample of depressed older
adults (Goveas et al., 2011b; Sheline et al., 2010). Second, there are
reciprocal inhibitory interactions between dorsolateral and ventro-
medial PFC (Phillips et al., 2003a,b; Mayberg, 2009; Hamani et al.,
2011; Pizzagalli, 2011), so a decreased level of activity in the dorsal
system could simply follow from increased activity in the ventral
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
system. Indeed, there is evidence that this is the case: for exam-
ple, in depressed patients performing a cognitive task, an increased
ventral PFC response to errors was associated with a decreased
recruitment of the dorsal PFC on the following trial (Holmes and
Pizzagalli, 2008). A third mechanism, involving the dorsal striatum,
is discussed below (Section 3.8).
There are also strong reciprocal anatomical connections
between the hippocampus and amygdala (Pitkänen et al., 2000);
their reciprocal functional relationship is nicely illustrated by a
study showing that amygdala memory coding was enhanced by
lesions of the hippocampus, and vice versa (Richardson et al., 2004).
Interestingly, lesions of the basolateral amygdala, or reduction of
its activity, suppress hippocampal neurogenesis (Kirby et al., 2012).
It is also evident from the opposite influences of hippocampus and
amygdala on the HPA axis (Fig. 3) that a decrease in hippocampal
inhibition of HPA activity leads to an increased hormonal stim-
ulation of amygdala activity. As activity in the amygdala drives
activity in the ventromedial PFC, an effect that is particularly promi-
nent in emotional disorders (Carlson et al., 2006), it follows that
a decreased level of hippocampal functioning causes a reciprocal
increase in the activity of the ventral “affective” system.
3.4.1. Anhedonia
Anhedonia, the inability to experience pleasure, is a core symp-
tom of depression that, in animal studies, has primarily been
associated with a decreased level of activity in the mesolimbic DA
projection from the ventral tegmental area (VTA) of the midbrain
to the nucleus accumbens, the major structure of the ventral stri-
atum (Willner and Scheel-Krüger, 1991; Wise, 2008; Treadway and
Zald, 2011). Animals exposed to CMS are anhedonic to both natural
and drug rewards (Willner et al., 1992) and have subsensitive DA D2
receptors in the nucleus accumbens (Dziedzicka-Wasylewska et al.,
1997), as well as lower DA release within the nucleus accumbens in
response to rewarding, but not to aversive, stimuli (Di Chiara et al.,
1999). A recent study showed that the stress-responsive neuro-
peptide CRF causes DA release within the nucleus accumbens, and
a rewarding effect, but following acute exposure to severe stress,
CRF no longer releases DA, and its effect is now aversive (Lemos
et al., 2012). These results parallel the clinical finding of decreased
responsiveness to reward but no change in responsiveness to pun-
ishment in the ventral striatum of depressed patients (Robinson
et al., 2011). The severity of anhedonia is negatively correlated
with activity in the ventral striatum, in both unipolar depression
(Keedwell et al., 2005; Dunn et al., 2002; Surguladze et al., 2005;
Epstein et al., 2006) and postpartum depression (Moses-Kolko et al.,
2011), but positively correlated with activity in the ventromedial
PFC (Keedwell et al., 2005). Inversely to the PFC, activity in the ven-
tral striatum increases with antidepressant treatment (Stoy et al.,
2012; Ossewaarde et al., 2011), and DBS of the nucleus accumbens
is an effective treatment for depression (Schlaepfer et al., 2008;
Bewernick et al., 2010; Grubert et al., 2011).
Like other aspects of depression, anhedonia might also be
explained by a stress-induced decrease in hippocampal func-
tioning. There are several pathways through which stress could
influence activity in the ventral forebrain. Information regarding
the anticipation of reward (Schultz et al., 1997; Treadway and Zald,
2011) reaches the VTA to activate the mesolimbic DA system via the
dorsolateral PFC (Ballard et al., 2011), suggesting a potential rela-
tionship between anhedonia and decreased activity in this region:
the projection to the VTA is a very minor output of the dorsolat-
eral PFC and could be affected by changes in activity too small to
detect in a neuroimaging study. However, there is also an indirect
excitatory connection from the ventral subiculum of the hippocam-
pus to the VTA, via the nucleus accumbens and ventral pallidum,
suggesting that a decrease in DA cell firing could follow from a
decrease in hippocampal activity (Cooper et al., 2006; Lisman and
2339
Grace, 2005). Monosynaptic projections from the subiculum and
basolateral amygdala have opposite effects on individual nucleus
accumbens neurons (French and Totterdell, 2003), controlling their
firing rate as well as that of VTA dopaminergic neurons (Gill and
Grace, 2011); and there is a similar convergence of monosynap-
tic subicular and prefrontal cortical inputs to projection neurons
of the nucleus accumbens (French and Totterdell, 2002; Sesack and
Grace, 2010). Finally, the hippocampus may influence activity in DA
(and 5HT) systems via the habenula, a limbic-striatal relay nucleus
that occupies an important position in the depression circuitry, as
discussed in the following section.
To summarize, the symptoms of depression appear to reflect
changes in the activity of frontal brain areas that represent a height-
ening (the ventral system) or an inhibition (the dorsal system) of
their usual role in the processing of and coping with affective infor-
mation. Both sets of changes can be related to decreased activity
in the hippocampus. The data are for the most part correlational,
leaving open the question of where, precisely, the primary changes
occur that propagate to other regions. However, the greater suscep-
tibility of hippocampal cells to suffer dysfunctional consequences
when exposed to prolonged stress provides a plausible point of
origin for most if not all of these systemic dysregulations.
3.5. Mechanisms mediating affective information-processing
biases
As already discussed, the amygdala and nucleus accumbens
are key structures in the appraisal of and response to affectively-
valenced stimuli. As described in the introduction to this review,
depression is characterized by a heightened response to negative
information and a blunted response to positive information (Beck,
1967; Disner et al., 2011). Increased activation of the amygdala
and decreased responsiveness of the nucleus accumbens are key
mediators of these affective information-processing biases.
3.5.1. Amygdala and nucleus accumbens
The amygdala is involved in stimulus processing and the nucleus
accumbens in response selection and contemporary accounts of
these structures emphasize that these functions are to some extent
independent of the appetitive or aversive context (Sesack and
Grace, 2010; Gill and Grace, 2011). Thus, the amgdala has been
shown to respond not only to aversive stimuli but also to appe-
titive stimuli, and to be involved in memory formation for both
types of stimuli, perhaps by coding their affective value (Paton
et al., 2006; Morrison and Salzman, 2010; Murray et al., 2011; van
Wingen et al., 2010). Likewise, the nucleus accumbens, as output
station of the PFC, is involved in decision-making in relation to
response costs in both appetitive and aversive contexts (Salamone,
1994). In both amygdala (Herry et al., 2008; Morrison and Salzman,
2010, 2011) and nucleus accumbens (Reynolds and Berridge, 2008;
Faure et al., 2008; Richard and Berridge, 2011) there is some degree
of anatomical separation between appetitive and aversive regions.
Distinct appetitive and aversion regions within the ventral PFC
and orbital cortex (Kringelbach and Rolls, 2004; Kringelbach, 2005)
receive information from corresponding regions of the amygdala
and project to corresponding regions of the nucleus accumbens
(Humphries and Prescott, 2010; Haber and Knutson, 2011).
Notwithstanding these generalized functions, the amygdala has
traditionally been discussed primarily in relation to its very well-
established role in fear conditioning and anxiety disorders (Phelps
and LeDoux, 2005; Etkin and Wager, 2007), and there is some
evidence that the amygdala has a greater involvement in the
processing of aversive stimuli (Meseguer et al., 2007; Cybulska-
Klosowicz et al., 2009; Dwyer, 2011). Thus, depressed patients
showed not only a greater amygdala activation than controls when
processing negative or aversive stimuli, such as sad faces (Peluso
2340 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
et al., 2009a,b), but also, greater amygdala responses to sad than
to happy faces, whereas the reverse was true in healthy controls
(Victor et al., 2010). The increased amygdalar response persists
after removal of the negative stimulus (Schaefer et al., 2002; Siegle
et al., 2007) and this effect is reversed by antidepressant therapy
(Fu et al., 2007).
Conversely, the nucleus accumbens has been discussed primar-
ily in relation to reward processing. Indeed, as the structure through
which emotional information gains access to the motor system
(Mogenson et al., 1980), the primary role of the nucleus accumbens
could be conceptualized as seeking positive behavioural outcomes:
by generating behaviours aimed at acquiring rewards and avoiding
punishment, activity in the nucleus accumbens improves hedonic
tone in both appetitive and aversive environments (Willner, 1985;
Ikemoto and Panksepp, 1999). Consistent with this formulation,
depressed patients showed blunted accumbens responses to mon-
etary gains but did not differ from controls in their accumbens
response to losses (Pizzagalli et al., 2009). Similarly, depressed
patients showed lower activity in the ventral striatum when
reappraising rewards in a reversal-learning task, but not when
reappraising punishments (Robinson et al., 2011). Furthermore,
depressed patients show difficulty in maintaining positive mood
after a reward, associated with an inability to sustain activity in the
accumbens over time (Heller et al., 2009), suggesting that decreased
activity within the dorsal PFC may reduce reward sensitivity of the
accumbens (Disner et al., 2011), either directly (Ballard et al., 2011)
or indirectly via the hippocampus, as discussed earlier.
3.5.2. The habenula
The lateral habenula is a key structure mediating the response to
emotionally negative states (Hikosaka et al., 2008; Hikosaka, 2010),
and the balance of activity between the amygdala and nucleus
accumbens. The habenula is activated by stressful events in humans
(Ullsperger and von Cramon, 2003) and animals (Matsumoto and
Hikosaka, 2009). Metabolic activity in this region is increased in ani-
mal models of depression (Caldecott-Hazard et al., 1988; Shumake
et al., 2003) and following the induction of a depressive episode by
tryptophan depletion in patients (Morris et al., 1999; Roiser et al.,
2009). Conversely, lesions of the lateral habenula reverse depres-
sive behaviour induced by learned helplessness or CMS (Amat et al.,
2001; Yang et al., 2008). Similarly, pharmacological or DBS inhi-
bition of the lateral habenula has been shown to reverse learned
helplessness (Winter et al., 2011; Li et al., 2011a,b), and benefi-
cial effects of DBS have recently been reported in one severely
treatment-resistant depressed patient (Sartorius et al., 2010). Expo-
sure to stress increases the excitability of habenular output cells,
and the extent of this effect is correlated with the degree of learned
helpessless (Li et al., 2011a,b).
A major output of the lateral habenula is to the dorsal raphe
nucleus (DRN), and this projection is responsible for the stress-
induced activation of 5HT cells in the DRN (Amat et al., 2001; Takase
et al., 2004; Yang et al., 2008). A second major output of the lateral
habenula is to the VTA, causing inhibition of DA cells (Hikosaka
et al., 2008; Hikosaka, 2010; Li et al., 2011a), resulting in anhedo-
nia (Friedman et al., 2011). It is noteworthy that both stress and
antidepressant drugs increase 5HT function. The effect of stress is
mediated by the projection from the DRN to the amygdala, where
it potentiates increases the salience of threat stimuli (Maier and
Watkins, 2010). But, as described below, serotonergic antidepres-
sants act by potentiating the 5HT projection from the median raphe
nucleus (MRN) to the hippocampus. The pro-anxiety effect of 5HT
in the amygdala counteracts the antidepressant effect in the hip-
pocampus, and the need to overcome the pro-anxiety effect may
be one reason for the slow onset of antidepressant action.
Thus, activation of the habenula by stress increases the salience
of aversive stimuli (via the 5HT projection from the DRN to the
amygdala) and decreases the salience of positive events (via the DA
projection from the VTA to the nucleus accumbens). The stimula-
tion of the habenula by stress, leading to an increase in the salience
of aversive stimuli (preferentially processed in the amygdala) and a
decrease the salience of appetitive stimuli (preferentially processed
in the nucleus accumbens), provides a plausible neurobiological
substrate for the information-processing biases that characterize
depression (Beck, 1967; Disner et al., 2011).
3.6. Failure to cope
There is a crucial distinction between exposure to a stressor
and the experience of stress. An intense stressor may cause little
stress if coping mechanisms are adequate, while conversely, if cop-
ing mechanisms fail, a mild stressor may be experienced as highly
stressful. An account of the neurobiology of stress and depression
must engage with the fact that the critical setting is a failure to cope
with stress, rather than exposure to stress per se.
3.6.1. Stimulus appraisal
This question has received considerable attention in the psycho-
logical literature (e.g. Kessler et al., 1985; Bedi, 1999; Olff, 1999;
Compass et al., 2004; Christensen and Kessing, 2005). The ability
to cope with stress depends in part on the neurobiological mech-
anisms already discussed, but also, and importantly, on how the
stressor is appraised. Indeed, unlike physical stressors, the inten-
sity of which is communicated to the brain directly, psychological
stressors only come into existence at the point when they are
appraised within the brain. (Or as Shakespeare observed over 400
years ago, “there is nothing either good or bad but thinking makes
it so”.) Appraisal of the meaning of an emotion-eliciting situation
is a continuous process, and an initial appraisal may be followed
by reappraisal in ways that could either increase or decrease the
perceived stress. The process of reappraisal is an important mech-
anism of self-regulation that has consequences for mental and
physical well-being (Davidson, 2000; Gross, 2002), as exemplified
by the central role of reappraisal processes in cognitive behavioural
therapy.
Brain mechanisms of reappraisal have been addressed directly
by neuroimaging studies in which participants are required to mod-
ulate their emotional response to aversive stimuli, using strategies
such as imagining negative or positive outcomes to the situa-
tion presented, or by imagining that the situation is happening to
themselves or to a stranger. These studies have shown that reap-
praisal involves increased activation in a diffuse network of PFC
regions, including elements of both the dorsal and ventral sys-
tems. The regions activated depend to some extent on the cognitive
strategy adopted: for example, self-focused regulation recruited
medial prefrontal regions implicated in internally focused infor-
mation processing, whereas situation-focused regulation recruited
lateral prefrontal regions implicated in externally focused infor-
mation processing (Ochsner et al., 2004; Ochsner and Gross, 2005;
Roiser et al., 2012).
Reappraisal-related activation within the PFC is largely indepen-
dent of whether the aim was to achieve an increase or a decrease
in negative affect. However, this is not the case in subcortical
structures. The act of reappraising a stimulus more negatively was
associated with increased activity in the amygdala and decreased
activity in the nucleus accumbens; conversely, a positive reap-
praisal was associated with decreased amygdalar activity (Ochsner
et al., 2004; Ochsner and Gross, 2005; Wager et al., 2008). More-
over, these changes in subcortical activity within the amygdala and
nucleus accumbens were shown to partly mediate the relationship
between PFC activity and success in reappraising a negative event
(Wager et al., 2008).
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
3.6.2. Learned helplessness
Parallel effects are observed in animal studies. Learned helpless-
ness could reasonably be viewed as an animal model of a specific
appraisal process. In the learned helplessness procedure, animals
display a range of behavioural impairments after being subjected
to uncontrollable aversive events that are not seen after expo-
sure to controllable events (Seligman, 1975; Maier and Seligman,
1976). This is typically studied using inescapable vs. escapable
footshock, such that animals in the two conditions receive the
identical amount and pattern of shock, and differ only in their
ability to control it. An elegant series of experiments demon-
strated that the perception of control depends on activity within
the ventral PFC (Maier and Watkins, 2010). Pharmacological inac-
tivation of the ventral PFC (using the GABA agonist muscimol)
during exposure to escapable shock resulted in impairments typ-
ical of animals exposed to inescapable shock, such as a failure of
subsequent escape learning and reduced social investigation. Con-
versely, pharmacological activation of the ventral PFC (using the
GABA antagonist picrotoxin) during exposure to inescapable shock
prevented subsequent behavioural impairments (Amat et al., 2005,
2008; Christianson et al., 2009; Maier and Watkins, 2010), con-
sistent with the antidepressant-like effect of DBS in this region
(Hamani et al., 2010). Moreover, experience of controllability, by
exposing animals to escapable shock, immunizes them against the
behavioural impairments caused by subsequent inescapable shock
(Amat et al., 2006), or a different stressor, social defeat (Amat et al.,
2010; Maier and Watkins, 2010). The learning process responsible
for this resilience also occurs within the ventral PFC, because it was
blocked by injection of a protein synthesis inhibitor into this region
during exposure to the controllable condition (Amat et al., 2006).
Therefore, the ventral PFC appears to be responsible for appraisal of
whether or not it is possible to cope with stress not only in humans
but also in the rat.
Studies using this model have shown that the PFC–amygdala
interaction operates via the ascending 5HT system. It has long been
known that the adverse behavioural effects of inescapable shock
are dependent on the integrity of 5HT neurons in the dorsal raphe
nucleus (DRN), because pharmacological or surgical inactivation of
these neurons prevents learned helplessness (Maier and Watkins,
2010). Stimulation of the ventral PFC inhibits DRN 5HT cells via
glutamatergic projections to GABAergic neurons within the DRN
(Hajos et al., 1998; Baratta et al., 2009). When control of stress is
appraised to be absent, this inhibition is lifted, leading to desensi-
tization of inhibitory 5-HT1A DRN auto receptors (Rozeske et al.,
2011) and increased stress-induced activation of a population of
5HT cells in the dorsomedial DRN (Lowry et al., 2008). This in turn
results in increased release of 5HT in the amygdala (Amat et al.,
2006), with a consequent activation of the HPA axis (Fig. 3).
The PFC also projects to the habenula, and this projection plays
a key role in setting the balance of negative and positive affectiv-
ity. The habenula and its outputs are activated by stress without
regard to the controllability of the stressor (Amat et al., 2001).
However, if stress is appraised as controllable, habenular outputs
to the amygdala (via 5HT) and nucleus accumbens (via DA), and
their behavioural consequences, are over-ridden by descending
projections from the ventral PFC (Maier and Watkins, 2010). Indeed,
individual neurons within the PFC project to both the serotonergic
DRN neurons and the dopaminegic VTA neurons (Vazquez-Borsetti
et al., 2011), and within the DRN these projections terminate on the
same cells innervated by the lateral habenula (Varga et al., 2003).
These effects parallel the observation that when negative informa-
tion is reappraised positively by human volunteers, the extent to
which increased activity in the ventral PFC results in a decrease in
negative emotion depends on the extent to which activity decreases
in the amygdala and increases in the nucleus accumbens (Wager
et al., 2008). The stimulation of the habenula by stress activates
2341
the amygdala, leading to an increase in the salience of aversive
stimuli, and inhibits the nucleus accumbens, leading to a decrease
the salience of appetitive stimuli; and the descending control of
those processes by the PFC identifies the PFC as the site at which
the events that result in an episode of depression originate.
3.7. Rumination
This conclusion ties in with evidence that the ventromedial PFC
is the crucial region for processing self-related information. For
example this region is activated when people reflect on their own
internal state or on the thoughts or intentions of others, and when
they consider their own personality characteristics or receive social
feedback about themselves from others (Passingham et al., 2010;
Lemogne et al., 2012; Murray et al., 2011). Negative self-referential
schemes are a crucial feature of cognitive models of depression
(Beck, 1967; Gusnard et al., 2001). Damage to, or a low level of
activation in, the ventral PFC is associated with an inflated self-
concept (Beer et al., 2006; Beer and Hughes, 2010), suggesting that
an elevated level of activation in this area could be responsible for
the low self-esteem and sense of social inferiority that characterize
depression (Sloman et al., 2003; Gilbert, 2006).
Further, high activity in the medial PFC, as well as the amyg-
dala, is associated with a trait that is predominant in depressed
patients, mental rumination, the inability to interrupt the pro-
longed processing of negative emotions (Cooney et al., 2010; Siegle
et al., 2006). Rumination is associated with self-referential attri-
bution, self-referential appraisal and a failure of inhibition; and
a decrease in rumination by cognitive reappraisal results in a
decrease in medial PFC activity (Ray et al., 2005). Depressed patients
have been reported to show greater activation in the medial PFC and
ventral ACC during self-referential processing of negative stimuli,
which was correlated with the severity of depression (Yoshimura
et al., 2010). Rumination may be reflective (problem solving aimed
at alleviating distress) or brooding (passively dwelling on the iniq-
uity of one’s current state). Reflective and brooding rumination are
predictive, respectively, of lower and higher levels of depressive
symptomatology years later, suggesting that reflective rumina-
tion is an adaptive cognitive process but brooding is maladaptive
(Treynor et al., 2003).
The ventral ACC and ventromedial PFC are part of the default
mode network (DMN) of cortical and subcortical regions that are
active when an individual is awake but not focused on the out-
side world (Broyd et al., 2009; Lemogne et al., 2012). The DMN is
inhibited when engaged in externally focussed task performance
and preferentially activated when engaged in internally focussed
processes such as daydreaming and memory retrieval. We hypoth-
esize that when stress is perceived as uncontrollable (an appraisal
that may be reached rapidly as in a learned helplessness experi-
ment or slowly in real world conditions), this results in a decision
to disengage from externally focussed coping attempts, thereby
engaging the DMN, and enabling internally focussed rumination.
Rumination, under these conditions, is likely to focus on the cur-
rent adversity, and significantly, in depressed patients, increased
activity in the DMN is associated with higher levels of maladap-
tive depressive ruminations (brooding) and lower levels of adaptive
reflective ruminations, implying poorer coping (Hamilton et al.,
2011). Furthermore, unlike non-depressed controls, depressed
patients fail to deactivate the DMN when asked to reappraise
negative pictures as positive (Sheline et al., 2009). The processes
whereby depressed patients become “stuck in a rut” and unable
to self-regulate their emotional state (Holtzheimer and Mayberg,
2010) remain to be fully established. However, three processes
that are known to be involved include: a dysregulated subcortical
network and HPA axis; a self-sustaining vicious circle in which
attention to negative information promotes negative thinking and
2342 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
vice versa (Beck, 1967; Disner et al., 2011); and in the longer term,
stress-induced neurotoxicity.
3.7.1. Rumination and recovery
Several of the functional changes seen in depression have been
found to normalize with successful treatment. A consistent pattern
of decreased activity in amygdala and ventral PFC (particularly, the
ventral/subgenual/rostral ACC) and increased activity in the dor-
solateral and pregenual ACC has been reported in patients who
recovered from depression following successful treatment with
antidepressant drugs or ECT, but not in patients who failed to
respond to treatment (Phillips et al., 2003b; Savitz and Drevets,
2009; Hamani et al., 2011; Mayberg, 2009; Holtzheimer and
Mayberg, 2011; Pizzagalli, 2011). Similar changes were also seen
in depressed patients who responded to placebo treatment, though
fluoxetine and placebo had different effects in other brain regions
(Mayberg et al., 2002).
Not only does activity within the ventral ACC decrease with
successful drug treatment of depression, but also, a high level of
activity in prior to treatment is predictive of a successful response
to antidepressants (Mayberg et al., 1997; Pizzagalli, 2011). This
has been hypothesized to mean that the increased activity in the
ventral ACC may reflect a greater proclivity to engage in adaptive
rumination (Pizzagalli, 2011). Conversely, difficulties in deacti-
vating the ventral ACC and providing top–down regulation of the
amygdala might foster the emergence of maladaptive emotional
and self-focused rumination, leading to treatment nonresponse
(Pizzagalli, 2011). Furthermore, as expected given the reciprocal
relationships between the ventral “affective” and dorsal “cognitive”
systems, the difficulty of deactivating the ventral ACC in depres-
sion is associated with difficulty in activating the dorsal PFC during
resource-demanding cognitive tasks, resulting in impairments of
executive functioning, cognitive control and emotional regulation
(Ochsner and Gross, 2005; Pizzagalli, 2011).
However, the opposite relationship has been observed for
psychological treatments (Roiser et al., 2012): a low level of pre-
treatment activity in the ventral ACC was associated with a better
response to CBT (Siegle et al., 2006; Fu et al., 2007) or behavioural
activation (Dichter et al., 2010). Indeed, in contrast to the decreased
activity in the rostral ACC that characterizes the response to antide-
pressant treatment, metabolic activity in this region increased in
patients who responded to CBT (Kennedy et al., 2007; Mayberg,
2009; Hamani et al., 2011).
Although there are anatomical subdivisions within the rostral
ACC (Jones et al., 2005; Palomero-Gallagher et al., 2009) it seems
unlikely that this can explain the different patterns of response to
physical and psychological treatments because the sites suppor-
ting these two effects are intermingled (Roiser et al., 2012). The
difference between treatment modalities may rather depend upon
the extent to thinking is dominated by maladaptive rumination.
Given that increased activity in the ventral ACC is associated with
rumination (Cooney et al., 2010), the suppression of this activity by
antidepressants and other physical treatments may improve the
depressed person’s ability to disengage from emotionally negative
thoughts. Consistent with this account, brief (7-days) SSRI treat-
ment has been found to decrease metabolic responses to negative
self-descriptors in neurotic individuals at risk for depression (Di
Simplicio et al., 2011), an effect that may be mediated by 5HT1A
receptors (Hahn et al., 2012). However, a high level of rumina-
tion interferes with cognitive processes that are used in cognitive
behavioural therapy (CBT), such as shifting attention, disengage-
ment from negative thoughts, problem solving and other executive
functions (Ray et al., 2005; Joormann and Gotlib, 2008; Nolen-
Hoeksema et al., 2008), and may impact negatively on the outcome
of conventional CBT (Haeffel, 2010). Indeed, specific techniques
of ‘rumination-focussed CBT’ have been developed for this reason
(Watkins et al., 2011). If activity in the ventral ACC is low, then
these resources are available to be recruited during the course
of psychological treatments (DeRubeis et al., 2008). It is gener-
ally assumed that CBT interventions restore emotional control by
providing top–down inhibition of amygdalar responses to threat
(Egner et al., 2008; Pizzagalli, 2011; Roiser et al., 2012). The ventral
ACC is central to this process by virtue of its having more extensive
connections with the amygdala than other cortical regions (Price
and Drevets, 2010, 2012).
In contrast to the different response of the ventral ACC to physi-
cal and psychological treatments, similar changes were seen in the
ventromedial and orbital PFC following antidepressant drug treat-
ment and CBT, involving a normalization of both resting metabolic
activity and the response to emotional stimuli (Kennedy et al.,
2007; Mayberg, 2009). Thus, while the ventral ACC is a critical
region for antidepressant effects, it appears that depressed mood is
generated primarily by the ventromedial PFC (as described already
in Section 3.6).
3.8. Basal ganglia involvement in coping
As previously discussed, the ventral ‘affective’ circuit, involv-
ing the ventral and orbital PFC and the ventral ACC is involved
in the production of affective states, while the dorsal ‘cognitive’
circuit is important for executive function, including the effortful
regulation of affective states. But in addition to the mechanisms
discussed above, the failure of the dorsal PFC to regulate emotion
in depression, reflected in an inability to disengage from negative
information (Gotlib and Joormann, 2010), may also involve the dor-
sal striatum.
Activity in the ventral striatum (nucleus accumbens) is trans-
mitted to the dorsal striatum (caudate nucleus, putamen) via a
well-characterized DA-dependent ‘spiralling’ of efferent informa-
tion from ventral striatum to the substantia nigra and thence to
more dorsal striatal regions, so channelling information from limbic
to cognitive and finally to motor circuits (Haber, 2003; Haber and
Knutson, 2010). Through this circuit, blockade of DA transmission
in the ventral striatum (nucleus accumbens core) causes an increase
in DA function in the ventrolateral striatum but a further decrease
in DA function in the dorsal striatum (A. Cools, pers. comm.). The
dorsal striatum, via its projections to the midbrain, innervates the
dorsolateral prefrontal and dorsal cingulate cortical regions (Haber
et al., 2006), and thus occupies a nodal position for the integration
of emotional processes with cognitive control.
Pathological volume changes in the caudate nucleus and puta-
men of depressed patients have been reported, which are particular
prominent in late-life depression and treatment-resistant patients
(Bora et al., 2011; Shah et al., 2002; Pizzagalli et al., 2009), and
involve decreases in gray matter volume (Kim et al., 2008) and
neuronal density (Khundakar et al., 2011). The extent of anterior
caudate reduction in late-life depressed subjects was associated
with more severe depression (Butters et al., 2009), and may also
contribute to suicidal behaviour in severely depressed patients
(Ahearn et al., 2001; Dombrovski et al., 2011; Vang et al., 2010), by
impairing their emotional decision-making and thereby increasing
impulsivity (Wagner et al., 2011). Depressed patients also have a
low level of DA activity in the caudate nucleus, which may in part be
secondary to an impairment of DA transmission in the ventral stri-
atum, but is also related to an increase in MAO-A activity, the extent
of which is associated with the severity of psychomotor retardation
(Meyer, 2012).
Depressed patients have been reported to show enhanced
metabolic activity not only in the ventral ACC, but also in the
left putamen when attempting to disengage from negative words
(Eugene et al., 2010; Surguladze et al., 2005). The extent of alter-
ations in the connectivity of the caudate nucleus to other brain
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
regions was correlated with disease severity and duration in drug-
naïve first-episode patients (Zhang et al., 2011). Other studies have
suggested that metabolic changes in left caudate nucleus (Gabbay
et al., 2007) and deficits in its connectivity with the resting-state
default mode network (Bluhm et al., 2009) may be early mani-
festations of depression. Recovered depressed patients also show
increased activity in caudate nucleus to aversive stimuli, in contrast
to the decreased response to pleasant stimuli that is typically seen
in the ventral striatum (McCabe et al., 2009). Similarly, increased
activation of the ACC and caudate nucleus by negative stimuli,
which was suggested to reflect the effort to disengage from and
cope with the negative information, has also been reported in
unaffected relatives of depressed patients (Lisiecka et al., 2011;
Levesque et al., 2011). These studies suggest that an altered pat-
tern of dorsal striatal activation by negative stimuli is present not
only in depression but also in risk states for depression, and may
contribute to failure to cope.
In addition to the dopaminergic interaction between the ventral
and dorsal striatum described above, a second mechanism for this
interaction is provided by the innervation of the medial part of the
caudate nucleus by the ventral ACC. Rats exposed to CMS showed
atrophy of not only the ventral ACC but also the dorsomedial
striatum, together with hypertrophy of the dorsolateral striatum
(Dias-Ferreira et al., 2009). The dorsomedial striatum is implicated
in the acquisition and execution of goal-directed actions, whereas
the dorsolateral striatum is critical for habit formation (Tricomi
et al., 2004; Yin et al., 2005, 2006; Balleine and O’Doherty, 2010).
Consistent with this anatomy, rats exposed to CMS were unable to
regulate their behaviour in response to sudden changes in reward
contingencies, and continued to respond in habitual ways that were
no longer appropriate (Dias-Ferreira et al., 2009). These results
suggest that changes in information processing within the dorsal
striatum, more specifically, the balance of activity within the ACC-
innervated medial region that is involved in behavioural flexibility
and the lateral region that promotes habitual responding, could
go some way to explain the emotional problem-solving difficulties
(Gotlib and Joormann, 2010) that leave depressed patients “stuck in
a rut” (Holtzheimer and Mayberg, 2011), as well as the high comor-
bidity between depression and compulsive disorders (Dias-Ferreira
et al., 2009).
3.9. Summary: stress and depression in conditions of low
vulnerability
Fig. 3 provides a simplified picture of the anatomical systems
involved in affect regulation that are described above. The green
arrows describe a basic input–output pathway, in which incom-
ing stimuli are appraised by the amygdala and hippocampus and
information is transmitted to the basal ganglia where an appro-
priate response is generated. Affective information-processing
biases are generated by the serotonergic and dopaminergic inputs
to this system from the DRN and VTA, which are themselves
modulated by the lateral habenula (blue arrows). These biases
may be over-ridden by top–down control from the PFC (red
arrows).
The story so far is summarized in Fig. 4, which describes a first
episode of depression in a person with a weak depressive diathesis.
In these conditions, vulnerability to depression is low, and the onset
of depression is driven by exposure to high levels of stress, which
activate the HPA axis via the amygdala. When stress is prolonged
(for example, following an unreplaced loss) this is likely to lead to
an appraisal that coping attempts have been and will continue to be
unsuccessful. This decision, which may be reached rapidly or grad-
ually, involves computations carried out by a distributed network
of PFC regions, but is housed primarily within the ventromedial PFC.
It leads to a disinhibition of subcortical stress-responsive systems,
2343
Fig. 4. Stress and depression. The etiological role of stress in depression is medi-
ated by activation of the HPA axis, leading to functional, and later, morphological,
damage in the hippocampus that results in a widespread disruption of information
processing in the forebrain, with the detailed disruptions determining the specific
symptoms displayed.
in particular the DRN with a consequent increase in 5HT release
within the amygdala and further release of CRF from the hypothal-
amus and stimulation of the other elements of the HPA axis. As a
consequence of prolonged exposure to stress hormones, the hip-
pocampus undergoes neurotoxic damage, with a loss of synaptic
connectivity and disruption of information processing in the fore-
brain circuits in which the hippocampus participates. This broadly
involves increased activity within a system that includes, inter
alia, the amygdala and ventral PFC, and decreased activity within a
system that includes, inter alia, the dorsal PFC and nucleus accum-
bens; and the symptoms of depression arise from the enhancement
or inhibition of the information-processing roles of the affected
regions in the normal brain. (We should add that our discussion
has greatly simplified the complex anatomy of the forebrain and
has not addressed in any detail the differentiation of subregions
within the ventral and dorsal systems.)
3.10. Vulnerability to depression: 1. Kindling
The model described provides a basis against which to consider
the nature of vulnerability to depression, which, as outlined above,
arises from a variety of diatheses, one of the most potent of which
is prior experience of depression.
We noted earlier that there is evidence that the depressed brain
does not fully recover. For example hippocampal volume changes
persist after remission of symptoms (Neumeister et al., 2005; Cole
et al., 2010), as do reduced frontocingulate functional connectivity
(Aizenstein et al., 2009) and neurochemical abnormalities in the
ACC and PFC (Bhagwagar et al., 2006, 2008). Consistent with these
observations, there are reports of persistent cognitive (Bhalla et al.,
2006; Preiss et al., 2009) and sensory (Naudin et al., 2012) impair-
ments, and increased responsiveness to aversive stimuli (McCabe
et al., 2009), following recovery from a depressive episode. Persis-
tent cognitive and neurochemical changes are also seen in rodents
after recovery from CMS (Elizalde et al., 2008, 2010; Surgetj et al.,
2009).
Also as noted earlier, successive episodes of depression are
triggered by progressively weaker and weaker episodes of stress
(Stroud et al., 2011; Slavich et al., 2011). Recurrent episodes are
2344 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
also associated with more intense symptomatology (Robinson
and Sahakian, 2008): for example, recurrent patients displayed
more intense electrophysiological responses to negative words
(Nandrino et al., 2004) and a greater cortisol response to a chal-
lenge with the 5HT-releasing drug fenfluramine (Sher et al., 2004).
Because there are very few studies using animal models of recur-
rent depression, little is known about the mechanisms of this effect.
However, the persistent hippocampal damage following an episode
of depression could decrease the threshold at which stress acti-
vates the amygdala and engages the processes summarized in Fig. 4.
The amygdala may well be involved in the kindling effect across
repeated episodes of depression, given the extensive literature on
amygdala kindling in relation to epilepsy (Post, 2004).
It was recently reported that the kindling phenomenon was
particularly apparent in relation to a specific type of stressor, inter-
personal loss: over the first four episodes of depression, there
was a 65% decrease in the intensity of stress associated with
the loss that precipitated the episode (Slavich et al., 2011). No
such change was observed in the intensity of non-loss stressors
(though it is unclear whether this reflects a qualitative differ-
ence between social and non-social stressors or simply that the
intensity of non-social stressors was relatively low in this study).
Like other stressors, social defeat in animals is known to increase
circulating levels of inflammatory cytokines (e.g. Avitsur et al.,
2001, 2009). Social stressors such as rejection also increase lev-
els of inflammatory cytokines in people (Dickerson et al., 2009;
Slavich et al., 2010). The increasing potency of social stress to elicit
depression (Slavich et al., 2011), and the observation of a greatly
accelerated age-related increase in cytokine production among
carers, who experience chronic high levels of social stress (Kiecolt-
Glaser et al., 2003), raise the possibility that cytokine-induced
‘sickness behaviour’, which closely resembles the symptomatology
of depression (Weisler-Frank et al., 2005; Sharpley and Agnew,
2011), might play a relatively greater role in recurrent depressions
than in first episodes. This would have implications for treatment.
In addition to structural changes that promote physiologi-
cal sensitization, associative learning processes may also operate,
such that weaker stressors are able to elicit symptoms of depres-
sion by virtue of a prior association between the physiology of
stress and depressive cognitive processes (Robinson and Sahakian,
2008; Roiser et al., 2012). A similar explanation has previ-
ously been advanced in relation to the depressogenic effect of
reserpine-induced catecholamine depletion, which, like the effect
of tryptophan depletion is only seen in people with a history
of depression (Goodwin et al., 1972; Willner, 1985). Tryptophan
depletion caused different changes in the neural response to emo-
tional words in remitted depressive patients and healthy controls
(Roiser et al., 2009) and similarly, AMPT affected reward processing
differently in remitted depressive patients and healthy controls
(Hasler et al., 2009), suggesting that there might be trait-like
abnormalities of monoamine systems in depressive individuals.
The associative learning hypothesis makes a general prediction
that physiological processes that contribute to the symptomato-
logy of depression may be relatively innocuous in people who
have not experienced a depressive episode, but would act as
risk factors for a later episode if still present after recovery. For
example, as already described, increased levels of MAO-A activ-
ity have been reported in the brains of unmedicated early-onset
depressed patients, consistent with decreased levels of 5HT, NA
and DA (Meyer et al., 2006; Meyer, 2012), and this abnormal-
ity was not corrected by SSRI treatment (Meyer et al., 2009).
Subsequently, high levels of MAO-A activity in the PFC and ACC
following recovery from depression predicted a recurrent depres-
sive episode in the following 6 months (Meyer et al., 2009; Meyer,
2012), in the absence of other factors predictive of recurrence.
These results are consistent with the notion that the potency of
a chronic risk factor to contribute to the onset of a depressive
episode may be amplified by its association with an episode of
depression.
3.11. Vulnerability to depression: 2. Predisposition
Recent research has established that early life stress has endur-
ing effects on the adult brain, many of which closely resemble the
changes observed in the depressed brain, and which are therefore
likely to underlie the established cognitive and temperamental vul-
nerabilities to depression (Heim et al., 2008; Pechtel and Pizzagalli,
2011). For example, people who had been abused or institutional-
ized as children were more anhedonic than non-abused controls,
and they had decreased reward-related activity in the nucleus
accumbens (Dillon et al., 2009; Mehta et al., 2010). Adults who
have been traumatized as children also show greater electrophys-
iological responses to angry faces or voices (Pechtel and Pizzagalli,
2011), as well as a greater amygdalar response (Taylor et al.,
2006). A decrease in hippocampal volume is also seen in adults
who experienced childhood trauma (Heim et al., 2008; Pechtel
and Pizzagalli, 2011), and in one study, decreased hippocampal
volume was present in depressed patients who had experienced
childhood trauma, but absent in those who had not (Vythilingam
et al., 2002). Moreover, both hyperactivity of the amygdala and
dorsolateral prefrontal hypoactivity have been reported in non-
depressed people with a strong cognitive diathesis for depression,
a high level of hopelessness; indeed, among depressed patients,
hopelessness was more strongly associated than severity of depres-
sion with these functional changes (Zhong et al., 2011). A decrease
in 5HT transporters has also been reported in the dorsolateral PFC
of non-depressed people with a genetic diathesis for depression (a
depressed co-twin: Frokjaer et al., 2009).
As in depression itself, these neurological vulnerabilities to
depression may result from dysregulation of the HPA axis. Many
studies in children and adults have reported that early life stress
leads to a more reactive HPA axis, which probably results from
a decreased expression of glucocorticoid receptors with a conse-
quent decrease in inhibitory feedback control (Heim et al., 2008;
Essex et al., 2011; Wilkinson and Goodyer, 2011). Maternally sepa-
rated rats, an animal model of early life stress, show a similar HPA
dysregulation when adult (Rentesi et al., 2010), as well as decreases
in levels of BDNF, hippocampal cell proliferation and synaptic plas-
ticity (Aisa et al., 2009).
As with repeated experience of depression, these effects of early
adversity prime the brain to respond in a depressive manner to
lower levels of stress (Slavich et al., 2011). Genetic diatheses appear
to operate in a similar manner. The most studied of these effects is
a functional polymorphism in the promoter region of the serotonin
transporter gene, 5HTTLPR, which has been reported to moderate
the effects of stressful life events on depression (Caspi et al., 2003,
2010; Uher and McGuffin, 2008). While one meta-analysis failed to
confirm this effect (Risch et al., 2009), a subsequent, larger meta-
analysis supported the original finding, but in relation to chronic
(family or medical) stress only, not to episodic life events (Karg
et al., 2011). The same result was reported in a recent prospective
study: the incidence of depression was increased under conditions
of chronic (but not episodic) stress by the presence of the short
allele of the 5HTTLPR gene (Jenness et al., 2011). The short allele
produces fewer 5HT transporters and therefore clears 5HT from
the synapse less efficiently than the long allele, with the result
that the 5HT system responds less flexibly and is more coarsely
attuned to changes in demand (Belsky et al., 2009). Consistent
with this observation, individuals at high familial risk for mood
disorders had lower levels of 5HT transporter binding in the PFC
(Frokjaer et al., 2009). The short allele of the 5HTTLPR gene, as
well as a polymorphism of the 5HT1A receptor, was associated
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
with increased amygdala activation in depressed patients (Frodl
et al., 2008b; Furman et al., 2011; Munafò et al., 2008). Carriers of
the short allele have been reported to have increased HPA stress-
reactivity (Gotlib et al., 2008), suggesting that these effects may
result from a potentiation of 5HT action in the amygdala (Lowry
et al., 2008; Rozeske et al., 2011; Furman et al., 2011). Conversely,
carriers of the long allele respond better to treatment of depres-
sion with SSRIs (Serretti et al., 2007), probably, as discussed below,
by potentiating 5HT in the hippocampus. A polymorphism of the
BDNF gene has been reported to protect against the depressogenic
effect of the 5HTTLPR polymorphism (Pezawas et al., 2008) and
to potentiate the clinical response to antidepressants (Zou et al.,
2010).
Many post-mortem studies of depressed patients have reported
an increase in the density of cortical 5HT2A receptors, which
is associated with a decrease in 5HT release (Arango et al.,
1997). In an in vivo study, 5HT2A receptor density was correlated
with the severity of dysfunctional attitudes (Meyer et al., 2003;
Meyer, 2012). High levels of 5HT2A binding in the PFC were also
found in unmedicated patients following recovery from depres-
sion (Bhagwagar et al., 2006). This marker was correlated with
the degree of neuroticism, and in particular, the sub-trait of vul-
nerability, in non-depressed volunteers (Frokjaer et al., 2008), but
only in those at high familial risk for depression (Frokjaer et al.,
2010). Thus, while an increase in cortical 5HT2A receptors may be
a marker of the depressed state, it also appears to be a trait marker
of vulnerability to depression.
3.11.1. Animal models of vulnerability
Vulnerability to depression can also be studied in animal mod-
els (Willner and Mitchell, 2002b). Like depressed people, rats
bred to display helplessness are anhedonic (Vollmayr et al., 2004)
and show decreased activity in the dorsal PFC but increased
activity in the ventral ACC (Shumake et al., 2000) and lateral
habenula (Shumake et al., 2003), and other metabolic changes
that resemble those seen in depression (Shumake and Gonzalez-
Lima, 2003), as well as lower levels of 5HT uptake and BDNF
in the hippocampus (Aznar et al., 2010). A similar mouse model
has recently been described (Yacoubi et al., 2011). Vulnerability
can also be approached via the individual differences in suscep-
tibility to stress that exist naturally in a large rodent population.
For example, vulnerability to social defeat has been shown to be
mediated by increases in the electrical activity of DA-producing
neurons in the VTA (Krishnan et al., 2007), while resistance to
learned helplessness is mediated by induction of the gene encod-
ing the transcription factor FosB in the periaqueductal grey region
(Berton et al., 2007). A recently gene profiling study identified sev-
eral hundred genes that were differently regulated in vulnerable
and resistant mice characterized as vulnerable or resistant to CMS
(Strekalova et al., 2011), and as discussed further below, parallels
in gene and protein expression between vulnerability to CMS and
resistance to antidepressant treatment have also been reported
(Bisgaard et al., 2007; Wilkinson et al., 2009; Christensen et al.,
2011).
A third approach involves the generation of transgenic mice
with modification of genes associated with resilience or vulner-
ability. There are now many such examples. For example, knock-in
mice expressing the variant of the BDNF gene (Met-66 BDNF
homozygotus mice) that protects against depression in people
(Pezawas et al., 2008) show resilience in the social defeat depres-
sion model (but not in models of anxiety) (Krishnan et al., 2007;
Chen et al., 2006). Genetic disruption of the acid-sensing ion
channel-1a (ASIC1a) produced an antidepressant-like effect in the
forced swim test, which was reversed by restoring ASIC1a in the
amygdala of ASIC1a (−/−) mice (Coryell et al., 2009). Conversely,
mice lacking the prostate apoptosis response 4 (Par-4), a protein
2345
that is essential for the inhibitory effect of DA D2 receptors on cAMP
signaling, display a depression-like phenotype (Park et al., 2005). A
similar effect was reported in two lines of knockout mice deficient
in the sigma1 receptor (Sabino et al., 2009). Depression-like phen-
otypes are also seen following genetic manipulation of the HPA
axis. For example, conditional mouse mutants overexpressing CRF
either in the entire central nervous system (CRH-COE-Nes) or only
in the forebrain (CRH-COE-Cam) both displayed increased rapid eye
movement (REM) sleep, which is a characteristic symptom of major
depression (Kimura et al., 2010). Mice deficient in CRF2 receptors
(CRF2−/− mice) also display depressive-like behaviours, accom-
panied by increased hippocampal levels of a variety of activated
(phosphorylated) protein kinases (Todorovic et al., 2009). Finally,
depressive-like behaviour is seen in ovariectomized ER␤ knockout
mice (Rocha et al., 2005), which seems to be mediated by hip-
pocampal estrogen receptors as intra-hippocampal administration
of estrogenic compounds elicits an antidepressant-like effect (Walf
and Frye, 2007). For the majority of genes that have been reported
to influence vulnerability in animal models that reproduce aspects
of depression, it is not yet known whether they are also of clinical
relevance.
3.11.2. The vulnerability brain and the depressed brain
While the evidence base concerning the mechanisms underlying
vulnerability to depression is less complete than that for depression
itself, the available evidence indicates strongly that both repeated
experience of depression and other diatheses – both experien-
tial and genetic – prime the brain to enter a state of depression
more readily by reproducing some of the neurobiological features
of depression. These parallels between the vulnerable brain and
the depressed brain are observed both in the clinic and in animal
models of depression. As a result of this priming, and the conse-
quent depression-like brain changes, depressions that occur in the
presence of a strong diathesis may be precipitated by lower levels of
stress, and accompanied by a smaller physiological stress response.
The treatment implications of this different physiology are illus-
trated by a study comparing the effectiveness of treatment of
depression with a serotonergic antidepressant (nefazodone), CBT,
or their combination. In patients with a weak depressive diathesis
(no early life stress), the drug treatment was somewhat better than
CBT and the effects were additive for the combination treatment.
However, in patients who had experienced early life stress, CBT
was significantly better than nefazodone, and adding nefazodone
to CBT did not improve the outcome. This result was interpreted
to suggest that psychotherapy might be an essential element of
treatment for depressed patients with childhood trauma (Heim
et al., 2008). An alternative interpretation is that the effectiveness
of some antidepressants may depend on the extent to which the
patient is currently stressed. We return to this issue below.
4. Mechanisms of antidepressant action
4.1. Potentiation of monoamine transmission
Antidepressant drugs are assumed to act primarily via
monoaminergic mechanisms, but there has been considerable
debate in the literature as to whether they potentiate transmission
at monoaminergic synapses, as originally proposed, or decrease it
(Segal et al., 1974). However, neurotransmitter depletion studies
provide strong evidence that the primary action of antidepressant
drugs is as conceived originally: enhancement of neurotransmis-
sion at 5HT and NA synapses. As discussed earlier (Section 2), in
both human and animal studies, the effects of SSRIs are blocked
by antagonizing transmission at 5HT synapses, while the effects
of NRIs are blocked by antagonizing transmission at NA synapses.
2346 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
As to the location of the relevant synapses, there is evidence that
antidepressant actions can be antagonized by various interventions
within the hippocampus (reviewed below) or prefrontal cortex
(Furr et al., 2011; Bondi et al., 2010).
The clinical selectivity of 5HT depletion for 5HT-selective
antidepressants (Delgado et al., 1990, 1999) and NA depletion
for NA-selective antidepressants (Delgado et al., 1993; Miller
et al., 1996) also demonstrates another important point: that 5HT-
and NA-selective antidepressants act via different mechanisms,
involving 5HT synapses and NA synapses, respectively. Studies of
antidepressant action in animal models of depression replicate
these effects. 5HT depletion reliably blocks the effects of SSRIs in
animal models of depression without affecting the action of NRIs.
Studies of NA depletion show essentially the opposite pattern:
blockade of the action of NRIs but not SSRIs (Lucki and O’Leary,
2004), albeit that these effects are less consistent: for example,
mutant mice deficient in NA do not respond either to NRI or to SSRI
(Cryan et al., 2004), which may reflect the fact that 5HT cells in the
DRN are silent in the complete absence of a tonic NA input from
the locus coeruleus, mediated through alpha1-adrenergic recep-
tors (Gartside et al., 1997; Tremblay and Blier, 2006). A limitation
of these studies is that they involved acute antidepressant treat-
ment in models (the forced swim and tail suspension tests) that
are useful as antidepressant screening tests, probably because they
mainly reflect the enhanced activity of monoaminergic systems in
the normal rodent brain, but have low validity as models of depres-
sion (Willner and Mitchell, 2002a). However, similar effects have
been described in the more valid CMS model: chronic treatment
with the SSRI citalopram and the NRI desipramine reversed dis-
tinct cognitive impairments in animals subjected to CMS, which
were blocked by acute antagonism of transmission at 5HT and NA
synapses, respectively (Furr et al., 2011; Bondi et al., 2010).
While actions of different classes of antidepressant drug origi-
nate at different sites, the various cortical or subcortical routes to
antidepressant action converge at a point downstream from the pri-
mary actions at 5HT and NA synapses. For example, after chronic
treatment, antidepressants of all classes increase the responsive-
ness of D2 DA receptors in the nucleus accumbens, the terminal
integrative area of the mesolimbic DA system (a specific effect
that is not seen in other brain regions). The functional signifi-
cance of this effect has been investigated using the CMS model.
In a series of studies, the recovery from CMS-induced anhedo-
nia following antidepressant treatment was reversed by an acute
challenge with low doses of D2 receptor-blocking drugs. This low
level of D2 antagonism reversed the action of SSRI, NRI or mixed
5HT-NA uptake inhibitors, while having no effect in non-stressed
or non-antidepressant-treated animals (Muscat et al., 1990, 1992;
Sampson et al., 1991). Significantly, like the effects of 5HT and NA
synthesis blockade described above, the effect of D2 receptor block-
ade is also seen in patients: as already seen in Fig. 2, administration
of a low dose of the D2 blocker sulpiride caused a profound return
of depressed mood in depressed patients successfully treated with
SSRIs (Willner et al., 2005).
As antidepressants do not affect DA uptake (except in the PFC,
where the effect is seen reliably only on acute administration, and
reflects the fact that in PFC, DA is cleared from synapses primarily
by the NA transporter: Tanda et al., 1996), the DA-antidepressant
interaction probably occurs indirectly. As illustrated in Fig. 3, the
ascending 5HT (and NA) projections terminate within the three
structures that have been identified as the predominant players
in our current understanding of the neuronal network underly-
ing depression, the hippocampus, amygdala and PFC, all of which
project to the nucleus accumbens, where their projections ter-
minate in partially overlapping fields, and to some extent on
the same cells (particularly within the nucleus accumbens shell:
French and Totterdell, 2002, 2003), that are innervated by the
mesolimbic DA system (Cador, 1992; Humphries and Prescott,
2010; Sesack and Grace, 2010; Haber and Knutson, 2011). This cir-
cuitry provides the basis for the role of the nucleus accumbens
as a ‘limbic-motor interface’, in which DA controls the transmis-
sion of information from limbic forebrain structures to the motor
system (Mogenson et al., 1980) feeding forward into the dor-
sal striato-pallido-thalamic-prefrontal psychomotor loop that has
been characterized in both humans and animals (Haber and Knut-
son, 2011; Humphries and Prescott, 2010). The expression and
functional sensitivity of DA D2 receptors in the nucleus accum-
bens is decreased by CMS and restored by antidepressant treatment
(Dziedzicka-Wasylewska et al., 1997), suggesting that the interac-
tion between DA antagonists and antidepressants (Fig. 2) occurs
via a primary action of antidepressants in hippocampus, amygdala
or PFC, leading to changes in the output to the nucleus accumbens
that in turn modulates DA D2 receptor sensitivity (Willner, 1997b).
4.2. Post-transductional mechanisms of antidepressant action
Fig. 5 summarizes the post-synaptic mechanisms engaged by
an increase in synaptic concentrations of monoamines. With the
single exception of the 5HT3 receptor, the synaptic actions of
5HT and NA are mediated by their binding to G-protein coupled
receptors that stimulate or inhibit synthesis of the intracellular sec-
ond messenger cyclic AMP (cAMP). This leads in turn to changes
in the activity of protein kinase A (PKA), which interacts in a
complex fashion with other protein kinases (MAPK and CaMK),
resulting in changes in the activity of the nuclear transcription
factor cAMP response element-binding (CREB). Following chronic,
but not acute, administration, antidepressants of all classes have
been found to increase the expression of CREB in the hippocampus
(Nibuya et al., 1996). The control of CREB expression is relatively
well understood, but the precise mechanisms by which antide-
pressants stimulate CREB remain uncertain (Tardito et al., 2006).
However, three relevant observations are that: the critical recep-
tor for 5-HT-mediated effects is the 5HT1A receptor (Santarelli
et al., 2003); 5HT1A-receptor activation inhibits PKA but stimu-
lates MAPK (Polter and Li, 2010); and inhibition of the MAPK
pathway blocked the effects of both serotonergic and noradren-
ergic antidepressants in the forced swim test (Duman et al., 2007).
According, it appears that the MAPK pathway is responsible for the
effect of antidepressants to increase CREB expression. Conversely,
CREB expression was decreased, in the dentate gyrus of the hip-
pocampus specifically, in anhedonic rats subjected to CMS (Grønli
et al., 2006). CREB expression has also been found to be decreased
in post-mortem studies of depressed suicide victims; conversely,
CREB expression was increased by pre-mortem antidepressant
treatment (Pittenger and Duman, 2008). In animal models, over-
expression of CREB produces antidepressant-like effects (Blendy,
2006). However, these effects are region-specific, as desipramine
and fluoxetine both decreased CREB function as well as CREB-
regulated target gene expression in the nucleus accumbens, and
blocked the effects of stress (Chartoff et al., 2009), while inhibition
of CREB in this brain region produces an antidepressant-like effect
(Newton et al., 2002). Thus CREB appears to have opposite func-
tions in the hippocampus (antidepressant) and nucleus accumbens
(pro-depressant).
CREB is a member of a much larger family of structurally and
functionally related transcription factors, which also include iso-
forms of cAMP response element modulator (CREM), ICER and
activating transcription factors (ATFs). These proteins can homo-
dimerize or heterodimerize to regulate gene transcription. ATF2,
ATF3, and ATF4 are all induced by stress in the nucleus accumbens
and their viral-mediated over-expression in the accumbens induces
emotion-related behaviours: over-expression of ICER or of ATF2
elicits depressive-like behaviours while over-expression of ATF3
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371 2347

Fig. 5. Cellular and molecular mechanisms of antidepressant action (red arrows). Antidepressants act by increasing levels of 5HT (blue circles) and/or NA (green circles),
which is generally achieved via inhibition of the 5HT and/or NA transporters. Serotonin then binds to 5-HT2B positive (stimulatory) auto-receptors located in the raphe
nuclei and to 5-HT1A, 5-HT4 and 5-HT7 post-synaptic receptors within the hippocampus, as well as to 5-HT1A receptors located on hippocampal neural progenitor cells.
NA binds to ␣2 auto-receptors located in the locus coeruleus, and to hippocampal ␤-adrenergic receptors. Within the post-synaptic hippocampal neurons, activation of
both serotonergic and noradrenergic receptors elicits activation of a cytoplasmic cascade of intracellular messengers. ␤-adrenergic receptors as well as 5-HT4 and 5-HT7
receptors are coupled to Gs, so their stimulation will sequentially activate cAMP and PKA. On the other hand, 5-HT1A receptors are coupled with Gi or Gq, which activates
Ca2+-dependant cascades as well as MAPK. All of these pathways lead to phosphorylation of CREB in the nucleus of the cell, which induces transcription of the BDNF gene
into pro-BDNF. In the cytoplasm, pro-BDNF will mature into mBDNF which is then trafficked to dendrites and axons. Once released, mBDNF binds to TrkB receptors located
on neural progenitor cells, which will contribute to the maturation of these cells and their differentiation into new hippocampal neurons. The following actions have been
shown to be essential for the neurogenetic and depression-relevant behavioural effects of SSRIs: stimulation of 5HT2B auto-receptors; inhibition of synaptic 5HT uptake;
stimulation of post-synaptic 5HT1A receptors, and stimulation of MAPK, CREB, and BDNF. In parallel, antidepressants inhibit membrance pumps such as MDR-PGP and
so increase access of Gc to the brain, resulting in a raised intracellular level of glucocorticoids (Gc), which bind to glucocorticoid receptors (GR). (These effects have been
demonstrated in embryonic stem cells. The figure assumes that a similar process occurs in neural progenitors. It is unknown whether this also takes place in mature neurons.)
Upon binding, GR activate PKA, leading to increased neurogenesis (probably via the CREB-BDNF pathway). GR also translocate to the nucleus, where the activated receptor
can activate or repress transcription of specific genes, which inter alia causes a resensitization of GR.

and ATF4 has the opposite effect (Green et al., 2008). Induction of
CREB in the basolateral amygdala produced an antidepressant-like
response in the learned helplessness model, similar to the effect in
the hippocampus: (Wallace et al., 2004).
CREB regulates the activity of a number of genes, with con-
sequent changes in the production of several proteins, the most
studied of which is brain-derived neurotrophic factor, BDNF. Like
CREB, hippocampal BDNF and BDNF mRNA levels are decreased
by chronic stress, and increased by antidepressant treatment,
although an increase in the BDNF protein is not always seen (Nibuya
et al., 1995; Russo-Neustadt et al., 1999; Coppell et al., 2003;
Molteni et al., 2006; Duman and Monteggia, 2006; Castrén et al.,
2007; Martinowich et al., 2007). Also like CREB, BDNF levels are
decreased in the brains of suicide victims studied post-mortem,
but increased by pre-mortem antidepressant treatment (Karege
et al., 2005; Pittenger and Duman, 2008). An increase in hippocam-
pal BDNF mRNA levels is also observed after electroconvulsive
shock treatment (Nibuya et al., 1995; Duman and Vaidya, 1998;
Zetterström et al., 1998). These effects parallel the clinical effects,
as increased BDNF is observed only after chronic antidepressant
treatment, with the exception of ECT, where the effect is seen more
rapidly.
The BDNF gene contains several exons that can be alterna-
tively spliced to form different mRNA transcripts, all coding for an
identical BDNF protein. Social defeat induces a severe decrease in
hippocampal BDNF mRNA levels that is mediated via the decreased
expression of only two of the transcripts (III and IV). Interest-
ingly, the effect of chronic imipramine to oppose the decrease
in hippocampal BDNF mRNA is also mediated via the same two
transcripts. The effect of social defeat relates to an increase in
histone H3-K27 dimethylation at the Bdnf P3 and P4 promoters
with no change at the other Bdnf promoters. However, chronic
imipramine does not reverse this effect as it increases BDNF expres-
sion via a different mechanism, H3-K9 dimethylation that is not
altered by chronic stress (Tsankova et al., 2006). This means that
chronic imipramine and chronic stress act via different mechanisms
2348 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
at the level of histone dimethylation. This again suggests that a
depression-like signature is still present in the hippocampus after
successful antidepressant therapy.
The response to antidepressant treatment in the forced swim
test was blocked in mutant mice with full or forebrain-specific
impairment of either BDNF or its receptor, Trk-B (Saarelainen et al.,
2003; Monteggia et al., 2004; Deltheil et al., 2008; Ibarguen-Vargas
et al., 2009). A region-specific knock-down of BDNF in the den-
tate gyrus or ventral subiculum of the hippocampus (but not in
the CA1 or CA3 fields) also induces depression-like behaviour and
confers resistance to the effects of antidepressant drugs such as
desipramine and citalopram (Adachi et al., 2008; Taliaz et al.,
2010). Conversely, a single BDNF infusion into the hippocampus
has been reported to produce a long-lasting recovery of depressive-
like behaviours in the learned helplessness model of depression,
comparable to that produced by chronic systemic antidepressant
treatment (Shirayama et al., 2002). In contrast to these effects in
the hippocampus, BDNF increases depression-like behaviour when
injected into the VTA, while inhibition of BDNF signaling in the
nucleus accumbens has the opposite effect (Eisch et al., 2003;
Berton et al., 2006a,b; Krishnan and Nestler, 2008). So like CREB,
the effects of BDNF are region-specific, with opposite effects in
the hippocampus and nucleus accumbens. However, chronic sys-
temic BDNF treatment has antidepressant-like effects (Schmidt and
Duman, 2010), suggesting that the effect in the hippocampus pre-
dominates.
CREB also regulates the expression of another neurotrophin,
vascular endothelial growth factor (VEGF) (Lee et al., 2009). Simi-
lar to BDNF, VEGF expression in the hippocampus is decreased by
stress and increased by chronic antidepressant treatment; block-
ade of VEGF receptors antagonized the behavioural effects of
antidepressants; and VEGF infusion into the lateral ventricle had
antidepressant-like effects (Warner-Schmidt and Duman, 2007;
Pittenger and Duman, 2008). The fact that antagonism of hippocam-
pal expression of either BDNF or VEGF was sufficient to block
antidepressant action suggests that an increased stimulation of
both of these neurotrophins may be required. There is evidence
suggesting that hippocampal levels of several other neurotrophins
are also increased by chronic antidepressant treatment, (Schmidt
and Duman, 2007): some of these effects might similarly turn out
to be obligatory.
4.3. Neurogenesis
Neurotrophins have multiple roles in the developing nervous
system and also in the adult brain; they influence synaptic plas-
ticity, the morphology of dendritic spines, and the proliferation,
differentiation and survival of neurons (Kandel, 2001; Schmidt and
Duman, 2007). In the adult mammalian brain, new neurons are
found mainly in the dentate gyrus of the hippocampus, and to
a lesser extent the olfactory bulbs, although some evidence sug-
gests that neurogenesis may also occur in other areas, including
the hypothalamus, amygdala, neocortex, piriform cortex, substan-
tia nigra and striatum (Gould, 2007). In the subgranular zone of
the dentate gyrus, new adult neurons originate from a process that
includes different stages: first, Type-1 cells (radial-glia-like stem
cells) divide, which enables them to maintain themselves (by pro-
ducing other Type-1 cells) as well as to generate Type-2 daughter
cells (neural progenitor cells). These divide symmetrically produc-
ing Type-3 cells (neuroblasts) which migrate into the granule cell
layer. Type-4 cells are post-mitotic: they extend axons toward the
CA3 region, leading to the development of mature granule cells.
Chronic administration of BDNF directly into the hippocam-
pus increases neurogenesis (Scharfman et al., 2005), which, as
discussed earlier, is suppressed by chronic stress (Samuels and
Hen, 2011; Hanson et al., 2011). Chronic peripheral injection
of BDNF also increases survival of newborn hippocampal cells
(Schmidt and Duman, 2010). Chronic antidepressant treatments
also increase hippocampal neurogenesis. This effect occurs only in
the dentate gyrus of the hippocampus, but not in other regions
that support neurogenesis (Surget et al., 2008). It is seen not only
with commercially available antidepressants, but also with puta-
tive antidepressants from very different pharmacological classes,
including not only antidepressants that act at monoaminergic tar-
gets (Malberg et al., 2000; Manev et al., 2001) but also compounds
acting via non-monoaminergic pathways, such as glutamatergic
ligands (Yoshimizu and Chaki, 2004), the synthetic cannabinoid
HU210 (Jiang et al., 2005), tianeptine (Czéh et al., 2001; McEwen
et al., 2002), compounds acting on the stress axis such as CRF1
or vasopressin V1b receptor antagonists (Alonso et al., 2004),
or a melanin-concentrating hormone (MCH) antagonist (David
et al., 2007). This stimulant effect of antidepressant-like treat-
ments on hippocampal neurogenesis was also observed with
non-pharmacological therapies, such as electroconvulsive therapy
(Malberg et al., 2000) or vagus nerve stimulation (Revesz et al.,
2008). Increased hippocampal neurogenesis is also seen following
other treatments that have antidepressant-like effects in rodents,
such as physical excercice (van Praag et al., 1999; Kronenberg et al.,
2003) or rearing in enriched environments (Kronenberg et al., 2003;
Veena et al., 2009; Schloesser et al., 2010). The stimulant effect of
antidepressants on neurogenesis that is observed in adult rodents
is not seen in very young or very old animals (Hodes et al., 2009;
Couillard-Despres et al., 2009), and this might be relevant to antide-
pressant treatment resistance in children and older adults. Inbred
mouse strains have been reported to vary in the extent to which
neurogenesis was stimulated by fluoxetine, and this effect was seen
only in strains that also showed a positive behavioural response to
antidepressant treatment (Miller et al., 2008). Significantly, these
effects require chronic treatment consistent with the clinical situ-
ation. Antidepressant treatment has also been reported to increase
neurogenesis in the human hippocampus, studied post-mortem
(Boldrini et al., 2009).
Interestingly, neuronal progenitors and immature neurons
express the BDNF receptor TrkB, and conditional deletion of the
TrkB gene in these cells both decreases their proliferation and
survival, and suppresses the effects of antidepressant dugs on pro-
liferation and survival (Sairanen et al., 2007; Bergami et al., 2008;
Li et al., 2008). This demonstrates that BDNF mediates the stimu-
lation of neurogenesis by antidepressants. Similarly, central VEGF
infusion increases cell proliferation and the survival of immature
neurons (Jin et al., 2002; Warner-Schmidt and Duman, 2007). Fur-
ther, VEGF knockout mice have lower levels of hippocampal cell
proliferation and immature neurons (Sun et al., 2006), while viral-
mediated VEGF over-expression has the opposite effect (Cao et al.,
2004). It is therefore likely that the involvement of VEGF in the
effect of antidepressants is also via its effect on neurogenesis.
4.3.1. The pathway from synapse to neurogenesis
Stimulation of monoamine transmission is required for antide-
pressants to increase neurogenesis. Behavioural and neurogenetic
effects of SSRIs are absent in mice after genetic or pharmacological
inactivation of the 5HT2B receptor, which is a positive (stimu-
latory) autoreceptor situated on 5HT cell bodies, the absence of
which prevents SSRIs from increasing synaptic 5HT concentra-
tions (Diaz et al., 2012). Under normal conditions, serotonergic
antidepressants increase neurogenesis by increasing the impact
of 5HT at 5HT1A receptors: neurogenesis is positively correlated
with levels of 5HT in the hippocampus (Brezun and Daszuta, 1999,
2000; Banasr et al., 2004; Radley and Jacobs, 2002), and the effect
of the SSRI fluoxetine was absent in mutant mice lacking the
5HT1A receptor (Santarelli et al., 2003). These mice continued to
respond to tricyclic antidepressants, presumably acting through
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
noradrenergic mechanisms (Santarelli et al., 2003). However,
the noradrenergic system is also involved in neurogenesis, as
cell proliferation in the subgranular zone is decreased by NA
depletion while noradrenergic stimulation has the opposite effect
(Kulkarni et al., 2002; Rizk et al., 2006). Further, the proneurogenic
action of imipramine is speeded by blockade of ␣2 -adrenoceptor
receptors using yohimbine (Yanpallewar et al., 2010). Conversely,
the ␣2 -adrenoceptor agonists clonidine and guanabenz decrease
adult hippocampal neurogenesis through a selective effect on the
proliferation, but not the survival or differentiation of progenitors
(Yanpallewar et al., 2010), while ␣2 -adrenoceptor antagonists such
as dexefaroxan have the opposite effect (Rizk et al., 2006). As these
effects persist in dopamine ␤-hydroxylase knockout (Dbh−/− ) mice
(which lack NA) it has been suggested that they are related to the
presence of ␣2 -heteroceptors on progenitor cells.
As illustrated in Fig. 5, taken together, these studies confirm
that proneurogenic effect of chronic antidepressant administration
operates via (1) inhibition of 5HT or NA uptake, causing (2) stim-
ulation of 5HT1A and noradrenergic receptors with effects on (3)
intracellular second messengers and (4) protein kinases, leading to
increased expression of (5) CREB and (6) BDNF and VEGF, which (7)
stimulate neurogenesis.
4.3.2. Functional significance
The causal role of neurogenesis in antidepressant action has
been investigated in a series of studies using the CMS model, with
two behavioural endpoints, feeding in a novel environment and
grooming: both of these behaviours are suppressed by CMS and
reinstated by chronic, but not acute antidepressant treatment. Neu-
rogenesis was blocked by X-irradiation of the hippocampus, using
lead screens to shield other brain areas. X-irradiation of the hip-
pocampus also blocked the reversal of CMS-induced behavioural
changes by either the SSRI fluoxetine or the tricyclic antidepressant
imipramine (Santarelli et al., 2003; Surget et al., 2008, 2011). These
effects were also seen for physiological endpoints such as altered
negative feedback over the HPA axis: CMS attenuated the suppres-
sion of glucocorticoid release in a dexamethasone suppression test,
and fluoxetine restored normal HPA function in intact animals but
not in irradiated animals, demonstrating that the action of fluox-
etine required newly born hippocampal cells (Surget et al., 2011).
While X-irradiation blocked behavioural effects that are only seen
after chronic antidepressant treatment, it did not affect behavioural
effects of fluoxetine that are typically seen after acute administra-
tion (e.g. decreased immobility in the forced swim test) (David et al.,
2009). The opposite manipulation, amplification of neurogenesis,
did not produce an antidepressant-like phenotype in the forced
swim and novelty-suppressed feeding tests (Sahay et al., 2011),
but this experiment was conducted in ‘non-depressed’ animals: the
effects of this manipulation in, for example, the CMS model have
not yet been explored.
Discrepant results have been reported when blockade of
neurogenesis was achieved pharmacologically, using the drug,
methylaxoxymethanol (MAM), rather than by X-irradiation. This
study examined three behavioural endpoints in the CMS model,
anhedonia (decreased sucrose preference), increased immobility in
the forced swim test, and novelty-suppressed feeding. MAM abol-
ished the effect of antidepressant drugs on neurogenesis, but did
not interact with antidepressants on any of the behavioural meas-
ures (Bessa et al., 2009). However, this is probably related to the
experimental protocol used in this study, as MAM was applied
during the 2 weeks of antidepressant treatment, in contrast to
X-irradiation which was applied several weeks earlier (Santarelli
et al., 2003; Surget et al., 2008, 2011). When MAM was adminis-
tered during the 2 last weeks of the antidepressant treatment, but
behavioural testing was delayed until 4 weeks later, the antidepres-
sant effect was blocked (Mateus-Pinheiro et al., 2011), consistent
2349
with the effects seen following X-irradiation. This suggests that a
degree of maturation, to the point when the new cells are forming
effective synaptic connections, is necessary for a new cell to con-
tribute to the therapeutic action of antidepressant drugs.
While neurogenesis appears to play a critical role in antidepres-
sant action, blockade of neurogenesis, using X-irradiation or genetic
tools, does not in itself induce a depressive phenotype (Santarelli
et al., 2003; Airan et al., 2007; Bessa et al., 2009; Holick et al., 2008;
Revest et al., 2009; Samuels and Hen, 2011; Surget et al., 2008,
2011). This is not particularly concerning, because, as discussed
above, a depressive diathesis is only activated in the presence of
stress. Of greater concern, X-irradiation also did not influence sus-
ceptibility to stress (Santarelli et al., 2003; Surget et al., 2008, 2011),
and CMS decreased neurogenesis equally in both CMS-sensitive and
CMS-resilient animals (Jayatissa et al., 2010). But again, this would
be expected if neurogenesis is involved primarily in repairing dam-
age to the hippocampus. One recent study, using a genetic model
that reduced neurogenesis in both the hippocampus and in the
olfactory bulbs, reported that this did not cause a depressive-like
behaviour per se, but did increase stress-responsiveness (a pro-
longed increase in corticosterone) and depressive-like behaviours
when confronted with an acute stress (30 min restraint) (Snyder
et al., 2011). However, the stress-responsiveness seen in this study
could be related to peripheral side effects associated with both the
genetic model (Bush et al., 1998), and the drug used to initiate the
suppression of neurogenesis (Wei et al., 2011). The opposite effect
was not found using a genetic model in which adult neurogenesis
was increased (Sahay et al., 2011).
In addition to increasing neurogenesis, chronic antidepressant
treatment has also been reported to increase dendritic arborisation
in the hippocampus (Wang et al., 2008), and to increase the expres-
sion of plasticity-related proteins, including neural cell adhesion
molecule (NCAM) in the hippocampus and medial PFC. The study of
Bessa et al. (2009) found that, while MAM abolished neurogenesis,
it had no effect on other trophic effects of antidepressants. Specifi-
cally, CMS decreased the volume of both hippocampus and medial
PFC, which was associated with atrophy of the dendrites of pyrami-
dal cells, involving shortening and loss of dendritic spines. CMS also
decreased expression of the genes coding for NCAM in hippocam-
pus and PFC, and another plasticity protein, synapsin 1 in prefrontal
cortex. All of these changes were normalized by chronic antidepres-
sant treatment. This study provides support for the importance of
structural changes in the hippocampus and medial PFC in depres-
sion and antidepressant action. Indeed, since newly born neurons
need to mature for several weeks before their presence is essential
for antidepressant action (Mateus-Pinheiro et al., 2011), it is likely
that these other trophic actions of antidepressants mediate their
short-term behavioural effects.
4.4. HPA axis
As discussed earlier, a critical event in the breakdown of
homeostatic regulation under conditions of prolonged stress and
consequent glucocorticoid over-exposure is a decrease in the
responsiveness of glucocorticoid receptors (GR) on hippocampal
granule cells, leading to disinhibition of the HPA axis and a fur-
ther increase in corticosteroid stimulation (Raison and Miller,
2003). Antidepressants normalize HPA function, and part of this
effect involves a restoration of GR responsiveness. This effect
is independent of the monoamine uptake-inhibiting actions of
antidepressants, because it is seen in neuronal cell cultures
(Okugawa et al., 1999; Anacker et al., 2011a). In embryonic stem
cells, antidepressants influence a number of intracellular signalling
systems in vitro and also inhibit cellular membrane pumps such as
the multidrug-resistant glycoprotein (MDR-PGP) (Yau et al., 2007).
Inhibition of MDR-PGP by antidepressants increases the access of
2350 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
glucocorticoids to the brain, increasing intracellular glucocorticoid
concentrations (Fig. 5), and leading, after some days of treatment, to
an increase in the sensitivity of GRs (Carvalho and Pariante, 2008).
The effect of chronic SSRI treatment to increase neurogenesis in
vitro was blocked by a GR antagonist, and was only seen in the pres-
ence of a GR agonist (Anacker et al., 2011b). These findings suggest
that restoration of GR responsiveness by chronic antidepressant
treatment, and their subsequent stimulation by glucocorticoids,
may be critical for stimulation of neurogenesis by antidepressants.
However, there is inconsistency between these in vitro findings and
the effects of antidepressants in vivo, since the in vitro effects are
mediated by an increase in intracellular levels of PKA (Anacker et al.,
2011b), but, as discussed earlier, in vivo SSRIs increase transmis-
sion at 5HT1A receptors, which decreases PKA levels (Polter and
Li, 2010). Consequently, the relevance to their clinical action of
these monoamine-independent effects of antidepressants, which
have been described in embryonic stem cells in vitro, is at present
unclear. Alternatively, these actions may indeed be relevant, but in
brain regions other than the hippocampus, such as the PFC.
4.5. Why are antidepressants slow to act?
The traditional account of the slow onset of antidepressant
action is that this relies on neurobiological effects that develop
slowly under chronic drug treatment, such as increases or decreases
in the sensitivity of populations of neuroreceptors, and/or intrin-
sically slow processes that depend on changing patterns of gene
expression, such as neurogenesis and synaptic remodelling. More
recently, an alternative ‘cognitive neuropsychological’ model has
been proposed, which posits that antidepressants cause relatively
rapid changes in the emotional information-processing biases,
but improvements in mood are slow because the patient must
first relearn emotional associations (Harmer, 2008; Harmer et al.,
2009a; Clark et al., 2009; Pringle et al., 2011; Roiser et al., 2012).
There is good evidence that some emotion-processing effects
of antidepressants may occur rapidly. Single doses of SSRI or NRI
antidepressants have been reported to increase the processing of
positive information in both healthy volunteers (Harmer et al.,
2003a,b; Browning et al., 2007) and depressed patients (Harmer
et al., 2009b). Single doses of SSRIs do not reverse negative
information-processing biases: on the contrary, responses to threat
are increased (Harmer et al., 2003a; Browning et al., 2007). This
probably results from a potentiation of 5HT release in the amyg-
dala, which, as discussed above, is a critical element of the response
to stress (Maier and Watkins, 2010), and may correspond to the
increase in anxiety reported by many patients in the first few days
of SSRI treatment, which counteracts the antidepressant effect of
5HT release in the hippocampus. However, a week of antidepres-
sant administration to volunteers did decrease threat responses
(Harmer et al., 2004), and also decreased amygdalar activation by
threat stimuli (Harmer et al., 2006). Though requiring repeated drug
treatment, these changes occur earlier than changes in mood are
typically reported.
Tryptophan-depletion studies provide a second line of sup-
port for the cognitive neuropsychological account of mood
disturbance. As discussed above, tryptophan depletion does not
generally impair mood in people who have never been depressed.
However, tryptophan depletion does produce a variety of nega-
tive information-processing biases in never-depressed volunteers
that resemble those reported in depressed patients (Harmer,
2008). As described above, it has been argued that during an
episode of depression, an association is learned between these
information-processing biases and low mood, such that subse-
quently, tryptophan depletion may evoke low mood via this
association (Harmer, 2008; Robinson and Sahakian, 2008).
However, while there is increasing evidence that normalization
of cognitive biases to emotional stimuli may represent an important
early stage in the normalization of the frontal brain circuits that are
disordered in depression, evidence that this serves as a platform
for relearning new adaptive associations, and that this relearning
is the critical event in antidepressant action, is presently lacking.
Two predictions can be derived from this hypothesis, neither of
which is well supported. First, if experience of altered affective
biases is essential for antidepressants to improve mood, then rapid
onset of antidepressant action should not be possible. However,
as discussed below, at least four treatments are known that do
have a rapid onset: DBS (Hamani et al., 2011), ECT (Sienaert, 2011),
intravenous ketamine (Zarate et al., 2006a,b), and REM-sleep depri-
vation, which is effective after a single night, albeit only until the
next sleep (Dallaspezia and Benedetti, 2011). Assuming that at least
some of these treatments resemble antidepressant treatment in
eliciting a positive affective bias, there is a potential associative
account of these effects: just as tryptophan depletion can acti-
vate a depressive schema by virtue of a prior learned association
between negative information-processing biases and low mood, so
antidepressant treatments might activate a non-depressed schema
by virtue of a lifelong association between positive information-
processing biases and high mood. But this account would apply
equally to conventional antidepressants, and does not depend on
experience gained while under the influence of antidepressant
drugs. The second prediction is that later episodes of depression
should be easier to treat than first episodes. This follows because the
association between drug-induced positive biases and improved
functioning has already been learned during the first episode,
and therefore should be easier to activate. However, as discussed
below, far from being easier to treat, later episodes of depression
become increasingly treatment-resistant. With the exception of
these ‘natural experiments’, the central tenet of the cognitive neu-
ropsychological model of antidepressant action, the critical role of
experience under drug treatment, has not yet been tested.
4.6. Treatment implications
The model developed in this review is summarized in
Figs. 4 and 6. As already described, Fig. 4 summarizes the processes
that follow an appraisal that stress is unmanageable, leading, via
prolonged exposure to high levels of corticosteroids, to a compro-
mised hippocampal-cingulate system with an increase in activity
of the ventral PFC and amygdala and a decrease in activity of the
dorsal PFC and nucleus accumbens, which mediate an increased
sensitivity to aversive events and a decreased response to rewards
(anhedonia), respectively. The effects of currently used monoamin-
ergic antidepressants (Fig. 6) are mediated primarily by stimulation
of serotonergic and noradrenergic synapses in the hippocampus,
which increases the production of neurotrophins and neurogene-
sis leading to reorganization and/or repair of the stress-induced
morphological damage, involving recently born neurons, and a
rebalancing of activity in forebrain circuits, with a normalizing
decrease in the impact of aversive events and increase in the impact
of rewards. These two sets of processes are largely independent:
antidepressants reinstate normal functioning but do not directly
counteract the effects of stress.
Like any model of this kind, this is, of course, an over-
simplification: for example, stress and antidepressants may also
affect other structures directly, in particular, the PFC, amygdala,
nucleus accumbens and habenula. Antidepressant effects have
been reported following direct injection of antidepressants into the
amygdala (Garrigou et al., 1981; Duncan et al., 1986; Shirayama
et al., 2011) and PFC (Sherman and Petty, 1980), or following
interventions targeted at the nucleus accumbens (Corrigan et al.,
2000; Krishnan et al., 2007), and DBS is clinically effective when
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371 2351

Fig. 6. How antidepressants restore the affective information-processing brain circuitry (cf. Fig. 3) that has been disrupted in depressed patients: the example of a SSRI. First
(step 1), the antidepressant increases serotonin concentrations (yellow points) in the median raphe nucleus (RN) as well as in the hippocampus (HPC). This stimulates the
release of neurotrophins such as BDNF (step 2) and hippocampal neurogenesis (step 3). As the new hippocampal neurons develop they increase not only the function of the
hippocampus, but also the function of hippocampal outputs (step 4). This modifies the function of areas to which the outputs of the hippocampus project (step 5) and thus
restores most parts of the system to an almost normal state. See legend to Fig. 3 for other abbreviations.

applied to the prefrontal cortex (Hamani et al., 2010, 2011), nucleus
accumbens (Schlaepfer et al., 2008; Bewernick et al., 2010; Grubert
et al., 2011) or habenula (Sartorius et al., 2010). As the habenula
is responsive to light and shows intrinsic circadian rhythmicity,
this is also a promising candidate for involvement in the antide-
pressant effects of light therapy (in seasonal affective disorder)
and REM (rapid eye movement) sleep deprivation (Dallaspezia and
Benedetti, 2011). While current antidepressants are thought to act
primarily within the hippocampus, it appears that actions at any
point within the circuitry associated with depression may in prin-
ciple promote recovery.
However, an implication of the same distributed circuitry is that
drug actions may be inconsistent at different sites within it, and
this creates both problems and opportunities. As discussed above,
it appears that stress and depression are associated with high levels
of 5HT activity in amygdala and PFC, but low levels in hippocam-
pus (Lowry et al., 2008; Elizalde et al., 2010; Rozeske et al., 2011).
Conversely, the effect of SSRIs to increase 5HT activity is benefi-
cial in hippocampus, but detrimental in amygdala and PFC, and
this may limit the effectiveness of SSRIs. The addition of a NRI
component or a DA reuptake inhibitor further increases 5HT lev-
els in hippocampus but restricts 5HT levels in the PFC, probably
because NA uptake inhibition also potentiates DA in PFC but not
elsewhere (Weikop et al., 2007a,b), which might explain the greater
efficacy of SNRIs such as venlafaxine. This example illustrates a
theoretical limitation for antidepressant drug development: that
peripherally administered agents are not anatomically specific in
their actions, and actions remote from the site of antidepressant
action may counteract the benefits. Perhaps problems of this kind
could be circumvented by using nano-technology to deliver drugs
to specific brain areas, but this intriguing prospect is not yet within
reach.
The possibility of achieving antidepressant effects at multiple
points within the depression circuitry provides a framework for
understanding both the mechanism of action of many putative
antidepressant drugs and their limitations. We consider here the
prospects for agents that promote neural repair, neuroprotective
drugs, and anti-stress agents.
As discussed above, agents that promote neural repair includ-
ing CREB, BDNF and other trophic factors such as VEGF, have
been reported to show antidepressant-like effects when adminis-
tered within the hippocampus (Blendy, 2006; Warner-Schmidt and
Duman, 2007; Pittenger and Duman, 2008). Histone deacetylase
inhibitors are another class of drugs that promote the expression
of plasticity-related gene expression, and these drugs have been
reported to elicit antidepressant-like effects when infused within
either the hippocampus or nucleus accumbens (Covington et al.,
2009, 2011). (Peripheral administration of these drugs has not
yet been studied, but might be expected to cause extensive side-
effects.) Estrogens, which have frequently, but inconsistently, been
reported to show clinical antidepressant effects and to potentiate
the effects of conventional antidepressants, also have neurotrophic
actions and increase the expression of BDNF within the hippocam-
pus (Estrada-Camarena et al., 2010). However, as noted above,
while BDNF has antidepressant-like effects in the hippocampus,
it causes exactly the opposite, pro-depressive effect when admin-
istered within the nucleus accumbens (Eisch et al., 2003; Berton
et al., 2006a,b), which potentially limits the usefulness of strategies
that target BDNF directly, albeit that peripheral administration of
BDNF to rats had antidepressant-like effects, including reversal of
CMS-induced anhedonia (Schmidt and Duman, 2010).
Neuroprotective agents have also been proposed as antide-
pressants. Because of its high level of oxygen consumption, the
brain is at particular risk from the toxicity caused by reactive
2352 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
oxygen species: high levels of oxidative stress have been reported
in post-mortem studies of the depressed brain, and antidepressants
decrease oxidative stress. However, while many anti-oxidants are
under preclinical investigation, including several of plant origin,
there is minimal evidence that anti-oxidants are clinically effective
as antidepressants (Ng et al., 2008). The situation is similar for the
neurosteroids dihydroepiandosterone (DHEA) and DHEA sulphate,
which include neuroprotection among their many neurochemical
actions: a relationship between plasma concentration and mood
has been reported, but the literature regarding their clinical efficacy
in depression is highly inconsistent (Maninger et al., 2009).
Many putative antidepressants act primarily as anti-stress
agents. For example, HPA antagonists counteract the neuroen-
docrine effects of stress, by inhibiting glucocorticoid synthesis,
antagonising receptors for corticosteroids, vasopressin or CRF, or
blocking the actions of inflammatory cytokines, release of which is
stimulated by corticosteroids (Holsboer, 2000). All of these drugs
have shown some antidepressant-like activity in animal models
of depression (e.g. Koo and Duman, 2009). A cytokine antagonist
has shown antidepressant activity in patients treated for psoria-
sis, but this effect is difficult to interpret because it accompanied
an improvement in their physical condition (Tyring et al., 2006).
HPA antagonists have also shown clinical antidepressant activity,
but so unreliably and with unacceptable side effects, that clinical
development was stopped (Schüle et al., 2009; Zorrilla and Koob,
2010). This outcome is particularly disappointing because patients
with elevated HPA activity as assessed by the cortisol response to a
combination of dexamethasone and CRH (Heuser et al., 1994) have
a poor prognosis (Paslakis et al., 2010).
A part of the reason so many novel compounds fail to progress
from animal models of depression into the clinic is that, in order
to be marketed, a new antidepressant would need to demonstrate
superiority to currently available drugs, in terms of onset of action,
efficacy, or side effect profile. Current drugs have a relatively benign
side effect profile, so the challenge for a new agent is to decrease
onset latency or to improve on efficacy, either by increasing the
therapeutic effect in patients who respond to treatment, or by elic-
iting a response in treatment-resistant patients. Phase 3 studies
to demonstrate such profiles will be lengthy and costly, and ani-
mal models with proven validity in relation to treatment-resistant
patients are lacking. HPA antagonists and neuroprotective agents
have not demonstrated superiority in these respects; rather, the
reverse. This unreliability could, of course, reflect the fact that the
role of stress in depression decreases with successive episodes
and with the strength of the depressive diathesis (Kendler et al.,
2001), and so in many people is minimal: indeed, only around
30% of depressed patients show a significant increase in CRF lev-
els (Arborelius et al., 1999). Perhaps anti-stress measures would be
more effective early in the course of depression, and particularly,
in first episodes of depression in people with a weak diathesis, in
whom the effect of stress is most pronounced. However, according
to the current understanding of antidepressant action, the mech-
anism by which anti-stress agents achieved their antidepressant
effect would be to enable natural repair processes to proceed,
protected from the countervailing effect of stress. But as antide-
pressants are efficient in stimulating neurogenesis and related
processes of cell repair even in the presence of stress, it might
prove impossible to demonstrate superiority via anti-stress meas-
ures alone. In principle, protection from stress might augment the
effectiveness of antidepressants, but in practice there is little evi-
dence for a synergistic effect of this kind.
4.7. Treatment resistance
As many as 30% of patients treated with antidepressants fail
to respond, despite multiple treatment attempts, and around 50%
of those who do recover relapse within 6–12 months (Warden
et al., 2007; Holtzheimer and Mayberg, 2011): this, alongside the
slow onset of antidepressant action, provides the major impetus for
the continuing need for improved treatments. For example, in the
largest open-label study of the effectiveness of antidepressant ther-
apy, the Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) trial, fewer than one-third of patients achieved remission
with an adequate trial of a standard antidepressant after up to 14
weeks of treatment. Some further improvement may be obtained
by switching non-responders to another antidepressant from a dif-
ferent class, but even after treatment with two antidepressants and
24 weeks of treatment, only half of the patients in the STAR*D study
remitted (Trivedi et al., 2006; Rush et al., 2011). The intractabil-
ity of this problem raises the question of whether the efficacy of
antidepressant treatments is intrinsically limited. For example, if,
as suggested, the key event in the onset of depression involves
a computation within the PFC (concerning the controllability of
adverse events), the mechanisms encoding the elements of this
decision may not be differentiated neurochemically in ways that
would render them differentially susceptible to drug treatment.
Happily, the evidence that drug treatment-resistant depressions do
respond to ECT, DBS and, as discussed below, intravenous ketamine,
refutes this nihilistic prospect by demonstrating that treatment
resistance can in fact be overcome.
4.7.1. Pharmacokinetics, misdiagnosis and comorbidity
A major cause of treatment resistance, which is clinically impor-
tant but neurobiologically trivial, arises because antidepressant
drugs may have difficulty in reaching the brain in sufficient con-
centrations. Many single nucleotide polymorphisms (SNPs) of liver
cytochrome P450 proteins have been identified that alter the
metabolism of antidepressants (Brøsen, 2004; Yin et al., 2006). For
example, non-responders to the SSRI citalopram were found to
carry the allele of the enzymes CYP2D6 and CYP2C19 associated
with extensive metabolism of citalopram and treatment response
was improved by adding an inhibitor of these two enzymes to
increase plasma levels of the drug (Bondolfi et al., 1996). Different
antidepressants vary greatly in their interaction with cytochrome
P450 enzymes (Preskorn, 1997). The association between antide-
pressant plasma levels related to genetic differences in liver
metabolism has not always been observed (Grasmäder et al.,
2004; Peters et al., 2008), but considering that many antidepres-
sants show non-linear dose–response functions (Perry et al., 1994;
DeVane and Gill, 1997) this is hardly surprising.
Antidepressants may also be ineffective because they fail to
penetrate the blood brain barrier (BBB) sufficiently. The function-
ing of the BBB relies crucially on transporter molecules such as
P-glycoprotein (P-gp) (Cordon-Cardo et al., 1989; Thiebaut et al.,
1987). P-gp is a member of the ATP-binding cassette (ABC) trans-
porter protein superfamily (Ambudkar et al., 1999), and is encoded
by the ABCB1 gene, also known as the multidrug-resistance 1
(MDR1) gene (Callen et al., 1987). A SNP in the ABCB1 gene pre-
dicts antidepressant resistance in patients receiving drugs that
have been identified as substrates of P-gp, but not drugs that are not
substrates of P-gp such as mirtazapine. Therefore, putative antide-
pressants should be analysed for their P-gp substrate status, which
can be determined by using abcb1 knockout mice.
Another cause of treatment resistance that does not relate
directly to the neurobiology of depression is misdiagnosis (Souery
et al., 1999). For example, depression in older adults may be an
early sign of dementia arising from vascular causes or Alzheimer-
type pathology. Late-onset depression (patients having their first
depressive episode after the age of 60 years) is associated with
MRI hyperintensities (Fujikawa et al., 1993; Alexopoulos et al.,
1999; Krishnan et al., 1997; see Camus et al., 2004 for a review)
and greater neuropsychological impairment (Salloway et al., 1996;
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
Lesser et al., 1996; Alexopoulos et al., 1997), suggesting that
ischemic cerebrovascular disease might increase vulnerability to
depression in late life by causing structural damage affecting
prefrontal–subcortical circuits (Alexopoulos et al., 1999). A poor
response to antidepressant therapy is seen particularly in older
patients who have high vascular risks (Iosifescu et al., 2005), includ-
ing burden of cardiac disease (Alexopoulos et al., 2004), and high
levels of cholesterol (Sonawalla et al., 2002; Papakostas et al., 2003,
2004). This has also been demonstrated in an animal model: mice
that were fed a high-fat diet became resistant to the antidepressant
effect of fluoxetine in the CMS model (Isingrini et al., 2010). This
subtype of depression may be related to ischemic lesions causing
cognitive deficits. As antidepressants do not target the pathophy-
siological lesions shown by these patients, it is hardly surprising
that their ability to improve symptoms may be poor. The same
applies to depressive features shown by patients with Alzheimer’s
disease, where depression is frequent and may precede the cog-
nitive dysfunction. In this case, the depressive symptomatology
is caused by histopathological lesions in brain areas involved in
depression, including prefrontal cortex, hippocampus and cingu-
late cortex and would not be improved by therapies targeting
monoaminergic neurotransmission, as the symptoms are caused
by Alzheimer-type plaques and tangles. A number of studies have
reported that patients who perform poorly on tests of executive
function are likely to be poor treatment responders (Dunkin et al.,
2000; Baldwin et al., 2004; Gorlyn et al., 2008; Pimontel et al., 2012).
These findings may to some extent reflect the inclusion of patients
with neuropathological lesions of prefrontal cortex.
Treatment resistance may also arise because depression occurs
in the context of other medical disorders, with no primary dys-
function of the brain circuitry related to depression. For example,
thyroid dysfunction (Gold et al., 1981) or folate deficiency (Gilbody
et al., 2007) can cause depressive symptomatology and treatment
resistance, which may respond to thyroid hormone (Abraham et al.,
2006) or folate (Fava and Mischoulon, 2009) supplementation.
The factor most strongly associated with antidepressant treat-
ment resistance is the presence of comorbid anxiety conditions,
including generalized anxiety disorder, panic disorder and social
phobia (Souery et al., 2007). These conditions are associated with
a decreased density of 5HT1A receptors in cortex and midbrain
(Meyer, 2012). The likely explanation for this type of antidepres-
sant resistance is that these three anxiety disorders are themselves
difficult to treat pharmacologically (Bystrisky, 2006; Pollack et al.,
2008). It goes beyond the scope of this review to examine this prob-
lem, but given the close psychological relationship between anxiety
and depression, it seems inevitable that the presence of an ongoing
anxiety disorder would interfere with recovery from depression.
Consistent with high anxiety, a poor response to antidepressant
treatment is also seen in patients with high levels of activity in the
amygdala prior to treatment (Saxena et al., 2003). It has also been
argued that cases of intense normal sadness are frequently misdi-
agnosed as depression, where perhaps a response to antidepressant
treatment should not be expected (Horvitz and Wakefield, 2007).
4.7.2. Parallels with vulnerability to depression
Setting aside treatment resistance that is associated with
pharmacokinetic factors, misdiagnosis and comorbidity, most of
the other factors identified as contributing to treatment resis-
tance are similar or identical to those that confer vulnerability
to depression. In particular, recurrent depressions are more dif-
ficult to treat than first-episode depressions (O’Reardon et al.,
2007; Souery et al., 2007; Kaymaz et al., 2008; Rush et al.,
2011). This may reflect the neurological damage associated
with recurrent depression, as suggested by the observation that
patients who responded to treatment had a larger hippocampus
2353
than those who were treatment-resistant (MacQueen et al.,
2008).
Treatment resistance is also associated with other factors that
increase the diathesis for depression, including neurotic premor-
bid personality, familial predisposition for affective disorder, or
the experience of multiple loss events (Souery et al., 1999). Treat-
ment resistance is also associated with several genetic diatheses
for depression, such as the short allele of the 5HTTLPR gene (Zobel
and Maier, 2010; Licinio and Wong, 2011), and polymorphisms of
genes coding for the CB1 receptor (Domschke et al., 2008; Juhasz
et al., 2009) and the 5-HT1A receptor (Kato and Serretti, 2010). But
not all genetic variants associated with antidepressant treatment
resistance are related to vulnerability to depression, such as genes
coding for a glutamate receptor (dystrobrevin-binding-protein 1
gene: Arias et al., 2009) and the 5HT2A receptor (Horstmann and
Binder, 2009; Licinio and Wong, 2011). There are also some genetic
variants that are associated with treatment resistance for which
the association with vulnerability has not been evaluated. These
include the C allele of the −182T/C SNP in the promoter region of
the noradrenaline transporter (Shiroma et al., 2010) and a variant
of the gene coding for the neurotrophin VEGF (Viikki et al., 2010).
A high level of activity in the HPA system also predicts treatment
resistance. Treatment outcome is associated with polymorphisms
of genes coding for proteins involved in HPA functioning, including
the CRH receptor 1 gene and the hsp90 co-chaperone FKBP5, a part
of the mature glucocorticoid receptor (GR) heterocomplex that reg-
ulates the GR response (Kato and Serretti, 2010). Patients who fail
to show a decrease in HPA activity after 2–3 weeks of treatment
are unlikely to recover from depression with prolonged treatment
(Brouwer et al., 2006; Ising et al., 2007), and if they do recover are
very likely to relapse (Zobel et al., 2001; Appelhopf et al., 2006).
This suggests, as discussed previously, that a major component of
antidepressant action is the anti-stress effect, and that additional
actions may be needed for improvements in treatment.
Other studies have explored the association of brain activ-
ity with treatment resistance. As discussed earlier, the most
convincing evidence points to a relationship between antide-
pressant resistance and low pretreatment activity in the rostral
ACC (Mayberg et al., 1997; Pizzagalli, 2011), which was observed
in 19 out of 23 studies included in a recent meta-analysis
(Pizzagalli, 2011). This marker is a predictor of treatment outcome
not only in patients treated with conventional monoaminergic-
acting antidepressants such as SSRIs, but also in patients treated
with intravenous ketamine (Salvadore et al., 2011) or by non-
pharmacological modalities such as ECT (McCormick et al., 2007),
transcranial magnetic stimulation (TMS: Kito et al., 2008), or sleep
deprivation (Wu et al., 1999). As discussed above, this marker is
specific to physical treatments, as the opposite relationship is seen
with psychological treatments, where a low level of activity in the
rostral ACC predicts a better outcome (Pizzagalli, 2011; Roiser et al.,
2012).
The similarities between the factors associated with vulner-
ability to depression and those associated with antidepressant
treatment resistance, prompt the question of whether activity in
the rostral ACC, identified as one of the most reliable markers of
antidepressant treatment resistance, is also associated with vulner-
ability to depression. A number of observations are consistent with
this hypothesis. For example, depressed patients showed increased
rostral ACC activation in response to errors (Holmes and Pizzagalli,
2008), and the same effect has been observed in non-depressed vol-
unteers who carry the short allele of the 5HTTPR gene that confers
vulnerability to depression (Holmes et al., 2010). Also consistent
with an association between high rostral ACC activity and vulnera-
bility to depression are observations that high rostral ACC activity is
associated with depressed mood in healthy (non-depressed) chil-
dren (Boes et al., 2008), and with pessimism (Sharot et al., 2007)
2354 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
Table 1
Some sources of resistance to antidepressant drugsa .
Factors unique to treatment resistance
Pharmacokinetics
SNPs of liver cytochrome 450 enzymes
Failure to penetrate the blood–brain barrier
Misdiagnosis
Vascular or Alzheimer-type pathology
Thyroid insufficiency
Folate defiency
Bipolar disorder
Normal sadness
Comorbidity
General anxiety disorder
Panic disorder
Social phobia
Post-traumatic stress disorder
Factors common to treatment resistance and vulnerability to depression
Developmental
Familial predisposition to depression
Childhood trauma
Multiple loss events
Neuroticism
History of previous depressive episodes
Physiological
HPA dysregulation
Decreased hippocampal volume
Increased amygdalar activity
High activity in the rostral ACC
Genetic
Short allele of the 5HTTLPR gene
5HT1A receptor polymorphism
CB1 receptor polymorphism
a
The table summarizes only factors that have been identified in the clinic. Further
examples of commonality between vulnerability and treatment resistance that have
been identified in animal models are discussed in the text.
and negative emotionality (Santesso et al., 2012) in non-depressed
adults.
Parallels between vulnerability to depression and treatment
resistance have also been observed in animal studies. Per-
haps unsurprisingly, antidepressant responsiveness was lower in
mutant mice expressing low levels of BDNF in the hippocampus
(Adachi et al., 2008; Ibarguen-Vargas et al., 2009). Congenitally
helpless rats are also said to be resistant to antidepressant drug
treatment (Vollmayr et al., 2004). However, the extent of antide-
pressant resistance in these animals is unclear, as the data have
not been published in full: reponsiveness to fluoxetine has been
reported (Shumake et al., 2010), but there are no published compar-
isons comparing the effectiveness of antidepressants on acquired
and congential helplessness. Antidepressant-like properties in con-
genitally helpless rats have been reported for a highly selective
5HT2A antagonist (Patel et al., 2004), consistent with the clinical
picture of increased 5HT2A receptors in difficult-to-treat vulner-
able patients. The CMS model has been used to make direct
comparisons of vulnerability and treatment resistance: similar
patterns of gene expression (Wilkinson et al., 2009; Christensen
et al., 2011) and protein expression (Bisgaard et al., 2007) were
observed between animals that were resilient to CMS, and those
that developed anhedonia but subsequently responded to antide-
pressant treatment; these two groups differed in gene and protein
expression from animals that developed anhedonia but were
treatment-resistant.
Broadly speaking, therefore, it appears that two sets of factors
are largely responsible for antidepressant treatment resistance,
which are summarized in Table 1. On the one hand, there are factors
that are not directly related to depression, including pharmacoki-
netics, misdiagnosis and comorbidity. On the other hand, there
are factors that are essentially the same as those that are associ-
ated with vulnerability to depression, including recurrent episodes,
early life stress and its psychological sequelae, neurotic personality,
and genetic diatheses for depression. Antidepressants are most
effective in people with a low depressive diathesis (first episode
and few vulnerability factors), whose depressions are associated
with high levels of recent stress. As depressions become increas-
ingly autonomous of stress (later episodes and other vulnerability
factors), conventional monoaminergic antidepressants become less
effective and different strategies are needed to address treatment
resistance.
4.8. Approaches to the treatment of resistant depression
Resistant depression is typically treated by supplementation
of ongoing antidepressant therapy. The two classic augmentation
strategies are the addition of thyroid hormone (T3) or anti-manic
drugs (lithium or anticonvulsants). Both are widely used, albeit that
the evidence for their effectiveness is largely in combination with
tricyclics and there is less evidence that they enhance the effect of
newer antidepressants (Connolly and Thase, 2011). There is good
evidence that the response to SSRIs can be augmented by a more
recent strategy, the addition of a second-generation antipsychotic
agent, such as quetiapine or aripiprazole (Komossa et al., 2010;
Kennedy et al., 2011; Connolly and Thase, 2011), administered at
doses much lower than those that would be used in the treatment
of psychosis. At these low doses, second-generation antipsychotics
act selectively at DA synapses in the VTA, resulting in an increase
DA release in the nucleus accumbens and PFC, and as partial 5HT2
receptor antagonists; both actions may contribute to the antide-
pressant effect (Möller, 2005; Blier and Blondeau, 2011). However,
the benefits of augmentation are small (Gaynes et al., 2012).
As discussed earlier, a good response to antidepressant drug
treatment is associated with changes in metabolic activity in the
ventral ACC and nucleus accumbens, which are also produced
by DBS of these structures. There is some evidence that simi-
lar metabolic changes in the PFC and ACC can be achieved by
repeated transcranial magnetic stimulation (rTMS) but it is not yet
clear whether rTMS can improve on the effectiveness of antide-
pressant drugs (Dell’osso et al., 2011). Strategies to increase DA
activity in the nucleus accumbens are similarly embryonic. A recent
study reported an effect on congenital helplessness of the MAO-B
inhibitor deprenyl, which preferentially protects DA rather than NA
or 5HT; uniquely, this effect required experience of repeated test
trials, suggesting some form of learning process that has not been
described for any other antidepressant (Schulz et al., 2010). There is
some evidence that DA D2/D3 receptor agonists have antidepres-
sant activity (Rakofsky et al., 2009), and triple uptake inhibitors,
which add DA uptake inhibition to the NA and 5-HT uptake inhibi-
tion shown by tricylics and SNRIs, have been confirmed as effective
antidepressants (Chen and Skolnick, 2007), but again, it has not yet
been established if they have superior efficacy to antidepressants
with a more restricted spectrum of activity.
It remains the case that electroconvulsive therapy (ECT) is the
most effective treatment for resistant depression, with remission
rates in excess of 75% after a course of treatment (Sienaert, 2011),
though this may include a powerful placebo component, as is also
the case after the classical antidepressant treatments (Rasmussen,
2009; Read and Bentall, 2010). It also remains the case that the
mechanism of action ECT is poorly understood (Bolwig, 2011).
ECT is more effective than antidepressant drugs in stimulating
hippocampal neurogenesis (Malberg et al., 2000), but generalized
seizures cause many other neurochemical changes that are also
associated with antidepressant-like effects (Merkl et al., 2009),
including an increase in striatal DA D1, D2 and D3 receptor bind-
ing (Strome et al., 2007), which is implicated in the mechanism
of action by the fact that a polymorphism of the gene coding for
COMT, an enzyme that degrades DA, is associated with the treat-
ment response to ECT (Huuhka et al., 2008). ECT also powerfully
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
reverses dysfunctions of the HPA axis, probably via direct actions
within the hypothalamus (Bolwig, 2011).
The factors responsible for the superiority of ECT to antide-
pressant drug treatment remain uncertain, though it is probably
relevant that unlike antidepressants, ECT is not subject to
pharmacokinetic problems such as liver metabolism or blood–brain
barrier penetration. However, the fact that it is possible to improve
on the efficacy of antidepressants (and the reluctance of many clini-
cians to use ECT) encourages continuing research to develop more
effective drug treatments. One strategy is to build molecules that
combine neuroreparative effects in the hippocampus with actions
elsewhere within the depression circuitry. We briefly review four
examples.
4.8.1. New targets
A compelling case has been made for an involvement of endoge-
nous cannabinoid systems in depression: depression is associated
with decreased levels of circulating endocannabinoids (Gorzalka
and Hill, 2011; McLaughlin and Gobbi, 2012), and single nucleotide
polymorphisms in the CB1 receptor have been reported to increase
neuroticism and vulnerability to develop a depressive evidence
following exposure to life stress (Juhasz et al., 2009), as well
as increasing resistance to antidepressant treatment (Domschke
et al., 2008). Decreasing endocannabinoid signalling produces in
animals a depressive-like phenotype (including anhedonia) and
increased HPA activity, while endocannabinoids and CB1 agonists
have antidepressant-like effects (Gorzalka and Hill, 2011; Hill et al.,
2009; McLaughlin and Gobbi, 2012). There are as yet no clinical
data on cannabinoid agonists, but there is strong clinical evidence
of depressogenic effects of the cannabinoid antagonist rimona-
bant, including depressive effects in people with no prior history
of depression (Hill and Gorzalka, 2009). Rimonabant also sup-
pressed positive affective memories and responses to reward in
the nucleus accumbens and ventral PFC (Horder et al., 2009, 2010).
Like antidepressants, facilitation of endocannabinoid signalling
enhances monoaminergic transmission, increases cellular plastic-
ity and neurotrophin expression in the hippocampus, and decreases
HPA activity, and there is evidence that these effects depend in
part on actions within the hippocampus (Gorzalka and Hill, 2011;
McLaughlin and Gobbi, 2012). However, there is also evidence that
at least a part of the antidepressant-like cannabinoid effect may
be mediated at CB1 receptors within the prefrontal cortex, which
inhibit the release of glutamate and GABA (Bambico et al., 2007;
McLaughlin and Bambico, 2012).
The glutamate system provides a second example of drugs
that may have wider, or at least, different, anatomical targets
than current antidepressants. There are many inconsistent reports
of changes in glutamate levels in the brains of people who are
depressed (both post-mortem and in vivo), but a consensus is
developing that glutamate levels are decreased in the PFC and ACC;
changes have also been reported in hippocampus, but less fre-
quently and less consistently (Sanacora et al., 2008; Hashimoto,
2011). Furthermore, genetically modified mice with impaired glu-
tamate function exhibit a depressive-like phenotype (Tordera et al.,
2007, 2011). At the same time, there is extensive evidence for
antidepressant-like effects of glutamate NMDA receptor antag-
onists in animal models of depression (Sanacora et al., 2008;
Hashimoto, 2011), albeit that the weak NMDA antagonist meman-
tine was ineffective in the only double-blind clinical trial (Zarate
et al., 2006a). Following an initial report on seven patients (Berman
et al., 2000), a large number of studies, including two randomized
controlled trials (Zarate et al., 2006b; Diazgranados et al., 2010)
have reported rapid antidepressant effects following a single intra-
venous infusion of the NMDA antagonist ketamine, which appear
within 2 h, last for around a week, and are seen in patients who
are refractory to treatment with conventional antidepressants. A
2355
single injection of ketamine also reversed not only the anhedo-
nic and other behavioural deficits in the CMS model, but also the
atrophy of dendritic spines (and consequent loss of synapses) in
the PFC (this study did not assess hippocampal synapse loss), and
the associated electrophysiological deficits (Li et al., 2010, 2011a,b;
Duman et al., 2012).
The antidepressant effects of NMDA antagonists may appear
paradoxical, given that glutamate levels are decreased in depres-
sion, and an NMDA antagonist further depresses glutamate
function. However, ketamine indirectly increases presynaptic glu-
tamate release in the PFC, via its interaction with NMDA receptors
on GABA interneurons (Moghaddam et al., 1997), which increases
stimulant effects at the other major class of glutamate recep-
tors, AMPA receptors. The clinical response to ketamine was
negatively correlated with a marker of glial cells in the ventral
PFC (Salvadore et al., 2011), perhaps because a decrease in glial
cells would mean lower clearance of glutamate from the synapse
and therefore a larger increase in glutamate concentration and
a greater stimulation of AMPA receptors. This effect is essential
for the antidepressant action of ketamine because it is blocked
by AMPA receptor antagonists (Maeng et al., 2008). Accordingly,
knockout mice lacking an AMPA receptor sub-unit have been
reported to show a depressive phenotype (Chourbaji et al., 2008).
Ketamine itself is unlikely to be developed for general antide-
pressant use because it may produce psychotomimetic effects, it
has abuse potential and it is neurotoxic at high doses (Behrens
et al., 2007), but these observations do presage the potential devel-
opment of new antidepressants based on actions at glutamate
synapses. Examples of drugs under development include positive
modulators of AMPA receptors and antagonists of several sub-
types of metabotropic glutamate receptor (Sanacora et al., 2008;
Hashimoto, 2011). Antagonists at mGluR2/3 receptors in particular
may be promising targets, as the density of these receptors in the
PFC is increased in depression (Feyissa et al., 2010).
A third example is the novel (and expensive) antidepressant
agomelatine, which, since its introduction less than 10 years ago,
has been shown to be among the most effective antidepressant
drugs available, and has been approved for the treatment of depres-
sion in over 40 countries (Carney and Shelton, 2011). Agomelatine
is an agonist at 5HT2C and melatonin receptors, and both of these
actions appear to be essential for its antidepressant properties:
agomelatine decreases stress-induced glutamate release in the PFC
and increases BDNF in hippocampus and PFC, and hippocampal
neurogenesis, but agonists at either 5HT2C or melatonin recep-
tors alone do not share these effects (Racagni et al., 2011). But,
differently from other antidepressant drugs, agomelatine also nor-
malizes circadian rhythms by its action at melatonin receptors in
the suprachiasmatic nucleus (Quera Salva et al., 2011; Dallaspezia
and Benedetti, 2011). As the habenula, like the suprachiasmatic
nucleus, also shows intrinsic circadian rhythmicity, and is respon-
sive to melatonin (Hikosaka, 2010), a potential role for the habenula
in the antidepressant action of agomelatine must be a distinct pos-
sibility.
Cognitive enhancers present a fourth potential route to
improved antidepressant efficacy, building on the proposal that
antidepressant-induced neuroplasticity might serve as the basis
for new learning (e.g. Castrén and Rantamäki, 2010). There is some
evidence that combined treatment with antidepressants and CBT
has significant advantages over either treatment modality alone
(Pampallona et al., 2002; de Maat et al., 2007; Roiser et al., 2012),
but the differences are unimpressive, and relate in part to treatment
compliance. (Indeed, one study reported that non-depressed vol-
unteers treated with an SSRI and a cognitive intervention showed
smaller decreases in negative thinking than participants treated
with either intervention alone: Browning et al., 2011). An alter-
native approach contemplates combining CBT with a cognitive
2356 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
enhancer to promote the learning process that occurs during CBT.
Compounds under investigation include ampakines (Knapp et al.,
2002), agents that interact with the nicotinic cholinergic receptor
(Mineur and Picciotto, 2010), and erythropoietin, a neuroprotective
compound that, in addition to antidepressant effects in animal
models and initial clinical trials also improves memory in animal
models of neurodegenerative conditions and in patients with cog-
nitive decline (Miskowiak et al., 2012). However, the possibility that
a cognitive enhancer could promote both adaptive and maladap-
tive change, injects an element of hazard into this strategy (Branchi,
2011).
We finally consider a strategic issue, taking as an example the
inhibitory neurotransmitter GABA: whether the search for novel
antidepressants should begin from what is known about conven-
tional antidepressants or from a different starting point. There
is increasing evidence that cortical GABA levels are decreased
in depression (Hasler et al., 2007; Croarkin et al., 2011; Hasler
and Northoff, 2011), particularly so in treatment-resistant patients
(Price et al., 2009). Chronic antidepressant treatment decreases
activity at GABA-B receptors (Cryan and Slattery, 2010; Ghose et al.,
2011). This suggests that GABA-B antagonists might have antide-
pressant properties, a hypothesis that has been amply confirmed
in animal models but not yet tested clinically (Cryan and Slat-
tery, 2010; Ghose et al., 2011). However, there is no good reason
to suppose that an approach derived from the known actions of
currently used antidepressants would improve on their clinical
efficacy: on the contrary, the problems that remain uncorrected
in treatment-resistant patients are more likely to be rectified by
agents that have novel actions. Dysfunctions of GABA could be cor-
rected by actions at either the GABA-B receptor, which is modulated
by antidepressants, or the GABA-A receptor, which is not. It was
recently reported that a GABA-A agonist, gaboxadol, not only has
antidepressant-like effects in the CMS model comparable to those
of escitalopram, which is among the most efficacious antidepres-
sants in clinical use, but also potentiated the effect of escitalopram,
such that a higher reponse rate was achieved when the two drugs
were co-administered than with either drug alone. Gaboxadol did
not increase hippocampal neurogenesis, and its mechanism of
action has not yet been established (Christensen et al., 2012). How-
ever, GABA, acting via GABA-A receptors, promotes the survival
and maturation of newly born hippocampal neurons (Wang and
Kriegstein, 2009), and it is plausible that this could be the mecha-
nism whereby gaboxadol acts synergistically with a conventional
antidepressant. There is some evidence that GABA-enhancing anti-
convulsants such as carbamazepine and sodium valproate have
antidepressant efficacy as monotherapy or adjunctive treatment
(Vigo and Baldessarini, 2009), which perhaps should be further
studied in light of the reported effects of gaboxadol.
From this brief review it is evident that the approaches
to treatment-resistant depression are largely consistent with
attempts to intervene in the depression circuitry summarized
above, but also include other approaches that were arrived at
empirically and for which the mechanisms of action are not well
understood. Animal models of treatment resistance are now being
developed (Samuels et al., 2011), which may contribute to a better
understanding of existing strategies and improved prospects for
the treatment of those patients who currently are difficult to help.
5. Conclusions and research implications
Despite the efficacy of currently available antidepressant med-
ications and somatic therapies, residual depressive symptoms and
relapse are common. This creates a challenge for clinicians as they
seek to eliminate symptoms completely and help fully recover
patients. To reach these goals, improved treatment strategies are
‘Normal’ brain ‘Depressed’ brain
- + +
vm-PFC dl-PFC onset
- dl-PFC
vm-PFC NAcc
AMG NAcc
AMG
recovery
Hippocampal
damage
Involvement
of stress in
precipitation Vulnerability
of depression (pre-existing
or ‘scar’)
Treatment Brain
resistance repair
Antidepressant response
Fig. 7. Some key conclusions. The upper part of the figure summarizes some of the
structures involved in the shift between the ‘normal’ brain and the ‘depressed’ brain,
which is mediated by the balance between responsiveness to negative (amygdala:
AMG) and positive (nucleus accumbens: NAcc) information, and between rumi-
nation (ventromedial prefrontal cortex: vm-PFC) and cognitive control of emotion
(dorsolateral prefrontal cortex: dl-PFC). In depression, activity is increased in the
AMG and vm-PFC and decreased in the NAcc and dl-PFC, resulting in an inbalance
within this circuitry. This brief summary omits some key structures (e.g. habenula)
and processes (e.g. appraisal) discussed in the text. The lower part of the figure
shows the relationship between the role of stress in the onset of depression and the
effectiveness of monoaminergic antidepressants in treating depression. Antidepres-
sants are effective against depressions that are precipitated by high levels of stress,
because they promote the repair of a damaged hippocampus. However, in the pres-
ence of vulnerability factors, which could be constitutional and/or consequential to
previous episodes of depression, depression is precipitated by lower level of stress
of stress, causing less of an insult to the hippocampus, and thereby decreasing the
response to antidepressant treatment.
needed. Understanding the neurobiology of depression has helped
researchers uncover a number of novel targets for antidepressant
therapies, which are under investigation in animal models, case
reports, and small open-label studies. While many of these new
approaches have suggested antidepressant potential, pivotal trials
will be needed to clarify which of these treatments may be realized
clinically. Over the next few years, the treatment of depression may
be improved by the introduction of several of these novel interven-
tions that no longer rely solely on monoamine reuptake inhibition.
However, the history of the past 50 years does not give cause for
unrestrained optimism.
Perhaps some new conceptual approaches are needed. In this
review, starting from the established role of monoamines in antide-
pressant action, we have attempted to expand the horizon to
integrate this early understanding into the wider neurocircuitry
that is now known to be involved in the symptomatology of depres-
sion, and the cellular and systemic mechanisms that underlie the
ability of antidepressants to provide relief. We have focussed also
on the overlapping constellations of constitutional and experiential
factors that promote both vulnerability to depression and resis-
tance to treatment. Some of our key conclusions are summarized
in Fig. 7. The evidence suggests that depression results from an
inbalance between forebrain systems involved in processing and
responding to affective information. This can arise either from the
action of high levels of stress, causing damage to the hippocam-
pus, or from the combination of low levels of stress with a variety
of factors that confer vulnerability to depression, which may be
present from an early age, or may represent ‘scars’ left by previous
depressive episodes. Monoaminergic antidepressants (i.e. almost
of those currently available) act primarily by repairing a damaged
 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
hippocampus, and are therefore ineffective in depressions where
stress has had only a minor precipitating role. These conclusions are
based firmly on the position that depression is a stress-related con-
dition, while acknowledging that the role of stress may sometimes
be minor and decreases during the progression through a life his-
tory of depressive episodes. This distinction has important strategic
implications for both preclinical and clinical research.
From the perspective of a diathesis/stress model, animal mod-
els of depression are mostly models of a first episode of depression.
They include models in which depressive-like behaviour is precip-
itated by external events, typically stressors of various kinds, and
models of a depressive diathesis involving individuals rendered
vulnerable by virtue of their history (for example, a brain lesion) or
genetic endowment (including both inbred strains and genetically
modified animals) (Willner and Mitchell, 2002a,b). With very few
exceptions (e.g. Isingrini et al., 2010), animal models of depression
have not addressed the progressive vulnerability that develops over
successive episodes of depression. Consequently, the preclinical lit-
erature has almost nothing to say about the mechanisms by which
depression becomes progressively more autonomous of stress. As
discussed above, this is a critical issue for both vulnerability to
depression and resistance to antidepressant treatment.
Conversely, clinical research rarely distinguishes between first
and recurrent depressive episodes. If, as envisaged here, the man-
ner in which patients enter a depressive episode changes across
episodes, then this could potentially account for much of the incon-
sistency in the neurobiological literature, in relation to, for example
HPA activity or the changes reported in structural and functional
imaging studies. It is also a distinct possibility that if the neuro-
biological mechanisms change across episodes of depression, then
different antidepressant strategies might be appropriate at differ-
ent stages, and this might account for the clinical failure of so many
compounds predicted to show antidepressant activity from pre-
clinical studies.
So this analysis suggests two research strategies. Firstly, it will
be necessary to develop animal models of repeated depressive
episodes. As the object is to approximate the clinical situation,
these models should aim to use realistic conditions based, for
example, on the CMS model rather than, for example, the tail
suspension or the forced swim tests, which have only the most
tenuous relationship to depression (Cryan and Holmes, 2005). And
as the rationale is to investigate changes in the role of stress, it
would be better in general to use environmental precipitants (e.g.
CMS) rather than a labour-saving short cut such as corticosterone
administration (David et al., 2009; Samuels and Hen, 2011), which
could be a useful way of identifying systems of interest, but pre-
empts investigation of important elements of the stress system.
The research envisaged in this proposal would provide a more
solid backdrop against which to test the mechanisms of depres-
sive diatheses, such as genetic polymorphisms, than is currently
available, and could engender novel leads for antidepressant drug
development.
Secondly, clinical research should rigorously attempt to exam-
ine separately first and recurrent episodes of depression (Meyer,
2012). Indeed, the population of greatest research interest at
present are first-episode depressed patients with a weak depres-
sive diathesis, in whom the effects of stress are greatest. It should
be possible in this homogeneous group to iron out the inconsis-
tencies in the literature and achieve a much clearer picture of
the neurobiological mechanisms. In tandem with the preclinical
research, this would provide a sounder basis for understanding
the growth of the depressive diathesis over episodes of depres-
sion, and interactions with other factors that confer vulnerability
to depression.
We have attempted in this review to provide a clear account of
the current state of research in the neurobiology of depression and
2357
antidepressant drug action, but in so doing, we have tended, in the
interests of clarity, to smooth over discrepancies and inconsisten-
cies in the literature. For example, we have given prominence to the
role of neurogenesis in antidepressant action, albeit that, according
to a recent commentary the neurogenesis hypothesis “has triggered
reactions ranging from messianic conviction to total scepticism”
(Anacker and Pariante, 2012). As discussed above, many of the
apparent inconsistencies in this area can be resolved: the neuro-
genetic effect of antidepressants is strain dependent, but so too is
their behavioural effect (Miller et al., 2008); the blockade of antide-
pressant action by suppression of neurogenesis appeared to be
technique-dependent (Bessa et al., 2009), but was later shown to be
actually time-dependent, involving relatively mature young neu-
rons (Mateus-Pinheiro et al., 2011); and while neurogenesis is not
necessary for all behavioural effects of antidepressants (David et al.,
2009), the forced swim test, where neurogenesis is not required,
is an acute test that is not considered a valid model of depres-
sion. Nevertheless, there are some exceptions that cannot readily
be assimilated to the neurogenesis story: in particular, there are
antidepressant-like drugs that promote neurogenesis but whose
behavioural effects are not blocked by suppression of neurogene-
sis, including a melanin-concentrating hormone (MCH) antagonist
(David et al., 2007), and CRF1 and vasopressin V1b antagonists
(Surget et al., 2008). But there is no reason to expect that all antide-
pressants must hit the identical spot. There is evidence that the
site of action of the HPA (CRF1 and V1b) antagonists may be the
amygdala (Salome et al., 2006), and there is every possibility that
the habenula may be the site of action of the MCH antagonist.
The DBS literature demonstrates that antidepressant effects can
be elicited from a variety of sites within the depression circuitry,
including the habenula and the nucleus accumbens (Hamani et al.,
2010). The nucleus accumbens is likely to be the site of antidepres-
sant action of DA agonists such as pramipexole (Willner, 1997b),
notwithstanding that they also stimulate neurogenesis (Albrecht
and Buerger, 2009). So the intense attention focussed on hippocam-
pal neurogenesis may be a case of looking in the light. There are
very good reasons to shine an intense light on the hippocampus: it
does seem to be a critical region for the neuropathological effects
of stress, and repair within this region is important, if not uni-
versally critical, for recovery. But other parts of the depression
circuitry that have been less brightly illuminated also merit atten-
tion.
A broader focus is essential because, according to our cur-
rent understanding, the hippocampus is almost incidental to
the symptomatology of depression. Neurogenesis simply main-
tains an efficient level of functioning within the hippocampus
(Airan et al., 2007), which is concerned primarily with contex-
tual learning (Rudy, 2009). The importance in depression of the
hippocampal formation, including the subiculum and entorhi-
nal cortex, derives from its connections with other regions that
have more direct involvement in the psychological (amygdala,
PFC and other areas of association cortex, nucleus accumbens)
and physiological (hypothalamus) phenomena that characterize
depression. The most critical regions appear to be the ante-
rior cingulate and ventral prefrontal cortex, but, as discussed,
all parts of the system can be related to specific symptoms of
depression: in particular, rumination and negative self-referential
attributions reflect hyperactivity in amygdala and ventral pre-
frontal regions, and anhedonia reflects hypoactivity in the nucleus
accumbens and dorsal PFC. It is obvious that such a complex
network will generate a wide variety of symptom patterns, depend-
ing on the degree of dysfunction elicited in each component,
which will in turn depend upon the individual patient’s pro-
file of vulnerability factors and precipitants, and the manner in
which they affect different brain regions. It is to be expected that
in the future novel compounds might target specific syndromes
2358 P. Willner et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 2331–2371
such as rumination or anhedonia, or specific physiological vul-
nerabilities; but the prospect of personalized antidepressant
medication (Holsboer, 2008) is unlikely to be realized any time
soon.
It is also obvious that traditional ways of thinking about depres-
sion, based around a single brain region or a single neurotransmitter
system, are no longer adequate for dealing with the complex sys-
tem that is now known to underly depression. A potentially more
appropriate conceptualization was proposed by Tanti and Belzung
(2010). They describe a theoretical neural network model that has
a number of input nodes representing vulnerability and triggering
factors, a set of inter-connected intermediate nodes representing
physiological endpoints (brain regions or neurotransmitter sys-
tems) that are influenced to varying extents by each of the inputs,
and a range of output nodes representing cognitive and behavioural
functions that are underpinned to varying degrees by the physio-
logical elements of the model. The authors show, inter alia, how
such a model could represent different routes to the same outcome
(e.g. via dysfunction either of a critical physiological function, or of
several functions none of which is critical in itself); how antidepres-
sants could promote recovery of key symptoms with or without
a reversal of the original pathophysiological process; and how a
change in cognition following CBT could back-propagate through
the system to affect the functioning of the physiological compo-
nents. The explanatory potential of the model is considerable, but
this will only be realized in the future, as the model has not yet
been built.
There is also a need for formal mathematical models of
physiological components of the depression circuitry, where the
inter-relationships are so many and complex as to defy accurate
intuitive prediction of the effects of any perturbation. Belzung and
Billette de Villemeur (2010) have presented such a formal compu-
tational model of the hippocampal control of the HPA axis, which
integrates hippocampal and HPA dysfunction in depression, and
their normalization by antidepressant drugs, and enables the spec-
ification of precise hypotheses that can be tested empirically. There
is evidently scope to develop computational models of other facets
of the depression circuitry, such as the 5HT projections to forebrain
structures and the reciprocal projections from the forebrain to the
DRN, or the relationships between the amygdala, PFC and nucleus
accumbens.
Finally, a concept that demands attention is the suggestion that
what is important about depression is not so much its sympto-
matology as its chronicity: that is, that the phenomenology of
depression is frequently a natural response to adversity, and what
distinguishes people who become depressed from those who do
not is that they become “stuck in a rut” and unable to recover
(Holtzheimer and Mayberg, 2011). In this conceptualization, the
onset of and recovery from depression are seen as transitions into
and out of a stable state. As discussed above, the cognitive appraisal
that stress is uncontrollable appears to play a critical role in the
transition into depression, and a drug- or stimulation-induced neu-
rogenetic boost to the efficiency of information processing in the
hippocampus appears to provide one exit route. While these phase
shifts may be captured by conventional connectionist or computa-
tional models such as those described above, they may also require
the inclusion of non-linear computational methods such as those
provided by chaos theory.
So to summarize, our three key recommendations for future
depression research are: greater attention to the diathesis-stress
model in clinical studies, and in particular, a rigorous separation of
first-episode and recurrent depression; greater attention in preclin-
ical research to issues of vulnerability, including the development
of models of recurrent depression; and the involvement of math-
ematicians in research teams, with the aim of improving their
capacity to break out of the traditional focus on single structures
(hippocampus, PFC, habenula . . .) or neurotransmitters (5HT, NA,
DA, cannabinoid . . .) in order to engage effectively with the com-
plexity of the neurobiological systems that are now known to be
implicated in depression.
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