Neurobiology of Depression: An Integrated View Of Key Findings

V. Maletic; M. Robinson; T. Oakes; S. Iyengar; S. G. Ball; J. Russell


Int J Clin Pract. 2007;61(12):2030-2040. 

In This Article

Major Depressive Disorder as a Progressive Illness

Epidemiological studies have consistently shown that MDD is one of the most prevalent lifetime psychiatric disorders. In the National Comorbidity Replication Survey, based on DSM-IV criteria for MDD, the lifetime prevalence rate was 16.2%, with a 12-month estimate of 6.6%.[5] The presentation of MDD is heterogeneous with respect to both core and associated symptoms.[6] In the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision,[7] the diagnosis of MDD requires the experience of major depressive episodes that are defined by at least five of the following symptoms for at least 2 weeks duration: loss of interest, depressed mood, appetite/weight disturbance, sleep disturbance, psychomotor change, loss of energy, worthlessness/guilt, concentration difficulties/indecisiveness and thoughts of death/suicide. Depressed mood or loss of interest must be one of the symptoms, but with the inclusion of compound criteria (e.g. worthlessness or guilt), a diagnosis of MDD can be met by various permutations, and episodes may then be further qualified by other associated features (e.g. postpartum, seasonal pattern, with melancholy or psychotic symptoms).

Even though MDD is characterised as an episodic illness, prospective studies have found that recurrence is the norm rather than the exception. For example, in a naturalistic, 15-year follow-up of a sample of 380 patients experiencing an index MDD episode, 73% experienced a recurrent episode,[8] with each subsequent episode increasing the probability of further episodes.[9] Similarly, in the STAR*D Project (Sequenced Treatment Alternatives to Relieve Depression) that includes 1500 patients with MDD, 74% of patients had experienced more than one episode.[10] Recurrence of MDD appears to be driven in part by neurobiological vulnerabilities. In the STAR*D Project, patients who experienced multiple episodes were more likely to have a positive family history of depressive illness and an earlier age of onset of their index depressive episode compared with patients who were in their first episode.[10]

Consistent evidence has also supported a 'kindling hypothesis' in which depressive episodes become more easily triggered over time.[11] As the number of depressive episodes increase, future episodes are predicted more by the number of prior episodes rather than by life stress.[12] Figure 1 Kindling can be described as a process which occurs by a lowering of the threshold for the impact of stressful life events (i.e. sensitisation to minor events) or by an increase in spontaneous dysregulation, both of which could indicate progressive effects of MDD.[13] An analysis of the risk of recurrence in a large study of twins also suggests genetic contributions as patients with a high genetic risk were 'prekindled'; that is, they had a lower association between stressful life events and the onset of depressive episodes compared with patients having a low genetic risk.[14]

Major depression as a progressive illness. As the number of major depressive episodes increase, the risk for subsequent episodes is predicted more from the number of prior episodes and less from the occurrence of a recent life stress. Figure adapted from ref. no.[14]

Early adverse experiences may also contribute to long-term neurobiological alterations associated with depression. In preclinical studies, maternal deprivation of rat pups during critical development periods resulted in subsequent hyper-reactivity to stress and marked behavioural changes in adult rats.[15] In children who had a history of early maltreatment, the risk for depressive symptoms was associated with an interaction between genotypes [e.g. serotonin (5-HT) transporter] and history of maltreatment.[16] Considering these findings, some researchers have suggested that greater neurobiological changes occur in patients with depression who have early adverse experiences compared with patients who are depressed but do not have such a history, indicating that these patients may represent an especially vulnerable subtype of depressive illness.[17]

Chronicity also suggests long-term neurobiological consequences associated with the MDD illness. In the STAR*D Project, 25% of the patients (with single or recurrent MDD) were identified as having a chronic episode of more than 2 years duration.[10] In another large multicentre treatment study (n = 681), patients' depression was classified using DSM-IV modifiers into four categories: chronic MDD (episodes > 2 years), MDD with incomplete recovery (partial response), MDD superimposed on dysthymia (double depression) and chronic MDD superimposed on dysthymia (depressive symptoms > 4 years). Despite multiple comparisons across a broad range of clinical and psychological variables, few differences were found among the four groups, resulting in the conclusion that various manifestations of chronic depression represent the same illness.[18]

As the duration of depressive episodes increases, the probability of recovery substantially decreases over time. In a 5-year prospective study of outpatients with depression, approximately half recovered within the first 6 months, but afterwards the rate of recovery diminished substantially. For example, patients who had experienced depressive episodes of 1-year duration had a recovery rate of 16% compared with a 1% recovery rate for patients whose episodes persisted > 5 years.[19] Similarly, in a prospective study of new onset depressive episodes, a longer duration (> 12 weeks) of previous episodes reduced the likelihood of recovery from the new onset episode by 37%.[20]

Even if patients no longer meet full criteria for an MDD episode, studies have found that a substantial subset of patients continue to experience residual symptoms and diminished functioning. In a 3-year longitudinal epidemiological study, 165 patients were assessed before and after an MDD episode. Although mean values on functional measures returned to premorbid levels, 15-40% of patients experienced a worsening in psychosocial functioning that persisted after the episode, and the overall functioning of the entire sample continued to be lower than that of a healthy cohort.[21] In a 10-year, naturalistic longitudinal study, patients who experienced subthreshold depressive symptoms following an MDD episode were at significantly greater risk for a recurrence, and they also had a much faster onset of their next episode compared with patients whose episode had fully remitted, suggesting that residual symptoms represent vulnerability because of an active disease state.[22]

The recurrence and chronicity of MDD along with possible kindling effects have shifted the perspective of the appropriate treatment goal. The gold standard for treatment outcome has been raised from response (reduction in symptoms) to remission (absence of symptoms) or recovery (extended period of remission).[23] However, obtaining recovery implies not only the remission of symptoms but also a restoration of the underlying physiology associated with the illness. Therefore, further understanding of the neurobiological changes associated with MDD is necessary for identifying true recovery processes.


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