ReviewThe neurobiology of depression and antidepressant action
Highlights
► Antidepressant treatment does not mirror depression: a treated brain is not ‘normal’. ► Cognitive appraisals of stress-coping bias affective information-processing circuits. ► Similar brain changes in high-stress low-risk and high-risk low-stress depressions. ► Antidepressants reverse stress damage: so most effective in high-stress depressions. ► Common factors in depression vulnerability and antidepressant treatment resistance.
Introduction
Depression is the commonest psychiatric disorder. It is the most disabling medical condition, in terms of years lost to disability, and it is projected that by 2030 depression will be the foremost contributor to the worldwide burden of disease (WHO, 2008). In this review, we focus on unipolar major depressive disorder, which is defined in DSM-IV (American Psychiatric Association, 1994), as a condition characterized by the presence of loss of pleasure or interest in usually pleasurable activities (anhedonia), together with an array of other features, including anergia, changes in sleep and appetite, sadness, and suicidal ideation. Presentations of unipolar major depressive disorder (which we shall refer to as simply ‘depression’) can be very variable, but this fact has not featured prominently in the literature that we shall review.
Depression is characterized by a profoundly negative view of the world, oneself and the future (Beck, 1967), and this negative world-view has been related to negative biases in attention, interpretation and memory (Mathews and MacLeod, 2005). Specifically, studies of cognitive processing in depression have reported increased elaboration of negative information, difficulties disengaging from negative material, and deficits in cognitive control when processing negative information, which inter alia explain why depressed people experience a high level of negative automatic thoughts and pathological rumination (Gotlib and Joormann, 2010). Depressed people are particularly vulnerable to negative psychological feedback, which has a disproportionately disruptive effect on subsequent performance (Elliott et al., 1996). In addition to an increased response to aversive events, depression is also characterized by a decreased response to anticipated (McFarland and Klein, 2008) or actual (Pizzagalli et al., 2008, Chase et al., 2010) rewards, and this provides a cognitive explanation of the core symptom of depression, anhedonia. These two complementary biases, increased negativity and decreased positivity, are central to much of the recent neurobiological literature on depression, because they play directly into two of the major experimental methodologies, functional neuroimaging and animal models of depression.
Since its introduction almost 50 years ago, the monoamine hypothesis (“some, if not all, depressions are associated with an absolute or relative deficiency of monoamines at functionally important receptor sites in the brain”, with the corollary that antidepressants work by correcting these deficiencies) has provided the major neurobiological account of depression. Indeed, until recently, it was the only significant hypothesis, and while its predominance has been to some extent eclipsed by newer concepts over the past decade, it remains the case that the monoamine hypothesis has provided the only significant theoretical framework for antidepressant drug development, proving stubbornly resistant to the numerous and very expensive attempts by the pharmaceutical industry to break out of the monoamine straitjacket with drugs that act through novel mechanisms. As summarized in Fig. 1, newer antidepressants differ from the older drugs in decreasing the incidence of unwanted side effects and/or narrowing the neurochemical target, rather than by introducing novel mechanisms of action. However, improvements in both antidepressant response rates and the slow onset of clinical effect, requiring several weeks of chronic treatment to achieve the full effect, have been minimal. Tolerability has improved, but differences in efficacy are small and difficult to demonstrate, and there is little evidence that the newer antidepressants are more efficacious than the older antidepressants. Indeed, one of the oldest antidepressants, the tricyclic clomipramine, remains among the most efficacious, alongside the serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine, the selective serotonin reuptake inhibitors (SSRIs) sertraline and escitalopram, and the atypical antidepressant mirtazepine (Montgomery et al., 2007, Cipriani et al., 2009). Antidepressants have consistently shown only moderate response rates, with around 30–40% of patients being classified as non-responders, and the latency of clinical onset remains stubbornly long (Trivedi et al., 2006, Holtzheimer and Mayberg, 2011). While antidepressant efficacy has been claimed for a number of non-monoaminergic drugs that are marketed for other indications, and the failure of some novel agents may to some extent involve increased regulatory requirements, the relative lack of progress over the past 50 years is remarkable (Blier, 2010, Baghai et al., 2011).
In this paper we present a comprehensive overview of the neurobiology of unipolar major depression and antidepressant drug action, integrating data from affective neuroscience, neuro- and 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’ psychobiology 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 counteract and repair the effects of stress. We also show that the factors implicated in resistance to antidepressant treatment largely recapitulate the factors involved in vulnerability to depression, and argue that antidepressants are ineffective under these conditions because stress is of minor importance. In Section 5, we discuss the implications of these conclusions for the understanding and treatment of depression, and make some strategic recommendations for future research. But first (Section 2), we explain why it is necessary to give separate consideration to the analyses of depression and antidepressant action.
Section snippets
Different mechanisms for depression and antidepressant action
A feature of the monoamine hypothesis of depression that has gone largely unremarked is that it proposes a single mechanism for both depression and antidepressant drugs: depression results from a decreased functioning in NA and/or 5HT which antidepressants increase back to normal. The same symmetry is seen in most of the more recent hypotheses that will be discussed below. However, the assumption of symmetry is incorrect. There are many differences in the neural bases of depression and
The diathesis/stress model
Individuals within the population vary greatly in their vulnerability 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
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 neurotransmission at 5HT and NA synapses. As discussed earlier (Section 2
Conclusions and research implications
Despite the efficacy of currently available antidepressant medications 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 needed. Understanding the neurobiology of depression has helped researchers uncover a number of novel targets for antidepressant therapies, which are under investigation in
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