Duration and recurrence

According to the DSM 5, one of the features of MDD that makes it pathological and distinct from normal states of negative affect is its prolonged duration (American Psychiatric Association, 2013). Perhaps as a corollary, depressive episodes are believed to be long-lasting. For example, Joiner (Reference Joiner2000) cites Shapiro & Keller (Reference Shapiro and Keller1981) in reporting that the median duration of major depressive episodes (MDEs) is 8 months. It is also widely believed that MDD is highly recurrent such that individuals who recover from an episode are still considered to be at a very high risk for future episodes. For example, in a paper preceded by the quote ‘[s]ingle episodes are extremely rare if the period of observation is significantly extended’, Mueller et al. (Reference Mueller, Leon, Keller, Solomon, Endicott, Coryell, Warsaw and Maser1999) reported that 85% of individuals in a sample who recovered from an index episode had experienced a recurrence by the end of a 15-year follow-up. Both of these estimates come from analyses of the NIMH Collaborative Study of the Psychobiology of Depression and are widely cited because studies with such long follow-ups are few and far between. Taken together, these estimates suggest that MDD can be a disorder of a prolonged and highly recurring course.

However, as has been noted by Eaton et al. (Reference Eaton, Anthony, Gallo, Cai, Tien, Romanoski, Lyketsos and Chen1997, Reference Eaton, Shao, Nestadt, Lee, Bienvenu and Zandi2008), estimates of the chronicity and recurrence of MDD that come from clinical samples do not generalise to most patients who meet MDD criteria. Data from studies in naturalistic European and North American samples suggest that about half of individuals recover from a MDE within a period of 3 months and most (about 75%) experience recovery in a 3–6-month period (Eaton et al. Reference Eaton, Anthony, Gallo, Cai, Tien, Romanoski, Lyketsos and Chen1997, Reference Eaton, Shao, Nestadt, Lee, Bienvenu and Zandi2008; Spijker et al. Reference Spijker, de Graaf, Bijl, Beekman, Ormal and Nolen2002). Thus, long-lasting depressive episodes appear to be quite rare (see also Patten et al. Reference Patten, Wang, Williams, Lavorato, Khaled and Bulloch2010). Although recurrence rates from long-term follow-ups of population-based studies are lacking, the few studies there are suggest that single-episode MDD is more common than recurrent MDD. In one of the longest follow-up studies to date, Eaton et al. (Reference Eaton, Shao, Nestadt, Lee, Bienvenu and Zandi2008) reported that, in a 23-year period, about 35% of individuals experienced recurring depression and 15% experienced an unremitting course. Thus, half of the individuals recovered from their episode within 3–6 months and did not go on to have another episode. Similar findings were produced by a 30–39-year follow-up of a European cohort (Mattisson et al. Reference Mattisson, Bogren, Horstmann, Munk-Jörgensen and Nettelbladt2007), suggesting that significantly extending the observation does not lead to substantially higher rates of recurrence (see also Steinert et al. Reference Steinert, Hofmann, Kruse and Leichsenring2014).

Placebo responses

Another piece of data that bolsters the claim that the diagnosis of MDD can apply to individuals with a wide range of clinical profiles is the diversity and multiplicity of treatments available for depression. On the one hand, there are treatments for intractable cases which include electroconvulsive therapy and transcranial magnetic stimulation. These treatments share the features of acting directly on the brain and requiring extensive medical intervention. At the other extreme there are efficacious treatments for MDD, which are not very intensive. These include unguided self-help (Cuijpers et al. Reference Cuijpers, Donker, van Straten, Li and Andersson2010) and physical exercise (Babyak et al. Reference Babyak, Blumenthal, Herman, Khatri, Doraiswamy, Moore, Craighead, Baldewicz and Krishnan2000).

The most widely recommended and researched treatments for MDD, however, are antidepressants and psychotherapy. Reviews of the literature suggest that about 40–60% of individuals respond to antidepressants or psychotherapy (Walsh et al. Reference Walsh, Seidman, Sysko and Gould2002; Cuijpers et al. Reference Cuijpers, Karyotaki, Weitz, Andersson, Hollon and van Straten2014). This leaves a sizeable proportion of patients who are treatment non-responders. However, it is also noteworthy that around one-third of the patients who are randomised to placebo controls experience clinically significant improvement (Walsh et al. Reference Walsh, Seidman, Sysko and Gould2002; Cuijpers et al. Reference Cuijpers, Karyotaki, Weitz, Andersson, Hollon and van Straten2014). Meta-analytic reviews and aggregation of data from multiple studies suggest that antidepressants are only superior to placebos for individuals with very severe forms of depression (Khan et al. Reference Khan, Leventhal, Khan and Brown2002; Kirsch et al. Reference Kirsch, Deacon, Huedo-Medina, Scoboria, Moore and Johnson2008; Fournier et al. Reference Fournier, DeRubeis, Hollon, Dimidjian, Amsterdam, Shelton and Fawcett2010; Barbui et al. Reference Barbui, Cipriani, Patel, Ayuso-Mateos and van Ommeren2011) and analogous findings have emerged in regards to the efficacy of psychotherapy (Driessen et al. Reference Driessen, Cuijpers, Hollon and Dekker2010). Taken together, these findings suggest that the active treatments for depression are only superior to presumably inert placebos and control conditions for the minority of individuals who have severe or very severe MDD. Caution must be taken when considering severity in relation to treatment response, given that other variables such as chronicity and recurrence also predict treatment response (Hollon et al. Reference Hollon, DeRubeis, Fawcett, Amsterdam, Shelton, Zajecka, Young and Gallop2014). However, there is evidence that a high placebo response rate in depression trials is present even in patients with more complex clinical pictures (Brunoni et al. Reference Brunoni, Lopes, Kaptchuk and Fregni2009). Moreover, the placebo response seems to be increasing over time (Walsh et al. Reference Walsh, Seidman, Sysko and Gould2002), a finding that has been replicated and seems accounted for, statistically, by an increase in the heterogeneity of patient samples (Rief et al. Reference Rief, Nestoriuc, Weiss, Welzel, Barsky and Hofmann2009). It is not difficult to piece together the increase in placebo response with the arguments about the MDD criteria becoming overly inclusive.

Although the placebo response in MDD has often been attributed to non-specific relief that is not thought to endure, most patients who respond to placebos actually stay well (Khan et al. Reference Khan, Redding and Brown2008). Additionally, studies on the long-term course of untreated depression suggest that the outcomes of individuals who do not receive treatment for depression are comparable with the long-term outcomes of individuals who are treated with antidepressants (Hughes & Cohen, Reference Hughes and Cohen2009), again a somewhat puzzling findings if we assume most cases of MDD to be either severe, chronic, recurrent or treatment-resistant.

Patients in clinical trials are (self-)selected on the basis on severity and perceived need for treatment. That even these patients experience a substantial placebo response is consistent with the view that some individuals who meet MDD criteria may better be understood as experiencing normal reactions to life stressors that are self-ameliorating.

Diagnosing and treating depression

Depression is very clearly a significant public health concern. The amount of money that is spent on, as well as is lost to, symptoms of depression clearly attests to this. Highly chronic, frequently recurrent and treatment-resistant depressions are all real phenomena. However, the extremely high prevalence rates that have been reported in prospective studies ‘strain credulity’ and ‘undermine the [diagnostic] model's credibility’ (Parker, Reference Parker2008, p. 842). The evidence reviewed suggests that 35–50% of people will meet the criteria for MDD at some point in a 20–30-year period (Wilhelm et al. Reference Wilhelm, Mitchell, Niven, Finch, Wedgwood, Scimone, Blair, Parker and Schofield2006; Moffitt et al. Reference Moffitt, Caspi, Taylor, Kokaua, Milne, Polanczyk and Poulton2010; Rohde et al. Reference Rohde, Lewinsohn, Klein, Seeley and Gau2013; Angst et al. Reference Angst, Paksarian, Cui, Merikangas, Hengartner, Ajdacic-Gross and Rossler2015). It would not be unreasonable to conclude from these data that if a population of individuals were followed indefinitely and assessed more frequently, most would meet criteria for MDD at some point in their life. Most of these episodes would be brief (Eaton et al. Reference Eaton, Anthony, Gallo, Cai, Tien, Romanoski, Lyketsos and Chen1997, Reference Eaton, Shao, Nestadt, Lee, Bienvenu and Zandi2008; Spijker et al. Reference Spijker, de Graaf, Bijl, Beekman, Ormal and Nolen2002; Patten et al. Reference Patten, Wang, Williams, Lavorato, Khaled and Bulloch2010) and many individuals would not experience another episode (Eaton et al. Reference Eaton, Anthony, Gallo, Cai, Tien, Romanoski, Lyketsos and Chen1997, Reference Eaton, Shao, Nestadt, Lee, Bienvenu and Zandi2008; Mattisson et al. Reference Mattisson, Bogren, Horstmann, Munk-Jörgensen and Nettelbladt2007; Steinert et al. Reference Steinert, Hofmann, Kruse and Leichsenring2014). Most would not seek treatment, which is just as well because many would probably not receive treatment it even if they did seek it. Of those who did seek treatment and were able to obtain it, a sizeable amount would have experienced about the same clinically significant and long-lasting improvement from a sugar pill. This state of affairs is almost impossible to reconcile with a somewhat alarmist view that MDD is best, and perhaps only, understood as being underdiagnosed or underdetected.

Although it may not be appropriate to say that depression is underdiagnosed, it is also not appropriate to simply say that MDD is overdiagnosed. A Goldilocks retort that depression is appropriately diagnosed is obviously not a fair characterisation either. Instead, it seems to be the case that depression is both over- and underdiagnosed. For example, Mitchell et al. (Reference Mitchell, Vaze and Rao2009) reviewed 41 studies on the detection of depression in primary care and found that general practitioners (GPs) only correctly diagnosed depression in about half of patients who met the criteria. They failed to identify depression mostly in patients who had milder symptoms. However, these authors also found that the most common mistake GPs made was diagnosing depression in patients who did not meet the criteria. Thus, at least in primary care, it appears that depression is both over- and underrecognised. These findings should not be dismissed under the assumption that different findings would be obtained in more specialised settings. The diagnostic practices in primary care are very telling of the state of outpatient depression treatment because most treatment for MDD, namely prescription of antidepressants, occurs in the context of primary care (Wun et al. Reference Wun, Lamb, Goldberg, Lam, Donald Li and Yip2011).

In the USA, there are clear data evidencing that patients are increasingly being prescribed antidepressants without receiving a diagnosis of MDD from their physicians, a practice that is more common among GPs than psychiatrist (Mojtabai & Olfson, Reference Mojtabai and Olfson2010). It is not just that patients meet MDD criteria but are not diagnosed as such by their GPs. Rather they do not and have never met MDD criteria. For example, Mojtabai & Olfson (Reference Mojtabai and Olfson2008) reported that, in the USA, only 43% of those currently treated with antidepressants by a GP met the 12-month criteria for a mood or anxiety disorder. In one nationally representative sample, one out of four individuals currently on an antidepressant had never even met the retrospectively assessed criteria for a mood or anxiety disorder at any point in their life (Pagura et al. Reference Pagura, Katz, Mojtabai, Druss, Cox and Sareen2011). In a study that used prospective assessments, about 70% of individuals who took antidepressants never met criteria for MDD and around 40% never met criteria for any of the so-called ‘common’ mood or anxiety disorders assessed (Takayanagi et al. Reference Takayanagi, Spira, Bienvenu, Hock, Carras, Eaton and Mojtabai2014a ). Antidepressants are prescribed in the absence of psychiatric diagnoses for patients who present with sub-threshold symptoms as well as those with generalised psychosocial issues or non-specific somatic complaints (Salmon et al. Reference Salmon, Humphris, Ring, Davies and Dowrick2006; Pagura et al. Reference Pagura, Katz, Mojtabai, Druss, Cox and Sareen2011). Discussing these studies, Pagura et al. (Reference Pagura, Katz, Mojtabai, Druss, Cox and Sareen2011) concluded that ‘antidepressant use is becoming concentrated among people with less severe and poorly defined mental health conditions’ (p. 1441).

Future recommendations

Attention has been called to the fact that most research on depression has focused on its chronic and recurrent forms (Monroe & Harkness, Reference Monroe and Harkness2011, Reference Monroe and Harkness2012). A focus on chronic and recurrent depressions has led to an inability to identify what it is exactly that keeps cases from having a more benign course. In addition to research focusing on less chronic and recurrent depressions, more research is needed to understand milder cases, as well at those that seem to be placebo-responsive.

Depression is heterogeneous both in its symptomatic presentation and its prognosis. It is unsurprising then that whereas some prominent commentators have referred to it as the ‘common cold of psychopathology’ (Seligman, Reference Seligman1975, p. 75), others have emphasised its ‘severe, relapsing, and chronic’ nature (Judd et al. Reference Judd, Paulus, Schettler, Akiskal, Endicott, Leon, Maser, Mueller, Solomon and Keller2000, p. 1501). Although the current diagnostic criteria for MDD have been extensively criticised, discontent appears to be at an all-time high (Greenberg, Reference Greenberg2013; Frances, Reference Frances2014). In this context, in the USA, the National Institute of Mental Health has called for a new empirically derived and biologically based classification system informed by their Research Domain Criteria. Their priorities include a characterisation of the neural bases of depression and the identification of vulnerability genes. Identifying vulnerability genes is an important task. However, given the heterogeneity of depressive presentations, knowing that someone is at risk for MDD can be of limited value, especially if around half of the population is at risk. What are needed are attempts to predict more clinically relevant variables such as severity, chronicity, recurrence and treatment response. Indeed, limited evidence suggests that whereas the overall heritability of MDD is relatively modest, its more severe and recurrent forms are more highly heritable (Lyons et al. Reference Lyons, Eisen, Goldberg, True, Lin, Meyer, Toomey, Faraone, Merla-Ramos and Tsuang1998; Sullivan et al. Reference Sullivan, Neale and Kendler2000).

A characterisation of neural functioning in patients with depression is also likely to be a major contribution to our understanding of mood pathology. However, the pattern of neural activation seen in MDD patients often overlaps with the neural patterns that healthy controls exhibit after sad mood inductions (Andrews & Thomson, Reference Andrews and Thomson2009). Thus, the more informative characterisations of depression are likely to be those that differentiate patients who are depressed from those who are experiencing transient states of sadness. Along these lines, Wakefield et al. have brought attention to the need to focus on symptoms of depression that are not mere indicators of distress but are instead pathosuggestive (e.g., Wakefield et al. Reference Wakefield, Schmitz, First and Horwitz2007; Wakefield & Schmitz, Reference Wakefield and Schmitz2013; Wakefield & Schmitz, Reference Wakefield and Schmitz2014). A prolonged duration, thoughts of worthlessness, psychomotor retardation and psychoticism have emerged as useful variables in this regard. Parker (Reference Parker2007b ) has proposed a model of depression where psychomotor disturbances and psychoticism play a key role as variables that distinguish pathological affective states from more generalised distress. Malhi et al. (Reference Malhi, Parker and Greenwood2005) suggest a tiered model of depression as involving an additive dysfunction of monoamines, starting with serotonergic disturbances for more generalised states of negative affect and including noradrenergic and dopaminergic disturbances for psychomotor retardation and psychoticism, respectively. Examinations of these and other theories of specific pathologies are likely to be more effective than general contrasts between healthy individuals and those who meet criteria for MDD.

Depression can be conceptualised as involving the hyperactivation of negative emotional systems, especially those involved in reactions to losses, and diminished activation of positive emotional systems, especially those involved in reward processing. However, the determination of whether an emotional reaction is excessively or deficient relies on a consideration of the context in which it occurs (Horwitz & Wakefield, Reference Horwitz and Wakefield2007). Emerging research suggests that, like the symptoms of depression, the context in which depressive symptoms occur can also be reliably evaluated (Parker et al. Reference Parker, Fletcher and Hadzi-Pavlovic2012). Prospective studies exploring the association between the context, prognosis and pathophysiology of depressive states are needed. Even if these studies cannot provide conclusive evidence regarding the demarcation between pathological states of depression and adaptive states of sadness, they can shed light on the heterogeneity of depressive presentations.