Time in the course of major depressive disorder

Department of Psychiatry
University of Oxford
Warneford Hospital
Oxford, UK

Time in the course of
major depressive disorder

by G. M. Goodwin,Uni ted Kingdom

Time is an important defining feature in the diagnosis of major depression, its prognosis, and its tendency to recur over a lifetime. Major depression is conventionally defined as a collection of depressive symptoms present together for at least 2 weeks. The longer symptoms have been present and unremitting, the more confident one becomes of any diagnosis of major depression, and the greater the impact the depression is likely to have on personal, psychological, and social function. Depression lasting many months is more difficult to treat. The phases of treatment were established by consensus definition about 20 years ago. Response is defined as a 50% reduction in symptoms from baseline, followed by a continuing reduction in symptoms to a point defined as remission (usually a fixed point on a rating scale like the Hamilton Rating Scale for Depression). From remission, it is conventional to describe the treatment phase as “continuation” for the next 8 weeks, and “maintenance” after that point. The neurobiology that underpins the subsequent risk of recurrence is only now emerging. Acute treatment is now covered by many clinical guidelines, the most challenging problem being the next step after failure of an initial antidepressant. Continuation is that phase following remission when treatment should always be continued and further reduction of symptoms hopefully seen. Maintenance is continuation of treatment beyond full recovery to a phase in which the treatment is conceptualized as preventing new episodes of illness in the longer term. Its duration may be indefinite, but most guidelines recommend at least 6 months.

Medicographia. 2010;32:126-132 (see French abstract on page 132)

It can be argued that major depression is important because of the time it steals from people’s lives and the disability or burden of disease that it therefore imparts. The appearance, disappearance, and recurrence of depression occupy a central position in defining the disorder. Accordingly, the domain of time is central in the diagnosis of major depression, its prognosis, and its tendency to recur often over a lifetime.

The very long time constants that seem to be involved in the condition are still poorly understood, but they clearly have implications for our understanding of the neurobiology and finally for the treatment strategies that we currently adopt in trying to overcome individual episodes of depression. These aspects of time and depression will be the focus of this article.


Major depression is conventionally defined as a collection of depressive symptoms, which, according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR), must have been present together for at least 2 weeks.1 The choice of a 2-week cut-off is obviously arbitrary, and if a constellation of depressive symptoms is present for only 2 weeks, such an episode is likely to be of limited clinical significance. Indeed, broadly speaking, the longer symptoms have been present and unremitting, the more confident one becomes of any diagnosis ofmajor depression, the greater the impact it is likely to have on personal, psychological, and social function, and the more important treatment success becomes. It also turns out that the length of time during which an individual has been depressed is a predictor of subsequent outcome. Thus, in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the duration of illness was an independent predictor of failure to respond to treatment in a large population (over 3000) of index cases of major depression, all treated systematically with citalopram.2 The STAR*D finding echoes those from other studies showing that the duration of illness may well have an impact that is both statistically and clinically significant. However, the duration of illness that makes this impact is months rather than weeks. Hence the DSM-IV-TR definition of major depression is a relatively liberal one. It is durations of illness of up to 2 years that seem to have the most major impact in lowering subsequent rates of response to acute treatment.

The natural history of a depressive episode in the general population is recovery: symptoms remit, the subjective burden of depression disappears, and objective wellbeing eventually returns. The definition of the phases of this response rests on principles that were established by consensus about 20 years ago.3 The conventional terms and the time course that they describe are shown in Figure 1. The acute phase of depression is seen as requiring some form of acute treatment. For reasons of space, the episode is shown schematically as having a very recent onset, although in practice this is a little unlikely, as will be clear from the preceding discussion. Treatment will hopefully facilitate early response, which is often defined as a 50% reduction in symptoms (the point where the solid line in Figure 1 crosses the broken axis). Response rates allow comparisons between different early acute treatments. Response is followed by a continuing reduction of symptoms to a point defined as remission (usually a level of symptoms defined by a fixed point on a rating scale like the Hamilton Rating Scale for Depression [HAM-D]). However, remission takes time, and many acute placebo-controlled studies are kept short to enhance patient retention.

Figure 1
Figure 1. Definitions used in unipolar depression.

After reference 3: Frank E, Prien RF, Jarrett RB, et al. Arch Gen Psychiatry. 1991;48:851-855. Copyright © 1991, American Medical Association.

Response rates have significant limitations if one wishes to extrapolate research findings to expected clinical benefits. It has been argued more recently that remission is the key objective, and should thus be the primary outcome in shortterm treatment studies.4

“Time course” is a term used in defining other terms relating to the phases of treatment and the nature of any return of symptoms. From the point when a patient reaches remission, it is conventional to describe the treatment phase as “continuation” for the next 8 weeks, and “maintenance” after that point. Continuation is the phase following remission when treatment should always be continued and further reduction in symptoms should hopefully be seen. Maintenance is continuation of treatment beyond full recovery to a phase in which the treatment is conceptualized as preventing new episodes of illness in the longer term. Its duration may be indefinite, but most guidelines recommend at least 6 months.

Symptoms returning within the acute and continuation phases are described as relapse (of the original index episode), and those occurring after recovery (in the maintenance phase) are defined as a recurrence (and notionally as the appearance of a new episode). These ideas imply that there is some- thing unitary about a depressive episode, and that once it has gone away, the patient moves into a different state of risk and perhaps a different state of neurobiology. Thus, in effect, the treatment of a single episode can be thought of as taking place within a finite period of time. Whether this is actually true is not yet known, and indeed it is doubtful as to whether we yet have the measures that would necessarily allow us to know whether it is true. However, it is a potent hypothesis and a useful one. While it is now enshrined in our terminology, as shown, we should regard it as provisional, seek better understanding of what actually determines patterns of symptom response and remission, and be prepared to change our terminology if it does not correspond to the facts.

Prognosis and recurrence

Repeated episodes of illness are frequently similar clinically, but they show potentially different temporal patterns. Longterm study of severe episodes of depression requiring admission to hospital has shown that patients with unipolar depression tend to have characteristic rates of relapse, with rather different probabilities of recurrence after repeated episodes such that the probability of further illness is increased with each successive episode (see Figure 2). In unipolar disorder, the times to re-admission to hospital tend to be longer than for bipolar patients in the same clinical population.5 Although beyond the scope of this article, the differences (and similarities) between bipolar and unipolar depression are of great current interest.6

Figure 2
Figure 2. Time to recurrence of major depressive disorder as a function of number
of previous depressive episodes.

After reference 5: Kessing LV, Andersen PK, Mortensen PB, Bolwig TG. Br J Psychiatry.
1998;172:23-28. Copyright © 1998, The Royal College of Psychiatrists.

The process whereby an individual first episode is triggered and subsequent episodes develop remains of great interest. Most first episodes tend to be preceded by a set of identifiable risk factors. Those that confer vulnerability relate to family history of depression, personality (anxious worrying/high neuroticism), female gender, and/or early abuse and neglect. These factors seem to be translated into depressive episodes by themoderating effect of adversity, either in the formof acute life events or chronic difficulties in the face of which patients may develop episodes of clinical depression.7 The excess of depressive episodes usually reported in women was associated in a study by Kendler et al with depressive episodes in the context of low stress, but this finding requires confirmation. Most available twin data comes from women, although a parallel series of studies is also emerging for men.8 There are minor differences and, in particular, the genetic overlap between neuroticism and major depression in men may be greater than in women.9 However, there is broad convergence in the apparent causes of major depression between both sexes.

The pattern in women is best established for first episodes of depression, for which life events that apparently “trigger” the episode are a relatively common observation. They become less obvious for recurrence in individual patients, suggesting that in some sense, patients become primed to depression and therefore more likely to develop an endogenous pattern of illness as time goes by.10 Expressed another way, with recurrent episodes of major depression, the role of environmental stressors progressively diminishes. Proving that this occurs and determining its naturalistic properties requires control of a variety of confounding factors and has been best addressed in female twins. With increasing numbers of previous episodes (up to approximately 10 episodes), the association between life events and new depressive episodes fell approximately linearly. More than 10 previous episodes had little additional impact.10

The nature of this process—sometimes described as kindling—is poorly understood. It has been suggested that differences between individuals with high and low genetic loading may be that to be highly loaded means to start with a greater degree of priming for the onset of a first depressive episode. Whether a priming or kindling effect is a useful heuristic idea will depend upon developments in our understanding through neurobiological studies. In young people with a family history of depression but no personal history of a depressive episode, there is evidence of increased cortisol secretion and impaired modulation of the anterior cingulate cortex in response to emotionally valenced stimuli.11,12 There is also evidence that rather similar emotional biases can be detected in those with high neuroticism (and no family history) when studied at an early age before any personal history of mood disorder.13,14 However, interestingly, changes in cortisol secretion appear to be confined to subjects with a family history of depression at that age.

Figure 3.
Summary of
the UK National
Institute For
Health and Clinical
Stepped Care
model for depression

After reference 19:
UK National Institute
for Health and
Clinical Excellence.
Copyright © 2009,
National Institute
for Health and Clinical

There is also evidence that patients who have had an episode of depression and who have fully recovered show abnormalities in their underlying neurobiology. The most impressive demonstration, which links mood regulation directly to serotonin metabolism, is the precipitation in a matter of hours of a depressive syndrome as a result of tryptophan depletion.15 Such patients with a previous history of depression can also be challenged with a less severe depletion of tryptophan.16 Under these circumstances, there is no recurrence of any depressive symptoms, but there are differential effects on cognitive function compared with age-matched controls, with differential effects in the patient group for the amplitude of startle responses, episodic memory, and recognition of happy facial expressions. These changes suggest a dysregulation in emotional processing and memory function following acute reduction in serotonin function. These changes could represent the pathways in mood dysregulation per se. They were not, in this case, sufficient to cause a mood change.

While implicating serotonin directly, these findings do not of course exclude a contribution from other neurotransmitter systems in mediating different components of the depressive syndrome that remain incompletely understood. Reduced neural processing of positive primary consummatory cues (eg, chocolate) is also attenuated in recovered depressed patients and may implicate dopamine.17 Abnormalities of the circadian system may be yet more complex.

Major depression is a recurrent disorder, and over a period of many years may have a major impact on the lives of individuals simply by virtue of the impact of chronic or recurrent symptoms, which are socially and personally incapacitating. However, in addition, it is now understood that depression has an impact on simple memory performance, which is also potentially cumulative with episode recurrence and may contribute to a professional disability and difficulties in employment. Cognition as an end point in the treatment of depression is a new concept, but one that seems set to assume increasing importance. The time spent depressed during multiple previous depressive episodes in the clinical history seems to be an important predictor of minor, but nevertheless significant, cognitive impairment following recovery from individual episodes.18

Treatment guidelines for single depressive episodes

As already indicated, chronicity of the depressive episode predicts reduced responsiveness. It suggests that long delays in treatment are highly undesirable. On the other hand, short delays may make rather little difference, and for that reason, the UK National Institute for Health and Clinical Excellence (NICE) guidelines have recommended that for patients with minor levels of symptoms and relatively short histories, a time of watchful waiting may allow recovery without the need for active intervention.19 How effective this approach may be has not been addressed in effectiveness studies, but is simply derived from a consideration of first principles. It may be appropriate in health care systems with relatively easy access to primary care services, but it requires clinical vigilance and not neglect.

Long-term watchful waiting is clearly not likely to be a helpful strategy, and escalation through a system of stepped care to further treatments, either with effective psychotherapy or antidepressants, is the recommendation of almost all guidelines. The recommendations from NICE are summarized in Figure 3. The particular choice of antidepressant is not dictated overwhelmingly by weight of evidence favoring one treatment over another, although on average, some antidepressants are probably more effective/well tolerated than others. Head-to-head studies can be aggregated to allow meta-analysis, and a recent study suggested that published data favors, for example, sertraline compared with reboxetine.20 However, many other factors other than clinical evidence influence the first choice, from simple economics to patient preference.

_ Next step treatments after failure of an initial drug treatment
Treatment failure is not uncommon in a major depressive episode. Time is again an important determining factor in clinical decision-making. How long one should wait before failure is declared has not been established, and is perhaps always a complex clinical decision. Careful analysis of early time points in clinical trials has shown that improvement comes relatively early, and so, in principle, early decisions about treatment benefits (at 2 weeks, perhaps) may be possible.21 However, as with other aspects of clinical judgment in mood disorders, the greater the time that elapses, the greater the confidence in the clinical decision, and many guidelines have advocated waiting 4 or even 6 weeks before making a change. STAR*D was originally designed to guide the next treatment step after the failure of a selective serotonin reuptake inhibitor (SSRI; citalopram). Unfortunately, the randomization steps were largely subverted by planned patient preference options. There is a lack of direct evidence on the comparative efficacy of a range of next steps after initial treatment of a single episode has failed.

The treatment options are as follows (broadly taken from the British Association for Psychopharmacology [BAP] Guidelines 2008, which should be consulted for more detailed justification).22 Since there is a relative dearth of compelling evidence for one strategy over another, guidelines may produce rather different recommendations if attempts are made to concoct an algorithm to anticipate particular successive preferences. STAR*D provides an interesting example of just such an overall strategy, and it has been argued that overall response rates in the study support its use23: in the absence of anything better, this may be worth further study.

_ Increasing the dose of the medication after initial treatment nonresponse
There may be a dose response with agomelatine, escitalopram, TCAs, or venlafaxine that merits a dose increase from the recommended starting dose, but there is little experimental support in the case of other SSRIs. This strategy is obviously most attractive when there are minimal or no side effects at the prescribed dose, and/or there has been some improvement.

_ Switching to a different antidepressant
Switching to another antidepressant is probably the commonest approach, including switches within the same class. There is some evidence for enhanced efficacy with venlafaxine after switching from an SSRI. The potential for pharmacokinetic or pharmacodynamic interactions requires care in some circumstances. For example, a switch from monoamine oxidase inhibitors to serotonin reuptake inhibitors may provoke the serotonin syndrome. Where possible, recommended protocols should be followed to minimize risks.

Switching is worth consideration when there is poor tolerability as a result of significant side effects or no improvement on careful clinical assessment. The switch options include antidepressants of a similar class (sometimes recommended as the simplest first option), followed by a different antidepressant class after a second failure within a class. Venlafaxine is specifically supported after more than one SSRI failure.

_ Augmentation of the ineffective antidepressant
There is evidence for the efficacy of augmentation of antidepressants with lithium, olanzapine, risperidone, quetiapine, and aripiprazole. Aripiprazole appears to be the most promising of these.24 Tri-iodothyronine also has adherents, as does mirtazapine, tryptophan, methylphenidate, lamotrigine, modafinil, antiglucocorticoids, and estrogen (in perimenopausal women), although more specialized combinations probably require expert supervision. Augmentation may be logically preferred when there has been a partial/insufficient response on the current antidepressant, but with good tolerability, or when switching antidepressants has been unsuccessful.

_ Psychological treatment options
Addition of cognitive behavioral therapy to ongoing antidepressant treatment may be effective, but requires significant therapist expertise. Adding other psychological or behavioral treatments that have established acute treatment efficacymay also be merited.

_ Physical treatment options
Electroconvulsive therapy should be considered in more severely symptomatic patients in whom two or more treatments have failed. Electrode placement affects both efficacy and adverse effects on memory (which are probably positively correlated). Unilateral treatment is often preferred as first-line treatment.

Vagal nerve stimulation is an option for patients with chronic treatment-resistant depression, as is deep brain stimulation and even ablative neurosurgery. A full discussion of who could be considered eligible having proved refractory to pharmacological and psychological treatment, is beyond the scope of this article.

_ The long term
In addressing treatment, the objective is to enable the patient to achieve remission and a full recovery within at most 3-4 months, and to continue treatment for at least 6 months. Given the strong evidence of relapse prevention in studies that, for regulatory purposes, have been designed to confirm efficacy over longer periods of time, longer term treatment should clearly be considered in patients believed to be at increased risk of recurrence of depression.25

There have been rather few true maintenance studies in which patients have been allowed to recover, then been withdrawn fromantidepressants, and then re-randomized tomaintenance treatment de novo. The only large example with sertraline26 again showed a positive benefit reflecting the findings seen in relapse prevention studies.

More conventional relapse prevention studies involve open treatment with a single antidepressant to remission of the acute episode, followed by double-blind continuation or withdrawal (to placebo). Such designs are usually said to enrich the sample for responders to the acute treatment, and so may favor finding a positive effect when treatment is withdraw. A true maintenance study excludes this effect.


Elapsed time plays a key role in defining the diagnosis and course of single and recurrent episodes of major depression, treatment responses, decisions to change interventions when treatments fail, and outcomes. There is a certain symmetry in this when looked at from the patient perspective, since recurrent and chronic depression steal significant fractions of the lifetime of individual patients. In reflecting back on time spent depressed, patients rarely regard it as time well spent. This implies that a challenge for the future is to reliably shorten all the time periods that are currently too often long and uncontrolled in depression. This means time to diagnosis, time to effective treatment, and most critically time spent depressed. _


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