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Behavioural Pharmacology:
doi: 10.1097/FBP.0000000000000066
Review Articles

Resistance to antidepressant drugs: the case for a more predisposition-based and less hippocampocentric research paradigm

Willner, Paula; Scheel-Krüger, Jørgenb; Belzung, Catherinec

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aDepartment of Psychology, Swansea University, Swansea, UK

bCenter of Functionally Integrative Neuroscience, University of Aarhus, Aarhus, Denmark

cINSERM 930, University Francois-Rabelais, Tours, France

Correspondence to Paul Willner, DSc, Department of Psychology, Swansea University, Singleton Park, Swansea SA2 8PP, UK E-mail: p.willner@swansea.ac.uk

Received February 28, 2014

Accepted June 9, 2014

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Abstract

The first half of this paper briefly reviews the evidence that (i) stress precipitates depression by damaging the hippocampus, leading to changes in the activity of a distributed neural system involving, inter alia, the amygdala, the ventromedial and dorsolateral prefrontal cortex, the lateral habenula and ascending monoamine pathways, and (ii) antidepressants work by repairing the damaged hippocampus, thus restoring the normal balance of activity within that circuitry. In the second half of the paper we review the evidence that heightened vulnerability to depression, either because of a clinical history of depression or because of the presence of genetic, personality or developmental risk factors, also confers resistance to antidepressant drug treatment. Thus, although antidepressants provide an efficient means of reversing the neurotoxic effects of stress, they are much less effective in conditions where vulnerability to depression is elevated and the role of stress in precipitating depression is correspondingly lower. Consequently, the issue of vulnerability should feature much more prominently in antidepressant research. Most of the current animal models of depression are based on the induction of a depressive-like phenotype by stress, and pay scant attention to vulnerability. As antidepressants are relatively ineffective in vulnerable individuals, this in turn implies a need for the development of different clinical and preclinical methodologies, and a shift of focus away from the current preoccupation with the hippocampus as a target for antidepressant action in vulnerable patients.

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Introduction

The introduction of antidepressant drugs into clinical practice marked a turning point in the nascent discipline of psychopharmacology. In the early 1960s, the monoamine hypothesis of depression (‘some, if not all, depressions are associated with an absolute or relative deficiency of the monoamines at functionally important receptor sites in the brain’) was promulgated in relation to the recently established neurotransmitters noradrenaline (NA) and serotonin (5HT), and provided, for the first time, a plausible account of the mechanism of action of drugs that could be shown to be effective in alleviating mental distress. Thus was initiated a half century of remarkable progress in psychopharmacology and clinical neuroscience.

The monoamine hypothesis was based, in part, on some rather weak clinical evidence, but primarily on the evidence that antidepressant drugs enhance activity at monoaminergic synapses: the tricyclics by blocking the reuptake of NA and 5HT, and the monoamine oxidase inhibitors (MAOIs) by blocking their breakdown, resulting in higher concentrations of both neurotransmitters at the synapse (Willner, 1985). On these foundations was built a major research endeavour, the outcome of which, however, must be described as, at best, disappointing. After half a century of intensive research, the efficacy of antidepressants remains stubbornly low, at around 70% (compared with a no-treatment recovery rate of around 50%), the onset of action remains stubbornly slow, at around 4–6 weeks, and there has been almost no progress toward the identification of novel targets to improve these parameters (Belzung, 2013). With very few exceptions, drugs newly introduced into clinical practice have been ‘me-too’ variants of existing drugs. Specific 5HT or NA reuptake inhibitors and dual 5HT/NA reuptake inhibitors (SSRIs, NRIs and SNRIs, respectively) are functionally equivalent to tricyclic antidepressants, but with fewer unwanted side effects. Selective and reversible MAOIs, including reversible inhibitors of MAO-A (RIMAs), are similar to the original MAOIs except that they too have fewer unwanted side effects. The so-called atypical antidepressants similarly amplify 5HT or NA by other means, such as direct stimulation of postsynaptic receptors or disinhibition of NA/5HT release by blockade of inhibitory presynaptic receptors. As a consequence of this lack of real progress, the past two decades have seen a mass exodus from the antidepressant development arena, where few pharmaceutical companies still operate. Paradoxically, this has happened over a period in which unprecedented breakthroughs have been made in understanding the molecular mechanisms of antidepressant action.

All this is well-known. The purpose of the present paper is to clarify the reasons for the failure to improve on the efficacy of antidepressant drugs, and to suggest a way forward. Many of the ideas in this paper derive from a recent comprehensive review of the neurobiology of depression and antidepressant action (Willner et al., 2013), which provides detailed discussion and background. (There and here, the subject of our discussion is unipolar major depression; the extent to which the issues discussed generalize to bipolar disorder is beyond the scope of this paper.) The presentation here is more didactic than in our earlier review, with a focus on a smaller number of key studies, and a more linear direction of travel.

In brief, we argue that antidepressants provide an efficient means of reversing the neurotoxic effects of stress, but are much less effective in conditions where vulnerability to depression is elevated and the role of stress in precipitating depression is correspondingly lower; consequently, the issue(s) of vulnerability should feature much more prominently in antidepressant research than has hitherto been the case. Most of the current animal models of depression are based on the induction of a depressive-like phenotype by stress, and pay scant attention to vulnerability. As antidepressants are less effective in more vulnerable individuals, this in turn implies the development of different clinical and preclinical methodologies, and a shift of focus away from the current preoccupation with the hippocampus as a target for antidepressant action in vulnerable patients.

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Definitions

By stress we mean the psychological and physiological response to a forced confrontation with adverse events (stressors) that challenge coping ability and compromise homoeostasis. As coping ability depends to some extent on an individual’s psychological resources, subjectivity is an important determinant in the appraisal of an event as stressful.

Individuals within the population vary in their response to adversity, such that events that precipitate an episode of depression in some individuals may be assimilated without ill effects by others. The issue of the mechanisms that underlie resilience to stress is a topic of considerable current research interest (e.g. Russo et al., 2012; Neigh et al., 2013; Wiborg, 2013). However, in this paper we are primarily concerned with a different issue: factors such as childhood trauma (and others, described later) that are known to increase the risk of depression at the population level. When we use the term ‘vulnerability’ we are referring to the elevated vulnerability that is also described by the terms ‘predisposition’ and ‘diathesis’ (we use these terms interchangeably).

An increased risk of depression could reflect either an increased response to stress, such that a predisposed individual requires lower levels of stress to precipitate an episode, or that such individuals experience a higher frequency of stressful events. For the purposes of this paper we have assumed that an elevated level of risk involves an increased sensitivity to stress rather than an increased exposure to stressors. For some of the risk factors we discuss, there is evidence that this is indeed the case (e.g. recurrent depression: Kendler et al., 2000; childhood abuse: Kendler et al., 2004; Harkness et al., 2006; Shapero et al., 2014).

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Stress, depression and antidepressant action

The monoamine hypothesis of depression revisited

Given that the monoamine hypothesis remains unchallenged as the basis for the clinical pharmacotherapy of depression, it is worth reviewing briefly its evidence base. The hypothesis is in fact four hypotheses, concerning the role of 5HT and NA in depression and antidepressant action. For both NA and 5HT the evidence that these systems are underactive in depression has not stood the test of time. In the case of NA, the evidence was never compelling and did not improve with the development of more effective measurement techniques (Ressler and Nemeroff, 1999; Delgado, 2000). In the case of 5HT, an abnormality was confirmed, but not in a specific relationship to depression; a decrease in whole-brain 5HT turnover, first identified as a correlate of depression, was later narrowed to suicide, then broadened to aggression (self-directed and other-directed), and is now understood to relate to a trait of impulsivity and an involvement in a wide range of psychopathological conditions characterized by risky and impulsive decision making (Roggenbach et al., 2002; Carver and Miller, 2006; Homberg, 2012). Recently, a decrease in brain levels of 5HT, NA and dopamine (DA) has been reported in depressed patients, resulting from an increase in MAO activity, which itself may be secondary to an increase in cortisol levels (Meyer, 2012). However, as discussed below, decreased monoamine levels are unlikely to play a major causal role in depression.

In contrast to the failure of this half of the monoamine hypothesis, there is very strong evidence to support the hypothesis as an explanation of antidepressant action. This evidence derives primarily from studies initiated by Delgado and colleagues in the 1990s showing that the blockade of monoamine transmission causes a rapid and profound relapse to depression in patients who have been successfully treated with antidepressant drugs. A dietary manipulation, tryptophan depletion, which decreases brain levels of 5HT, 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, a pharmacological manipulation, AMPT, which inhibits the synthesis of NA and DA, precipitates a similar relapse in depressed patients successfully treated with NRIs (Delgado et al., 1993; Miller et al., 1996). Similar findings have been reported in animal studies; both 5HT depletion and NA depletion also block the action of SSRIs and NRIs, respectively, in animal models of depression (Lucki and O’Leary, 2004). These actions are specific; 5HT depletion does not block the action of NRIs and NA depletion does not block the action of SSRIs. Hence, SSRIs are shown to work by potentiating 5HT, and NRIs by potentiating NA (but not vice versa), exactly as predicted. Further evidence to support this conclusion comes from the observation that SSRIs, but not tricyclics (which act at both 5HT and NA synapses) are ineffective in genetically manipulated animals lacking the 5HT1A or 5HT2B receptor (Santarelli et al., 2003; Diaz et al., 2012).

Significantly, depletion of neither 5HT nor NA has major effects on mood in people who are not depressed or at high risk for depression (Ruhé et al., 2007). Similarly, neither manipulation produces a depressive phenotype in control animals that have not been subjected to animal models of depression and treated with antidepressant drugs (Cryan et al., 2004; Lucki and O’Leary, 2004; Yalcin et al., 2008). Thus, although antidepressant drugs are confirmed as working by potentiating monoamines, these studies also demonstrate definitively that depression is not caused by a loss of monoaminergic tone. To understand the neural basis of depression, we need to look elsewhere.

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The depressed brain

Neuroimaging studies have thrown light on the nature of the abnormalities that are present in the brains of people who are depressed. Two abnormalities in particular have been extensively described: functional changes in the prefrontal cortex (PFC) and structural changes in the hippocampus.

There is a large and complex body of functional imaging of depressed patients that is beyond the scope of this paper to review in detail. The most prominent feature, repeatedly confirmed, is that blood flow is increased in the ventromedial prefrontal cortex (vm-PFC) of people who are depressed, and decreased in the dorsolateral prefrontal cortex (dl-PFC). [In this paper, as elsewhere (Willner et al., 2013), we use the term vm-PFC loosely to denote a ‘medial prefrontal network’ (Price and Drevets, 2012), which, in addition to Brodman’s area 10, also includes the ventral anterior cingulate cortex (ACC) and parts of the orbitofrontal cortex. While cross-species comparisons are not straightforward, it is generally assumed that the prelimbic and infralimbic cortex represent the corresponding area in the rat (Roy et al., 2012)]. These changes can be understood in the context of an even larger literature reporting the results of functional imaging studies in people who are not depressed (including studies in which volunteers are subjected to a depressive mood induction), and neuropsychological studies of the effects of localized brain damage. Broadly speaking, these functional changes provide a basis for the expression of many of the symptoms of depression; symptoms such as psychomotor retardation, apathy and decreased attention are compatible with a decrease in activity within the dl-PFC, whereas symptoms such as increased psychological pain, anxiety, tension and depressive rumination are expected in relation to an increased activity within the vm-PFC. Less well characterized than the functional changes in PFC are corresponding functional changes in subcortical structures, including an increased responsiveness of the amygdala to aversive stimuli and a decreased responsiveness of the nucleus accumbens (NAc) to rewarding stimuli, which can be related, respectively, to features of depression such as increased anxiety and anhedonia (Phillips et al., 2003a, 2003b; Price and Drevets, 2012; Wiborg, 2013; Willner et al., 2013). The symptoms of depression appear to arise from a shift in the balance of activity in these cortical and subcortical systems (Fig. 1).

Fig. 1
Fig. 1
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Alongside the functional changes in PFC is evidence – again, extensive – that the volume of the hippocampus is lower in people who are depressed (Czeh and Lucassen, 2007; Cole et al., 2010; Willner et al., 2013). This decrease in volume increases with both severity and duration of depression, suggesting the presence of ongoing processes that causes some form of structural damage. However, unlike the situation in PFC, the involvement of the hippocampus in depression is somewhat unexpected on the basis of neuropsychological knowledge. The hippocampus is well placed to play a role in depression because the hippocampus and the overlying entorhinal cortex play a central role in integrating contextual information from all of the other cortical association areas, with connections to many limbic and motor subcortical structures (Van Hoesen, 1995; Sesack and Grace, 2010). However, the extensive literature on the effects of hippocampal damage in humans and animals deals almost exclusively with aspects of learning and memory (Mishkin et al., 1998; Spiers et al., 2001; Moscovitch et al., 2006). Although many people who are depressed may show some impairment of learning and memory, this problem is usually understood as being secondary to difficulties in concentration, does not form a prominent part of the symptom profile and is not included among the diagnostic criteria for depression.

Nevertheless, the hippocampus does play a central role in depression, and damage to this structure is the likely cause of the functional changes in PFC that underlie the symptoms of depression. This comes about because the hippocampus also controls the body’s response to stress through its position as one of the two central structures that control the main stress-responsive neuroendocrine system, the hypothalamus–pituitary–adrenal (HPA) axis (Jacobson and Sapolsky, 1991; Belzung and Billette de Villemeur, 2010). The other structure is the amygdala, and the relationship between the hippocampus and amygdala in the control of the HPA axis explains how stress can precipitate an episode of depression.

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How stress precipitates depression

After processing in sensory cortical areas, stressful stimuli activate the amygdala, which stimulates the HPA axis resulting, through activation of the hypothalamus and anterior pituitary, in the release of glucocorticoids (GCs) (cortisol in humans or corticosterone in rodents) from the adrenal cortex. (As described later, the PFC plays a critical role in the appraisal of stressful stimuli and in determining the extent of amygdala activation.) In addition to their peripheral actions, GCs also feed back centrally, where they excite the amygdala creating a positive feedback system that drives the HPA axis to ever higher levels of activity. However, GCs also feed back on the hippocampus, which inhibits the activity of the HPA axis. The hippocampus and amygdala also have reciprocal inhibitory neural connections. By these means, the hippocampal negative feedback system holds down the activity of the HPA system, maintaining GC concentrations within normal physiological limits. This negative feedback mechanism is crucial for limiting the activity of the HPA axis, as without it the positive feedback loop through the amygdala would drive the system to ever higher levels of activity (Jacobson and Sapolsky, 1991; Belzung and Billette de Villemeur, 2010).

However, chronic exposure to GCs is neurotoxic. The hippocampus has the highest density, within the brain, of glucocorticoid receptors (GR), and as a result, granule cells within the hippocampus are at particular risk from these effects. Prolonged GC exposure leads initially to a loss of GRs on hippocampal cells, with a consequent disinhibition of the HPA axis and a further increase in corticosteroid stimulation (McEwen, 1999). If further prolonged, the consequences of the loss of GR-mediated effects for hippocampal cell function, as well as hyperstimulation through the activation of other, primarily glutamatergic, mechanisms, become severe; they include a hyperactivation of calcium-dependent enzymes leading to the production 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 GC (Woolley et al., 1990) cause the death of hippocampal granule cells and severe atrophy of apical dendrites on hippocampal pyramidal cells (McEwen, 1999; Jayatissa et al., 2008; Yu et al., 2008). The extreme case of cell death is not typically observed in postmortem samples from depressed or steroid-treated patients (Swaab et al., 2005), albeit hippocampal atrophy is seen in socially-stressed primates (Uno et al., 1989); however, shrinkage of pyramidal and granule cells almost certainly contributes significantly to the loss of hippocampal volume in depressed patients.

The hippocampus is almost unique within the brain in its ability to recover from neurotoxic damage through a process of adult neurogenesis, the growth and differentiation of new neurons during adulthood, in addition to the recovery from cell shrinkage through processes such as increases in dendritic arborization and spine density, which are also seen in other areas such as the PFC. Despite their relatively small numbers, there is evidence that newly generated neurons can affect the functioning of hippocampal circuits. In rats, neurogenesis decreases across the lifespan, apparently as a function of chronological age (Amrein et al., 2011), but in humans, hippocampal neurogenesis has recently been shown to continue at a significant rate throughout the lifespan (Spalding et al., 2013). Adult hippocampal neurogenesis is powerfully suppressed by both psychosocial and physical stressors or by prolonged corticosterone exposure, as seen in many different species, including primates, and in postmortem 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 neurons into new functional networks. Stress interferes both with the early phases of this process (cell proliferation) and with neuronal survival, maturation of new neurons and the genesis of functional synapses (Wong and Herbert, 2004; Tanti and Belzung, 2013a, 2013b).

The decrease in hippocampal function under conditions of prolonged stress has widespread consequences, because the hippocampus forms part of a complex depression-related circuitry (Fig. 2). At its simplest, the reduction of hippocampal inhibition leads to an increased activity in the amygdala, which drives an increase in activity within the vm-PFC, the functional change that is most characteristic for depression. There are strong reciprocal connections between the vm-PFC and dl-PFC. Therefore, a decrease in dl-PFC function is a likely consequence of an increase in vm-PFC function, providing an explanation of the other major functional change associated with depression. (There are also other subcortical pathways that could alter dl-PFC function, and hence the balance of activity within the dl-PCF and vm-PFC, including a projection from the hippocampus through the NAc and other basal ganglia structures.)

Fig. 2
Fig. 2
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The functional changes identified in depression reflect an increasingly well-established model of the organization of information processing in the forebrain, based on a convergence of evidence from animal and human studies, and involving stimulation by emotionally salient stimuli, focal brain lesions, and functional neuroimaging techniques. In brief, 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 insular cortex, the ventral (subgenual) part of the ACC and the ventral and orbital PFC; and a dorsal ‘cognitive’ circuit involving the posterior (in rodents, dorsal) hippocampus, the dorsal (pregenual) part of the ACC and the dl-PFC. 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 significant situations, whereas the dorsal system is important for executive function, including selective attention, planning, and effortful regulation of affective states (Phillips et al., 2003a; Ernst and Paulus, 2005; Mayberg, 2009; Holtzheimer and Mayberg, 2010, 2011; Hamani et al., 2011). The rostral ACC, which represents a point of contact between these two systems, has been a particular focus of antidepressant research (Pizzagalli, 2011).

It is obvious that, within such a complex circuitry, there is ample scope for the symptoms expressed to vary between depressed individuals, dependent upon activity within discrete cortical and subcortical regions. A well-worked illustration concerns the extent to which stressors are stressful. It is well established that stressors are perceived as more stressful if they are appraised as uncontrollable or unpredictable (the helplessness effect), and this factor also determines the physiological consequences of stress. (Notably, suppression of hippocampal neurogenesis is not seen if chronic stress is predictable, or if coping with stress is possible; Lyons et al., 2010; Parihar et al., 2011.) An elegant series of experiments by Maier and colleagues identifies the vm-PFC and the lateral habenula (lHb) as crucial sites for this variability of outcome (Maier and Watkins, 2010). Stressors activate the amygdala, which in turn activates the lHb, through the lateral hypothalamus (Fig. 2). As a result, the activity of the lHb increases as a function of the intensity of stressors, including the nondelivery of anticipated rewards (Hikosaka et al., 2008; Matsumoto and Hikosaka, 2009; Hikosaka, 2010). The lHb projects in turn, through direct and indirect pathways, to the raphe nuclei (RN) and the ventral tegmental area (VTA). These connections are mainly inhibitory, by GABAergic interneurons (Hikosaka, 2010); for example, 5HT projections from the RN to the hippocampus and vm-PFC are inhibited, which further compromises information processing in these structures (Jasinska et al., 2012; Paul and Lowry, 2013). However, there are complex interactions between 5HT neurons within the RN that lead to activation of the 5HT projection from the dorsal raphe nucleus to the amygdala, resulting in anxiety (Amat et al., 2001, 2006; Jasinska et al., 2012; Paul and Lowry, 2013). At the same time, the lHb projection to the VTA, through the rostromedial tegmental nucleus, inhibits the mesolimbic DA projection to the NAc, resulting in anhedonia (Hong et al., 2011; Stamatakis and Stuber, 2012; Lamel et al., 2014). These two effects, taken together, provide a neurobiological substrate for the negative information processing bias that characterizes depression (Disner et al., 2011; Willner et al., 2013). However, if stress is controllable, lHb outputs are over-ridden by descending pathways to the RN and lHb from the vm-PFC (Maier and Watkins, 2010; Lamel et al., 2014). Activity in this projection can be manipulated pharmacologically, by microinjections within the prelimbic cortex (an area homologous to part of the PFC in the rat), such that controllable stress is perceived as uncontrollable, or vice versa (Maier and Watkins, 2010).

Thus, the vm-PFC is not simply a passive recipient of signals arising in subcortical structures, but can also engage in emotional self-regulation (Roy et al., 2012) with consequences for stress-related activity in other brain regions. In particular, by inhibiting the lHb, the vm-PFC interrupts a positive feedback system that drives up activity in the amygdala, and the loss of this restraint when stress is perceived as uncontrollable combines with the gradual neurotoxic loss of hippocampal function to shift the balance of the brain activity (Fig. 1) in a depressive direction. The dependence of the vm-PFC output to the lHb on the appraisal of stress controllability means that depression is not an inevitable result of hippocampal damage and the resulting disinhibition of the amygdala–HPA system. However, it is inevitably the case that, the greater those effects, the greater the probability that emotional regulation would fail (Clark and Beck, 2010), resulting in the precipitation of a depressive episode.

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Intracellular mechanisms of antidepressant action

We have already seen that, for SSRIs, their canonical action to increase activity at 5HT synapses is essential for their antidepressant action in both depressed patients and animal models of depression, with evidence that the action is mediated through 5HT1A and 5HT2B receptors. Over the past two decades, evidence has accumulated about the consequences of this effect in terms of post-transductional changes in the target cells, leading to a restoration of normal functioning and reversal of the neurotoxic effects of stress.

Much of this work has been conducted using an animal model of depression that has been extensively validated; the chronic mild stress (CMS) procedure. In this model, rats or mice are exposed chronically to a constant bombardment of unpredictable microstressors, resulting in the development of a plethora of behavioural changes, including decreased response to rewards, a behavioural correlate of the clinical core symptom of depression, anhedonia. Reward sensitivity is usually tracked by periodic (typically weekly) tests in which the animal is given access to a highly preferred sweet solution, or to a choice between a sweet solution and plain water. Consumption of, or preference for, the sweet reward decreases over weeks of exposure, but can be restored to normal levels by chronic treatment with antidepressant drugs. This effect typically takes several weeks, paralleling the clinical situation. In addition to a decreased response to sweet rewards, animals subjected to CMS are generally less responsive in other tests of rewarded behaviour, such as place preference conditioning or intracranial self-stimulation, and also show all of the other symptoms of depression that are possible to model in animals, such as decreases in sexual, investigative and other motivated behaviours, decreased self-care, weight loss, disrupted sleep patterns, and phase advance of the diurnal rhythm. Reversal of CMS effects has been seen with representatives of all of the clinically used chemical families of antidepressant drug, but not with nonantidepressants of various kinds. CMS also has extensive physiological and neurochemical parallels with depression. Overall, therefore, the model has a high degree of validity, and the results of experimental studies using it can with some confidence be generalized to depressed patients (Willner et al., 1987; Willner, 1997a, 2005).

Animals subjected to CMS show a pronounced atrophy of dendrites in the hippocampus and PFC and a substantial loss of hippocampal volume, all of which changes were reversed by chronic treatment with antidepressants (Bessa et al., 2009; Wiborg, 2013). Similarly, CMS produces a profound decrease in hippocampal neurogenesis, as also observed in the human depressed brain (Lucassen et al., 2010), which again, is reversed by chronic antidepressant treatment (Hanson et al., 2011; Samuels and Hen, 2011; Wiborg, 2013). 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 following chronic treatment with drugs from very different pharmacological classes, including not only commercially-available antidepressants that act at monoaminergic targets (Malberg et al., 2000; Manev et al., 2001) but also compounds acting through nonmonoaminergic 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 antagonist (David et al., 2007), as well as nonpharmacological treatments, such as electroconvulsive therapy (Malberg et al., 2000) or vagus nerve stimulation (Revesz et al., 2008), and other manipulations that have antidepressant-like effects in rodents, such as physical exercise (Van Praag et al., 1999; Kronenberg et al., 2003; Ota and Duman, 2013) or rearing in enriched environments (Kronenberg et al., 2003; Veena et al., 2009; Schloesser et al., 2010). Antidepressant treatment has also been reported to increase cell proliferation and neurogenesis in the human hippocampus, studied postmortem (Boldrini et al., 2009, 2012).

Chronic treatment with the SSRI citalopram and the NRI desipramine reversed distinct cognitive impairments in animals subjected to CMS, which were blocked by acute antagonism of transmission at 5HT and NA synapses, respectively (Bondi et al., 2010; Furr et al., 2012), confirming once again the importance of the canonical actions at 5HT and NA synapses in the therapeutic actions of antidepressants. With a single exception (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 second messenger cyclic AMP (cAMP). This leads in turn to changes in the activity of protein kinases, resulting in changes in the activity of the nuclear transcription factor cAMP response element-binding protein (CREB), which regulates the activity of a number of genes, with consequent changes in the production of several proteins, the most studied of which is BDNF. Both CREB expression and BDNF levels have been found to be decreased in postmortem studies of depressed suicide victims, but increased by premortem antidepressant treatment (Karege et al., 2005; Pittenger and Duman, 2008). In rats, levels of hippocampal CREB and BDNF mRNA and protein are decreased by stress procedures such as CMS, and increased by chronic, but not acute, administration of antidepressants of all classes (Nibuya et al., 1995; Duman and Monteggia, 2006; Martinowich et al., 2007). The functional significance of these changes in CREB and BDNF is nicely illustrated by a study by Song et al. (2006) in which exposure to CMS decreased CREB and BDNF levels in the hippocampus and also caused a pronounced increase in HPA activity and impairment in a spatial learning task, all of which effects were reversed by chronic treatment with imipramine or fluoxetine. Behavioural responses to antidepressant treatment are blocked in mutant mice with full or forebrain-specific impairment of either BDNF or its receptor, TrkB (Saarelainen et al., 2003; Monteggia et al., 2004; Ibarguen-Vargas et al., 2009), or by a region-specific knockdown of BDNF in the dentate gyrus or ventral subiculum of the hippocampus (but not in the CA1 or CA3 fields) (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).

These effects are region-specific, as opposite effects are seen in the NAc. Desipramine and fluoxetine both decreased CREB function as well as CREB-regulated target gene expression in this area, and blocked the effects of stress (Chartoff et al., 2009), whereas inhibition of CREB in this brain region produces an antidepressant-like effect (Newton et al., 2002). Similarly, BDNF increases depression-like behaviour when injected into the VTA, whereas inhibition of BDNF signalling in the NAc has the opposite effect (Eisch et al., 2003; Berton et al., 2006; Krishnan and Nestler, 2008). Thus, both CREB and BDNF appear to have opposite functions in the hippocampus (antidepressant) and NAc (prodepressant).

CREB also regulates the expression of another neurotrophin, vascular endothelial growth factor (VEGF) (Lee et al., 2009). Similar to BDNF, VEGF expression in the hippocampus is decreased by stress and increased by chronic antidepressant treatment; blockade 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 hippocampal 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.

Chronic administration of BDNF directly into the hippocampus increases neurogenesis (Scharfman et al., 2005), which, as discussed earlier, is suppressed by CMS (Hanson et al., 2011; Samuels and Hen, 2011; Wiborg, 2013). 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 drugs on proliferation and survival (Sairanen et al., 2007; Bergami et al., 2008; Li et al., 2008). This demonstrates that BDNF mediates the stimulation of neurogenesis and synaptogenesis by antidepressants. Similarly, central VEGF infusion increases cell proliferation and the survival of immature neurons (Jin et al., 2002; Warner-Schmidt and Duman, 2007). Further, VEGF knockout mice have lower levels of hippocampal cell proliferation and immature neurons (Sun et al., 2006), whereas viral-mediated VEGF overexpression has the opposite effect (Cao et al., 2004). It is therefore likely that the involvement of VEGF in the effect of antidepressants is also through its effect on neurogenesis and synaptogenesis.

As noted earlier, the antidepressant 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 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, whereas noradrenergic stimulation has the opposite effect (Kulkarni et al., 2002; Rizk et al., 2006). The crucial role of neurogenesis and synaptogenesis in antidepressant action was confirmed by a study in which Santarelli et al. (2003) used focused X-irradiation to block cell proliferation in the hippocampus and showed that this treatment blocked both neurogenesis and behavioural recovery in the CMS model following administration of both 5HT and NA uptake inhibitors.

Taken together, these studies confirm that the proneurogenic and synaptogenic effect of chronic antidepressant administration operates through (i) inhibition of 5HT or NA uptake, causing (ii) stimulation of 5HT1A/5HT2B and noradrenergic receptors, with effects on (iii) intracellular second messengers and (iv) protein kinases, leading to increased expression of (v) CREB and (vi) BDNF and VEGF, which (vii) stimulate neurogenesis and synaptogenesis, leading to (viii) restoration of hippocampal function and (ix) a rebalancing of information processing in the forebrain (Willner et al., 2013). Or to summarize, antidepressants act in the hippocampus (and to some extent, in the PFC) to reverse the neurotoxic effects of stress. Although most of the studies that contribute to this conclusion were conducted in animals, the literature contains a sufficient body of human work, reviewed above, to be reasonably confident that this conclusion also provides an explanation of the clinical effectiveness of antidepressants.

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Heightened vulnerability to depression and resistance to antidepressant treatment

Theoretically trivial and nontrivial factors in antidepressant treatment resistance

The elegant discovery that antidepressants are effective in repairing the stress-damaged brain makes it even more frustrating that the reach of antidepressant treatment is so limited. 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; Belzung, 2013).

Many cases of antidepressant resistance arise from causes that are clinically significant but theoretically trivial, in the sense that it is obvious why patients are resistant in those circumstances. These causes include pharmacokinetic factors (such as polymorphisms of liver cytochrome 450 enzymes or failure to penetrate the blood–brain barrier), misdiagnosis (as in the early stages of vascular or Alzheimer-type pathology, thyroid or folate deficiency, bipolar disorder or normal sadness) and comorbidity with other mental disorders that are themselves very difficult to treat (general anxiety, panic or post-traumatic stress disorder, social phobia) (Willner et al., 2013; El-Hage et al., 2013a). The extent of these problems is unknown, but it is unlikely that they approach anywhere close to the 30% of patients who fail to respond to antidepressants in clinical trials. However, in addition to these theoretically trivial factors, resistance to antidepressant treatment is also associated with a range of factors that are nontrivial, in the sense that the reason for the association is not obvious. A striking feature of these ‘nontrivial’ causes of treatment resistance is that they are also risk factors for the onset of depression.

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History of depression as a risk factor for heightened vulnerability and treatment resistance

Depression is a recurrent condition, in which each episode increases the probability of a further episode (American Psychiatric Association, 2000; Solomon et al., 2000). However, there are many studies demonstrating that the association between severe stress and depression decreases with each successive episode, as 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 likelihood 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). Thus, over the course of a lifetime of depressive episodes, the onset of depression becomes less stress-dependent and increasingly autonomous. This effect can be described both neurobiologically: 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). The decreasing role of stress in recurrent depression may also reflect that in some cases recurrent depression could be considered a form of bipolar disorder (characterized by alternation of depressive episodes and normal mood, rather than by cycling between depressed mood and mania or hypomania).

In addition to being more readily precipitated by lower levels of stress, recurrent depressions are more difficult 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 to some extent reflect the neurological damage associated with recurrent depression, which, as discussed below, does not fully recover. However, it is unlikely that this provides the whole explanation because the greater difficulty of treating recurrent depressions reflects a specific failure of antidepressant drug treatment; the efficacy of cognitive therapy for depression is maintained across repeated episodes (Leykin et al., 2007). Cognitive therapy and pharmacotherapy engage different mechanisms within the PFC (Kennedy et al., 2007; Mayberg, 2009; Clark and Beck, 2010; Hamani et al., 2011), and the maintenance of the efficacy of psychotherapy presumably reflects the fact that psychotherapy engages the PFC directly, unlike antidepressant drugs, which act primarily within the hippocampus. [Antidepressants do also influence monoamine activity within the PFC (Weikop et al., 2007), but, as discussed above, their actions within the hippocampus are critical for behavioural recovery.]

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Genetic factors in heightened vulnerability and treatment resistance

Similar to the aftermath of repeated episodes of depression, a genetic predisposition for depression also primes the brain to respond in a depressive manner to lower levels of stress. For example, in a study of women at low and high genetic risk for depression, those with a low genetic risk showed the typical pattern of high stress exposure before a first episode and decreasing stress exposure before subsequent episodes. However, in those with a high genetic risk (a family history of depression and a depressed co-twin) the first episode of depression was precipitated by very low levels of stress, and this did not change across episodes (Kendler et al., 2001a).

Genome-wide association studies (GWAS) have generally failed to support an association between depression and specific genes (Hek et al., 2013; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, 2013), perhaps reflecting a situation in which genes predispose to increased responsiveness to stress, rather than to depression per se. Nevertheless, several genes have been identified that are associated with both predisposition to depression and antidepressant treatment resistance – for example, polymorphisms of genes coding for the CB1 receptor (Domschke et al., 2008; Juhasz et al., 2009) and the 5HT1A receptor (Kato and Serretti, 2010). The genetic variant that has been most studied 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. In the absence of stress, all genetic subtypes have the same low risk of depression, but as the frequency of stressful events increases, the risk of depression is greatly elevated in individuals homozygous for the short allele of the 5HTTLPR gene relative to individuals homozygous for the long allele, with heterozygotes showing an intermediate level of risk (Caspi et al., 2003, 2010; Uher and McGuffin, 2008). [There has been some controversy over this finding (Risch et al., 2009), but it was confirmed in a large meta-analysis, albeit in relation to chronic (family or medical) stress only, not to episodic life events (Karg et al., 2011; see also Jenness et al., 2011); a potential mechanism is described by Jasinska et al. (2012).] The parallel finding is that individuals homozygous for the short allele of the 5HTTLPR gene are less responsive to antidepressant treatment than individuals homozygous for the long allele, with heterozygotes showing an intermediate response (Serretti et al., 2007; Zobel and Maier, 2010; Licinio and Wong, 2011).

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Developmental and personality factors in heightened vulnerability and treatment resistance

Developmental factors, such as multiple loss events (Souery et al., 1999), are also associated with both vulnerability to depression and antidepressant treatment resistance. The developmental factor that has been most studied is childhood maltreatment. A recent meta-analysis (Nanni et al., 2012) reported that, across 16 studies involving over 23 000 patients, childhood maltreatment was associated with a greatly elevated risk of developing recurrent or persistent depression (odds ratio=2.27 relative to children who had not been abused). The same study reported a significant increase (overall odds ratio=1.40) in the rate of failure to respond to treatment, combining data from 10 clinical trials with over 3000 participants. However, when the results are broken down according to treatment modality, significant increases in the odds ratio for failure were seen in studies of antidepressant treatment, or combined pharmacotherapy and psychotherapy, but no significant resistance to treatment was seen in studies of psychotherapy alone. This latter result demonstrates that it is not simply the case that depression is more difficult to treat in individuals who have been maltreated as children; the effect is again specific to treatment with antidepressant drugs, which act through the hippocampus, but is not seen with psychotherapy, which engages the PFC directly.

Much of the influence of both genetics and early traumatic events on chronic depressive symptomatology is mediated through the personality 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; Kendler and Myers, 2010). 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 (Bukh et al., 2011). Similarly to depression, a high level of neuroticism is also associated with a negative information-processing bias (Chan et al., 2007), and 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 cognitive vulnerabilities (Joiner et al., 2005; Lakdawalla and Hankin, 2008).

Neuroticism is also well established as a factor associated with resistance to antidepressant treatment (Souery et al., 1999; Bock et al., 2010).

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Physiological correlates of heightened vulnerability and treatment resistance

Recent research has established that early life stress has enduring 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 vulnerabilities to depression (Heim et al., 2008; Pechtel and Pizzagalli, 2011). For example, people who had been abused or institutionalized as children were more anhedonic than nonabused controls, and they had decreased reward-related activity in the NAc (Dillon et al., 2009; Mehta et al., 2010). Adults who have been traumatized as children also show greater electrophysiological responses to angry faces or voices (Pechtel and Pizzagalli, 2011), as well as a greater amygdalar response to negative events (Taylor et al., 2006; Joormann et al., 2012). 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 nondepressed 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 depression with these functional changes (Zhong et al., 2011).

As in depression itself, these neurological vulnerabilities to depression may result to some extent 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 GRs with a consequent decrease in inhibitory feedback control (Heim et al., 2008; Essex et al., 2011; Wilkinson and Goodyer, 2011). Maternally separated rats, an animal model of early life stress, show a similar HPA dysregulation (Rentesi et al., 2010), associated with an increase in reactivity to stressors (Holmes et al., 2005), and decreased levels of BDNF, hippocampal cell proliferation and synaptic plasticity (Aisa et al., 2009), reflecting stress-induced epigenetic changes in hippocampal gene expression (Weaver et al., 2004; Machado-Vieira et al., 2011; Bagot et al., 2012). Converging results are seen in relation to the genetic predisposition to depression. The short allele of the 5HTTLPR gene, as well as a polymorphism of the 5HT1A receptor, is associated with increased amygdala activation in depressed patients (Munafò et al., 2008; Frodl et al., 2008b; Furman et al., 2011), and carriers of the short allele have been reported to have increased HPA stress reactivity (Gotlib and Joormann, 2010). Similarly, first-degree relatives of depressed patients have increased HPA reactivity, as well as a ‘depression-like’ sleep EEG profile (Holsboer et al., 1995; Lauer et al., 1998).

Whereas some depression-related functional or structural changes are counteracted by pharmacological interventions or psychotherapy (Quide et al., 2012), others persist after remission of symptoms. Effects reported include hippocampal volume changes (Neumeister et al., 2005; Cole et al., 2010), reduced frontocingulate functional connectivity (Aizenstein et al., 2009) and neurochemical abnormalities in the ACC and PFC (Bhagwagar et al., 2006, 2008). Persistent cognitive, molecular and neurochemical changes are also seen in rodents after recovery from CMS (Elizalde et al., 2008, 2010; Surget et al., 2009). Consistent with these observations, there are reports of persistent cognitive (Bhalla et al., 2006; Preiss et al., 2009) and sensory (Naudin et al., 2012) impairments, and increased responsiveness to aversive stimuli (McCabe et al., 2009), following recovery from a depressive episode. But even against this background, physiological abnormalities that represent risk factors for depression are associated with resistance to antidepressant treatment; compared with patients who responded to treatment, nonresponders have been found to have a higher level of HPA activity (Ising et al., 2007), a smaller hippocampus (MacQueen et al., 2008) and a more active amygdala (Paillère Martinot et al., 2011; Ruhé et al., 2012).

One of the most reliable markers of resistance to antidepressant drug treatment (but not to cognitive therapy) is a persistent high level of activity in the rostral ACC (Pizzagalli, 2011; McGrath et al., 2013). The evidence suggests that this marker is also associated with vulnerability to depression. For example, an increased activation of the rostral ACC in response to errors is seen both in depressed patients (Holmes and Pizzagalli, 2008) and in nondepressed volunteers who carry the short allele of the 5HTTLPR gene that is thought to confer vulnerability to depression (Holmes et al., 2010). High rostral ACC activity is also associated with depressed mood in healthy (nondepressed) children (Boes et al., 2008), and with pessimism (Sharot et al., 2007) and negative emotionality (Santesso et al., 2012) in nondepressed adults.

It is uncertain how to interpret these findings of similarities between physiological precursors to and sequelae of depression, because, unlike genetic and developmental factors that were definitely present before the onset of depression, it is not known whether the physiological abnormalities that are associated with resistance to antidepressant treatment are consequences of the depressive episode, or are risk factors related to genetic or developmental factors that were already present before the episode of depression. However, a recent twin study found that abnormalities on a range of neuropsychological measures were present to an equal extent in individuals with a history of depression and in their never-depressed co-twins (Hsu et al., 2014). This raises the distinct possibility that the abnormalities of HPA axis, hippocampus, and amygdala seen in antidepressant-resistant patients, relative to patients who recovered, may have been present in those individuals even before they became depressed.

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A diathesis-stress model of depression and antidepressant efficacy

The literature reviewed above is summarized in Fig. 3, which depicts a relationship between the extent of depressive diathesis and the effectiveness of antidepressant drug treatment. Antidepressants are most effective in individuals for whom vulnerability is low and the precipitation of an episode of depression requires high levels of stress – essentially, first episodes of depression in individuals with few or no risk factors. As vulnerability to depression increases, the degree of stress needed to precipitate an episode of depression decreases and antidepressants are now less effective. The mechanisms underlying these differential outcomes are also summarized in Fig. 3. When the predisposition to depression is low, the high intensity of stress causes excessive stimulation of the HPA system, damaging the hippocampus and setting in train the constellation of physiological changes that result in expression of the symptoms of depression, illustrated in Fig. 1 as increased activity in the amygdala and vm-PFC and decreased activity in the NAc and dl-PFC. Antidepressants repair the damaged hippocampus and restore a normal balance. When the predisposition to depression is high, as a consequence of genetic factors or previous experiences, the physiological changes that characterize depression are already in place and only a low level of current stress is needed to cross the threshold into a depressive episode. Because levels of current stress are low, acute damage to the hippocampus – the substrate for antidepressant action – is minor or absent.

Fig. 3
Fig. 3
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As reviewed, these relationships appear to hold true across a range of different factors associated with risk and treatment. The only major exception relates to the sex difference in the risk for depression, which is 1.5–3 times more common among women compared with men. Unlike the other factors reviewed, this increased vulnerability among women is not accompanied by treatment resistance. Indeed, women have been reported to respond significantly better than men to SSRIs, though not to tricyclic antidepressants, possibly as a result of interactions between gonadal hormones and the 5HT system (Khan et al., 2005). However, nondepressed women do not obviously express the physiology associated with other risk factors for depression. In particular, HPA activity varies cyclically in women but is not generally more active or more reactive than in men (Uhart et al., 2006; Walder et al., 2012). Similarly, healthy men and women do not differ in the size of the hippocampus (Liu et al., 2003; Li et al., 2007), and if anything, women have a less reactive amygdala than men (El-Hage et al., 2013b). Thus, the basis for the sex difference in risk for depression appears to differ from that for other risk factors. Indeed, Kendler et al. (2001b) reported that, although men and women tend to experience, and be affected by, different types of stressful life events, the greater prevalence of depression in women could not be explained by differences in either frequency of exposure to stressful life events or sensitivity to their pathogenic effect. It may be that the greater vulnerability of women results to a large extent from differences in psychological factors (Kendler et al., 2001b; Simonds and Whiffen, 2003; Hyde et al., 2008) that engage physiological systems other than those discussed here. There has been remarkably little work on sex differences in animal models of depression, but one pointer to a psychological explanation of the sex difference in the risk of depression is that in the learned helplessness and CMS models, females rats are actually less likely than males to develop depressive behaviours (Dalla et al., 2010).

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Implications

Targets for antidepressant research

The growing evidence that antidepressants act by repairing a damaged hippocampus has stimulated an intensive search for new antidepressant agents that would act in a similar manner. Figure 4 lists some agents that act as HPA antagonists (to decrease the threat to the hippocampus), neuroprotective agents (to protect the hippocampus against GC-induced neurotoxicity), or promoters of neurogenesis (to repair the damage). For all of the drugs (or drug classes) listed in Fig. 4, there is evidence of an antidepressant potential, either from animal models of depression or in some cases, from clinical trials for treatment-resistant patients. However, despite the volume, it is questionable whether these lines of research will result in clinical gains, because there is little reason to expect that the efficacy of any of these, or similar, agents would exceed that of current antidepressants (with the possible exception of glutamate antagonists, which may also have antidepressant effects outside the hippocampus by actions other than neuroprotection). Current drugs already act efficiently to reverse the effects of stress, and it is difficult to see how the actions listed in Fig. 4 would be expected to increase this effect. Perhaps ways might be found to increase the speed of onset of antidepressant action, but there is as yet little to encourage optimism on this front.

Fig. 4
Fig. 4
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It would seem more productive to search for new antidepressants in parts of the depression neurocircuitry (Fig. 2) outside the hippocampus. There is precedent for such discoveries. For example, deep brain stimulation (DBS) of the lHb, using stimulation parameters that inhibit neural activity, has antidepressant-like effects in animal studies (Li et al., 2011; Winter et al., 2011), and a beneficial effect of DBS has been reported in one severely treatment-resistant depressed patient (Sartorius et al., 2010). Given that the lHb has strong interconnections with the suprachiasmatic nucleus and shows circadian rhythmicity, this might well turn out to be the site of action of the melatonin derivative 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 depression in over 40 countries (Carney and Shelton, 2011). For the same reason, the lHb is also a strong candidate for the antidepressant effect of REM-sleep deprivation, which is effective after a single night, albeit only until the next sleep (Dallaspezia and Benedetti, 2011).

The mesolimbic DA system is another potential target. DA was not included in the original monoamine hypothesis of depression, in part because DA had not been firmly established as a neurotransmitter at the time the hypothesis was proposed, but subsequent research established that, after chronic administration, antidepressants indirectly increase the responsiveness of D2 receptors in the NAc, and that blockade of D2 receptors reverses the behavioural recovery in the CMS model (Willner, 1997b) and clinical recovery in antidepressant-treated patients (Willner et al., 2005). Drugs acting directly on the mesolimbic DA system have been shown to have antidepressant efficacy (Willner, 1997b). These include atypical neuroleptics such as sulpiride (Chen et al., 2011), which act in the VTA to disinhibit DA neurons, and directly acting D2 receptor agonists such as pramipexole (Corrigan et al., 2000), which act in the NAc, another region where DBS has been shown to have antidepressant effects in treatment-refractory patients (Schlaepfer et al., 2008; Bewernick et al., 2010). The importance of the mesolimbic system is highlighted by recent reports that both depressive and antidepressant-like effects can be rapidly induced by optogenetic stimulation of the VTA (Lobo et al., 2012; Lamel et al., 2014), albeit that the results are inconsistent (Chaudhury et al., 2013; Tye et al., 2013), perhaps because the VTA–NAc pathway has both appetitive and aversive components (Di Chiara et al., 1999; Faure et al., 2010).

Perhaps the most promising area of research is that focussed on the vm-PFC, which, as discussed above is the major area in which symptoms of depression are generated. There is some evidence that PFC dysfunction in depression is normalized not only by antidepressant drugs, but also by psychological interventions, which cause a top-down reversal of amygdala hyperactivity (Quide et al., 2012). SSRIs increase 5HT release in the PFC (Weikop et al., 2007), and it was recently reported that the integrity of corticostriatal projections from the PFC is essential for the effectiveness of behavioural responses to chronic SSRI treatment in antidepressant screening tests (Schmidt et al., 2012). (It is not yet known whether this would also be the case for NRIs, or for SSRIs in animal models of depression.) Several treatments have been identified that appear to work rapidly, often in treatment-resistant patients, by directly targeting neural activity within the PFC, rather than doing this indirectly through actions in the hippocampus. In particular, DBS of the vm-PFC (which inhibits its activity) has been found to produce antidepressant effects in treatment-resistant depressed patients, which were maintained for up to a year (Mayberg, 2009; Hamani et al., 2011; McGrath et al., 2013). Rapid antidepressant-like effects have also been demonstrated in rats following DBS (Hamani et al., 2010) or optogenetic stimulation (Covington et al., 2010) of the vm-PFC. Antidepressant effects are also reliably observed following repeated transcranial magnetic stimulation of the dl-PFC (Slotema et al., 2010), which is typically applied to the right hemisphere to avoid potential adverse side effects of left hemisphere stimulation. Given the mutually inhibitory connections between the dl-PFC and vm-PFC, activation of the dl-PFC would again be expected to inhibit the vm-PFC.

The inhibitory projection from the vm-PFC to the lHb (Fig. 2) is of particular interest. As discussed above, by activating the lHb, stress modulates activity in ascending 5HT and DA pathways, which creates a negative information-processing bias by increasing the amygdala response to negative stimuli while decreasing the NAc response to positive stimuli. Recent work in human patients and volunteers has demonstrated that antidepressant treatment causes a rapid shift towards a more positive information-processing bias, which appears well in advance of mood improvement (Pringle et al., 2011; Roiser et al., 2012). This suggests that activation of the vm-PFC–lHb projection, with a consequent inhibition of the lHb and disinhibition of ascending 5HT and DA pathways, may be an early effect of antidepressant treatment that precedes a normalization of activity within broader prefrontal networks. DBS of the lHb has been reported to normalize behaviour not only in an animal model of stress-evoked depression, learned helplessness, but also a model of vulnerability to depression, congenital learned helplessness, in which rats are bred to display helplessness even in the absence of stress (Li et al., 2011); the significance of this finding is that congenital learned helplessness is said to be resistant to systemic antidepressant treatment (Vollmayr et al., 2004).

The most exciting recent innovation has been the demonstration of rapid improvements in antidepressant-refractory patients following single intravenous infusions of the NMDA receptor antagonist ketamine (Berman et al., 2000; Zarate et al., 2006; Diazgranados et al., 2010). These effects appear to be mediated by direct actions within the PFC, as ketamine has been shown to suppress activity in the rostral ACC (Salvadore et al., 2009), a strong predictor of successful antidepressant treatment (Pizzagalli, 2011), and this effect probably occurs too rapidly to be mediated through structural changes in the hippocampus. Decreased activity in the rostral ACC and other areas of the PFC is seen within 2 h of ketamine administration (Salvadore et al., 2011; Carlson et al., 2013). At the same time, decreased activity is also seen in the lHb (Carlson et al., 2013), which may be secondary to the effect of ketamine within the vm-PFC (Fig. 2). In rats, the antidepressant-like effects of ketamine have been shown to depend on an increase in glutamate release in the PFC, causing an increase in stimulation of AMPA-type glutamate receptors (Maeng et al., 2008). An increase in cortical excitability, which is consistent with an enhancement of glutamatergic neurotransmission, is seen in depressed patients during the acute recovery following ketamine administration (Cornwell et al., 2012). In the CMS model, a single injection of ketamine reversed not only the anhedonic and other behavioural deficits, 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. An increase in several synaptic proteins was seen within 2 h of ketamine administration, and growth of dendritic spines was seen at 24 h (Li et al., 2010, 2011; Duman et al., 2012). It remains to be determined whether the structural changes seen at 24 h are relevant to the acute clinical effect, which is seen within 2 h, or whether this is sufficiently explained by acute effects of glutamate release within the PFC.

From this brief survey of recent developments, particularly when placed in the context of the previous half century of research, it is evident that improvements in antidepressant therapy for vulnerable patients are more likely to emerge from a shift to new anatomical targets than from a continued research focus on the hippocampus. Even without the emerging literature on antidepressant effects that arise outside the hippocampus (by drugs such as ketamine and procedures such as DBS or cognitive therapy), the striking disconnect between the predominance of the hippocampus in preclinical research, and the much lesser importance of the hippocampus in recent clinical studies of functional changes in the depressed brain would constitute strong grounds for refocusing the preclinical research effort away from the hippocampus.

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Methodologies for antidepressant research

In addition to its implications for the anatomical focus of antidepressant research, the conclusion that antidepressants reverse the neurotoxicity associated with current or recent stress but do not reverse the long-standing brain changes associated with risk factors for depression also has important methodological implications (Table 1).

Table 1
Table 1
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Clinical research typically recruits heterogeneous groups of patients defined only by their meeting diagnostic criteria for depression. We suggest that future clinical research should rigorously define participants according to their clinical history (first vs. later episodes) and the presence or absence of major risk factors (e.g. childhood trauma or genetic markers). Clinical studies should include planned subgroup analyses to search for differential effects associated with degrees of vulnerability, and should be powered accordingly.

We also suggest that preclinical research should take a step back from stress-based models, and redirect the focus to animal models of predisposition to depression (Willner and Mitchell, 2002; Willner et al., 2013), based on the use of repeated episodes (e.g. Isingrini et al., 2010), early life stress (e.g. Rentesi et al., 2010; Uchida et al., 2010), genetic variants that model clinical risk factors (e.g. Kimura et al., 2010; Hoyle et al., 2011) or individual differences associated with resilience to stress (Russo et al., 2012; Neigh et al., 2013; Wiborg, 2013). Such research is in its infancy, and needs to be nurtured to full maturity. Antidepressant drug candidates emerging from such models will be of particular interest if they are more effective than conventional antidepressants. Indeed, the ideal models to investigate the potential reversal of risk factors would be those in which conventional antidepressants are ineffective, which poses severe problems for their validation. The challenges of this research agenda cannot be underestimated, but it holds promise for helping the people who are most at risk of developing depression, who have as yet received little benefit from 50 years of antidepressant research.

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Acknowledgements
Conflicts of interest

There are no conflicts of interest.

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Keywords:

antidepressant; depression; habenula; hippocampus; monoamines; prefrontal cortex; treatment resistance; vulnerability

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