Depression is an affective state of negative mood and low arousal. According to the current text revision version of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV-TR), about of depression constitutes an episode of major depressive disorder (MDD) if it is denoted by at least five of nine symptoms: (1) depressed mood; (2) anhedonia; (3) significant weight loss (or gain), or a decrease (or increase) in appetite; (4) insomnia (or hypersomnia); (5) psychomotor retardation (or agitation); (6) fatigue or loss of energy; (7) feelings of worthlessness or guilt; (8) diminished ability to concentrate; and (9) recurrent thoughts of death (not just fear of dying), or suicidal thoughts or actions. One of the symptoms must be either depressed mood or anhedonia. Additionally, the episode must last for at least 2
weeks, and it must cause substantial distress or impairment in an important domain of functioning. Finally, the episode must not be better accounted for by bereavement (which assumes that the episode is not disordered if it causes significant impairment for up to 2
months), and must not be caused by a substance or a medical condition (American Psychiatric Association, 2000
Millions of people are affected by depression each year. Approximately 6.6% of adults, or about 13 million of the adult US population, are estimated to have had episodes that meet current criteria for MDD within a year's time (Kessler et al., 2007
). Based on a single interview, the lifetime prevalence of MDD is estimated to be 16.2%, or 33 million of the adult population (Kessler et al., 2007
). However, lifetime estimates from single interviews are conservative because interviewees vary greatly in their current age and they have difficulty recalling prior episodes of depressive symptoms (Wells and Horwood, 2004
; Kessler et al., 2005
; Kruijshaar et al., 2005
; Moffitt et al., 2009
). Longitudinal studies of community samples in which participants are repeatedly interviewed yield higher estimates of the lifetime prevalence of MDD, often exceeding 40% (Wells and Horwood, 2004
; Kruijshaar et al., 2005
; Moffitt et al., 2009
Most episodes that meet diagnostic criteria for MDD are associated with stressors (e.g., bereavement, marital difficulties, interpersonal conflict, financial difficulties, health issues). For instance, in a longitudinal study of a large community sample of twins of both sexes, 88.1% of diagnosed episodes of MDD were associated with a stressor of some sort (Keller et al., 2007
). Only 11.9% of episodes appeared to be endogenous (depression in the absence of an environmental trigger). However, even many of the apparently endogenous episodes could have reflected a reluctance to disclose stressors of a sensitive nature (Leff et al., 1970
There are two broadly divergent approaches to the relationship between stressors and depression. In some way, the relationship must be mediated by the brain, but the neurological causes of depression are generally acknowledged to be unknown (Berton and Nestler, 2006
). Many researchers, certain that depressive symptoms are maladaptive, search for evidence of stress-induced malfunction in the brain (for recent reviews, see Krishnan and Nestler, 2008
; Savitz and Drevets, 2009
). These researchers attempt to identify the neurological mechanisms responsible for the chronic nature of depression and its association with a variety of medical conditions (McEwen, 1998
), the structural changes in the brain associated with depression and their effects on cognition (Sapolsky, 1996
; Duman, 2004
; Duman and Monteggia, 2006
; Savitz and Drevets, 2009
), and the neurochemical pathways of depression, including the mechanisms by which antidepressant medications (ADMs) reduce symptoms (for a review, see Krishnan and Nestler, 2008
). An integrating theme in this research is that the neurochemistry of depression is disordered, although the precise neurochemicals that are dysregulated are the subject of much debate and research. Monoamine neurotransmitters, glucocorticoids, neurotrophins, and cytokines are the major chemicals thought to be involved in depression (Krishnan and Nestler, 2008
). Regardless of the role of other chemicals, there seems to be consensus that the monoamine neurotransmitters – particularly serotonin (5-hydroxytryptamine or 5-HT), norepinephrine (NE), and, to a lesser extent, dopamine (DA) – are directly or indirectly involved in the biochemical pathways to depression (Krishnan and Nestler, 2008
). All ADMs, for instance, act on monoamines through a variety of mechanisms (see below). Moreover, research on rodents in which monoaminergic receptors have been knocked out, or monoamine transmission has been disabled, has provided strong experimental evidence that monoamines play a role in depressive symptoms and in the antidepressant response, particularly 5-HT and NE (Heisler et al., 1998
; Mayorga et al., 2001
; Cryan et al., 2004
; Dziedzicka-Wasylewska et al., 2006
Other researchers argue that depressive symptoms might be better described by adaptive mechanisms that respond to stressors and threats (Price et al., 1994
; Nesse, 2000
; Watson and Andrews, 2002
; Allen and Badcock, 2003
; Hagen, 2003
; Gilbert, 2006
; Horwitz and Wakefield, 2007
; Andrews and Thomson Jr., 2009
; Nesse and Ellsworth, 2009
; Price, 2009
). These hypotheses do not propose that all episodes of depression are adaptive since all evolved adaptations in the body are susceptible to malfunction and disorder at some rate. Rather, the issue is whether the symptoms currently used to diagnose depressive disorder accurately distinguish the disordered state from normal, adaptive processes (Spitzer and Wakefield, 1999
; Horwitz and Wakefield, 2007
; Wakefield et al., 2007
). Some adaptationist hypotheses restrict their application to symptoms and episodes that do not meet diagnostic thresholds, but such restrictions are intended to exclude true instances of disorder. Consequently, these hypotheses are not falsified in any rigorous sense by evidence that current diagnostic criteria are inaccurate. In any event, evolutionarily oriented researchers tend to focus on the ecological mapping of the symptoms of depression (and the cognitive and behavioral outputs) to the stressors that trigger episodes (Gilbert and Allan, 1998
; Hagen, 1999
; Badcock and Allen, 2003
; Gilbert et al., 2004
; Keller and Nesse, 2004
; Andrews et al., 2007
; Wrosch and Miller, 2009
), largely treating the brain as a black box whose internal structure and operation are unknown.
Both approaches agree that the body has evolved adaptations for responding to stress. They both believe that, in general, environmental stressors trigger mechanisms in the body that regulate multiple body systems so that cognition and behavior can be adaptively modulated to meet the environmental challenge. They also agree that these evolved stress response mechanisms can malfunction. They primarily differ in what constitutes evidence of depressive disorder and the causes of depressive disorder.
Most articulations of the monoamine disorder hypothesis propose that forebrain levels of monoamine neurotransmitters are depleted in depressive disorder – particularly serotonin (5-HT), norepinephrine (NE) and, to a lesser extent, dopamine (DA). However, some have suggested that monoaminergic transmission may be enhanced in depression (Sapolsky, 2004
). The precise direction of association between depression and forebrain monoamine levels is not crucial for the present paper. It is sufficient to say that the neurochemical disorder hypothesis proposes that monoamines, particularly 5-HT and NA, are perturbed in some way.
But monoaminergic perturbation, per se
, is not evidence of disorder. The most prominent definition of disorder is based in evolutionary theory (Spitzer, 2007
), and it argues that at heart of every disorder is an evolved adaptation that is malfunctioning (Wakefield, 1992
). Under this definition, the claim that depression is a disorder of too much or too little of a neurotransmitter is ultimately a claim that the evolved mechanisms that control neurotransmitter levels are malfunctioning.
Monoamine neurotransmitter levels are normally under homeostatic control (Best et al., 2010
involves the regulation of an important substance or physiological parameter within a narrow range around an equilibrium. Minimally, homeostatic mechanisms have a sensor for determining how far the parameter deviates from the equilibrium and feedback mechanisms for bringing the parameter back to equilibrium (Woods, 2009
). For instance, the homeostatic control of core body temperature involves neuronal sensors in the preoptic anterior hypothalamus that connect with various efferent pathways to exert feedback and keep temperature at equilibrium (Romanovsky, 2007
). Additionally, many homeostatic mechanisms can raise or lower the equilibrium in response to environmental contingencies. Thus, the body often responds to an infection by raising the core body temperature equilibrium
– otherwise known as fever (Romanovsky et al., 2005
). Feedback mechanisms then maintain core body temperature around this elevated equilibrium. Because some infections last for weeks or months, fever can last for extended periods of time.
If depression is, in whole or in part, a disorder in the homeostatic mechanisms that regulate monoamine transmission, then it could involve malfunction in: (1) the sensors that monitor monoamine levels (2) the feedback mechanisms that maintain monoamine levels at the equilibrium; or (3) the mechanisms that alter the equilibrium point.
Although most adaptationist research treats the brain as a black box, a common (if unstated) implication of all adaptationist hypotheses for depression is that the relevant neurochemistry is altered to change cognition and behavior in ways that adapt the organism to the environmental contingencies that triggered the episode. An adaptationist perspective on the chronic nature of depression suggests that, like fever, monoamines may be under the control of a homeostatic mechanism that maintains forebrain levels at an altered equilibrium for an extended period of time, presumably because the nature of the stressor requires it (see, e.g., Andrews and Thomson Jr., 2009
The disruption of a mechanism by pharmacological intervention can reveal whether it is under homeostatic control (Young and Goudie, 1995
). Acute exposure to opiates inhibits the firing of noradrenergic neurons in the locus coeruleus by suppressing cyclic adenosine 3′,5′-monophosphate (cAMP) levels (Nestler and Aghajanian, 1997
). However, with long-term (chronic) exposure, firing rates return to normal because a negative feedback mechanism upregulates the cAMP pathway so that it counteracts the drug's effect and returns the system to the equilibrium (Nestler and Aghajanian, 1997
). The neurological changes brought about by homeostatic mechanisms that counteract the disrupting effects of chronic drug exposure are referred to as oppositional tolerance
(Young and Goudie, 1995
; Fava and Offidani, 2011
). These counteractive forces can cause the system to overshoot the equilibrium when the drug is abruptly discontinued (Young and Goudie, 1995
; Fava and Offidani, 2011
). Thus, when an opioid receptor antagonist is used to abruptly block an opiate, the upregulated cAMP pathway causes firing rates to exceed the normal rate (Nestler and Aghajanian, 1997
Some researchers have called for greater research on the neurological responses of homeostatic mechanisms to chronic psychotropic drug use, including ADMs (Hyman and Nestler, 1996
). Others have specifically hypothesized that oppositional tolerance to ADMs may develop in depression (Fava and Offidani, 2011
). Whether the monoamines thought to cause major depression are under homeostatic control has important implications for debates about whether most episodes of MDD are instances of a properly functioning adaptation or true instances of disorder. Homeostatic mechanisms are classic examples of adaptations. Survival and reproduction require the internal environment of the organism to be regulated (Hochochka and Somero, 2002
; Woods, 2009
). The machinery needed to exert negative feedback to maintain physiological conditions within a narrow band around an equilibrium are often complex and difficult to explain by any process other than natural selection. Consequently, evidence that monoamine neurotransmitters were under homeostatic control in patients diagnosed with MDD would suggest that those mechanisms were not malfunctioning.
In this paper, we focus on a straightforward implication of the hypothesis that depression neurochemistry is under homeostatic control: ADM-induced perturbations to monoamine neurotransmitter levels should trigger oppositional tolerance. Previous research provides some support for oppositional tolerance to ADMs in patients diagnosed with MDD. It is not uncommon for depressive symptoms to reemerge after remission while patients are on maintenance ADM therapy (Byrne and Rothschild, 1998
), which is consistent with tolerance (Fava and Offidani, 2011
). Other support comes from a meta-analysis of studies examining the risk of relapse among patients with remitted symptoms after ADM treatment had been discontinued (Viguera et al., 1998
). The authors found that the risk of relapse was positively associated with the duration of ADM treatment. While this relationship was not statistically significant, it became marginally significant in a re-analysis that included an additional study (Baldessarini et al., 2002
). Such evidence suggests oppositional tolerance because longer treatment periods provide homeostatic mechanisms with more time to make neurological changes that oppose pharmacological perturbation (Fava and Offidani, 2011
). However, several subsequent meta-analyses have failed to find any evidence that treatment duration affected the risk of relapse after discontinuation (Geddes et al., 2003
; Kaymaz et al., 2008
; Glue et al., 2010
). At present, evidence of oppositional tolerance in depression is equivocal.
Antidepressant medications vary widely in the degree to which they perturb monoamine levels in the brain (see below). Consequently, perturbational differences in ADMs could affect the degree of oppositional tolerance. This is analogous to the negative feedback forces that springs exert when they are displaced from their equilibrium position. As one pulls a spring from its equilibrium position, the spring exerts an oppositional force that attempts to bring the spring back to equilibrium; the more further one displaces the spring from its equilibrium position, the greater the oppositional force that the spring produces. Similarly, ADMs with greater perturbational effects should trigger stronger oppositional forces that attempt to bring monoamine levels back to equilibrium. The buildup of oppositional tolerance under ADM treatment could then cause the system to overshoot its equilibrium upon discontinuation, and the degree of overshoot should be proportional to the perturbational effect of the ADM.
We hypothesize that monoamine levels are under homeostatic control in patients diagnosed with MDD, and that ADM treatment will cause oppositional tolerance. There are two implications for the present paper. First, the buildup of oppositional tolerance during ADM treatment will attempt to bring monoamine levels back to equilibrium, which will cause them to overshoot the equilibrium after ADM treatment is discontinued. Second, the degree to which monoamine levels overshoot the equilibrium will be positively related to the perturbational effect of the ADM. We do not directly test these implications because we lack relevant perturbational data in humans. Rather, we test two predictions that follow from them.
Since depressive symptoms are under monoaminergic control, ADM treatment tends to decrease depressive symptoms. However, oppositional tolerance during ADM treatment should build pressure for increasing symptoms (Fava and Offidani, 2011
). After ADM treatment is discontinued, the overshoot of monoamines will cause an increase in symptoms that could exceed diagnostic thresholds for a relapse or a recurrence of MDD (hereafter, just relapse
). Since oppositional tolerance will be absent in patients who resolve their episodes without ADM treatment, we predict that the risk of relapse among patients who discontinue ADM treatment will be higher than the risk of relapse among patients who remit without ADM treatment. Second, and more importantly, we predict that the risk of relapse will be positively related to the perturbational effect of the ADM.
We conduct a meta-analysis to test these predictions. Other meta-analyses of ADM discontinuation studies have been conducted (Viguera et al., 1998
; Geddes et al., 2003
; Kaymaz et al., 2008
; Glue et al., 2010
), but they have not been specifically designed to address these questions. Moreover, our meta-analysis offers an important methodological improvement. ADM discontinuation studies vary widely in the criteria that are used to define a relapse. Some studies use a threshold score on a single assessment instrument, while others may use a complex combination of different instruments assessed over multiple time periods. These definitional criteria can have a dramatic affect on the relapse rate (Montgomery and Dunbar, 1993
; Keller et al., 1998
). Studies that use more stringent relapse criteria make it more difficult for an increase in symptoms to qualify as a relapse, resulting in lower relapse rates (Montgomery and Dunbar, 1993
). Prior meta-analyses have not attempted to control for the variability in the stringency of relapse criteria in discontinuation studies, possibly because it is difficult to objectively compare relapses defined by different instruments. For each study, we construct a variable (called stringency
) that can be objectively calculated as the number of assessment hurdles that have to be passed before an increase in symptoms will be defined as a relapse. In general, studies with more assessment hurdles should make it more difficult for an increase in symptoms to qualify as a relapse. If so, our stringency variable should be a negative predictor of the relapse rate.
Before describing the design of our meta-analysis in detail, we discuss how the major ADM classes differ in the degree to which they perturb monoamine neurotransmitter levels.