Residual symptoms and relapse in depression

b y E . S . P a y k e l , U n i t e d K i n g d o m

Eugene S. PAYKEL
MD, FRCP, FRCPsych, FMedSci
Department of Psychiatry
University of Cambridge

Residual symptoms indicating incomplete remission from depression present an important clinical problem. They occur in up to a third of depressed patients after acute treatment, and they span the typical symptoms of depression, except those of severe depressive disorder. Their most important consequence is a much increased risk of relapse, particularly in the first year. Residual symptoms point to the need for further acute treatment to produce greater improvement, if possible. They are a strong indication for longer than usual continuation treatment at an adequate dose, to prevent relapse. There is now also good evidence for cognitive therapy as an adjunct. Other persistent abnormalities after depression include social dysfunction, dysfunctional attitudes, hypothalamic-pituitary-adrenal (HPA) axis overactivity, shortened latency of rapid eye movement (REM) sleep, and mood lowering after tryptophan depletion. It is not clear how much some of these are associated with residual symptoms or occur independently, although continuing HPA axis overactivity and shortened REM latency are also associated with increased risk of relapse. In addition, there is growing evidence for residual symptoms in bipolar disorder, particularly after bipolar depression, and for increased risk of relapse when they are present.
Medicographia. 2009;31:157-163. (see French abstract on page 163)

Keywords: partial remission; residual symptom; relapse; depression; prevention

Course of depression

After the introduction of a range of modern antidepressants in the early 1960s, it was assumed that the longer-term outcome of depression had become benign. However, in the 1980s and early 1990s it became clear that in many patients this was not the case. After recognition of this problem, a paper published in 1991 by Frank et al1 established and formulated operational definitions for some important concepts and distinctions among various aspects of outcome, based on severity and time intervals. A more recent US paper2 has updated the concepts and definitions.
The term remission has usually been applied to short-term achievement of low or absent symptom levels, representing an end to the immediate episode. The term recovery has been used to reflect remission beyond this state, persisting for a longer time period, and being more complete. A further term, response, has sometimes been used, implying considerable improvement, variously defined, but not necessarily to remission.
Even before recovery is fully achieved, relapse may occur. The term relapse has been used in affective disorders particularly to describe an early return of the depressive episode after remission, up to approximately 9 months to a year following the acute episode. This has been assumed to be a return of the original illness. This assumption reflects views that were common in the early days of antidepressants, ie, that the disorder is merely suppressed and that the underlying disturbance continues until spontaneous remission occurs. It is difficult to prove this theoretical distinction, other than by inferring it from the length of the symptom-free period. The term recurrence has been reserved for development of a subsequent episode, assumed to represent a new episode.

Partial remission and residual symptoms

Missing from the original schema was consideration of an intermediate state, in which remission might be partial in degree, with residual symptoms, rather than complete. This has since emerged as being very important, as it has become clear that it is a key pointer to relapse and recurrence.

Residual symptoms received relatively little attention before the mid 1990s, but they are evident in some studies if the detail is examined, and some aspects were briefly reviewed.3 Indeed, clinical experience had long suggested that many patients improved only partially after initial treatment, leaving residual symptoms that persisted and fluctuated in the community, causing much disability. Because most studies grouped these patients either with those who had not remitted or with those who had relapsed, their proportion had not been very well documented.
A few studies described them separately. Among inpatients treated with amitriptyline, approximately one third were found to be complete responders, partial responders, and nonresponders, respectively. 4 In a follow-up study5 to 4 years of a sample of female depressives who had responded to initial treatment with amitriptyline and had been included in a controlled trial of continuation antidepressant therapy and psychotherapy, many were still found to show moderate or fluctuating symptoms, corresponding approximately to residual chronicity, although these included some subjects who had relapsed and then remitted. Occurrence of residual symptoms was noted in general practice patients with depression and anxiety,6 and in 38% of elderly depressives at 1 year, and 20% at 2-4 years.7
A study of ours first published in 1995 drew specific attention to the problem and gave impetus to an increased subsequent emphasis. In a prospective longitudinal follow-up of depressed patients treated in Cambridge in the early 1990s,8,9 a sample of 64 depressed patients meeting the Research Diagnostic Criteria for definite primary unipolar major depression was studied on presentation, and followed to remission or 15 months. Only 6% of the sample failed to remit to the criterion of 2 months below definite major depression by this point. However, on examining the findings in more detail, although the majority of remitters scored in the lower ranges of the 17-item Hamilton Rating Scale for Depression, an important proportion of 32% scored 8 or more on the Hamilton scale, 8 or less being the criterion proposed by Frank et al1 as indicating full remission or recovery. They spanned a range from 8 to 18, although they did not satisfy the criteria for major depression.
We explored further the nature of these residual symptoms by examining individual symptom ratings. The residual symptoms were those typical of depression, with ratings at the level of moderate or greater on the Hamilton scale items of depressed mood, impairment of work and activities, psychic anxiety, and genital symptoms. The remaining depressive symptoms were present to at least a mild degree in most subjects, the exceptions being a group of symptoms typical of severe depression: late insomnia, retardation, agitation, hypochondriasis, weight loss, and loss of insight. A parallel set of analyses carried out on the Clinical Interview for Depression,10 which has a wider range of symptom items, gave similar findings. Depressed mood, guilt, hopelessness, impaired work and interests, psychic anxiety, and anorexia were prominent. The remain- ing depressive symptoms were present to at least a mild degree, except for delayed insomnia, retardation, agitation, panic attacks, increased appetite, and depressed appearance.
We also looked for initial predictors of later residual symptoms upon remission. Using an extensive set of ratings made at the initial assessment, we found very few significant predictors, and those that were found reflected higher initial severity. Patients with residual symptoms had higher initial scores on the Clinical Interview for Depression anxiety total score and on the Hamilton scale 17-item total score. Life events, social support, and expressed emotion did not predict residual symptoms. We also examined diagnoses made at the initial interview, using the DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders–Third Edition Revised) criteria for dysthymia. Those patients with residual symptoms were not predominantly previous dysthymics. Only 11% of those with residual symptoms satisfied the DSM-III-R criteria for dysthymia, as opposed to 17% of those without residual symptoms. Residual major depression did not represent a return to dysthymia, but indicated a different phenomenon: persistence of the episode in spite of treatment.
We also examined treatment data, to explore whether deficient drug treatment might have been responsible for residual symptoms. This was not the case. In fact there was a general trend for patients with residual symptoms to be receiving higher rather than lower levels of treatment. This would be expected in a naturalistic follow-up, with good treatment assignment in practice based on the presence of more symptoms. It does not mean that higher treatment levels would not be beneficial, but does indicate that the symptoms were not a consequence of failure to give standard treatment.
More recent studies of residual symptoms have been reviewed by Fava et al.11 They have been reported both after drug treatment and psychotherapy. Fava et al,12 in a study of their own, reported a strong relationship between prodromal and residual symptoms. The most common symptoms were irritability and anxiety. The large Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,13 which reported higher non-remission rates for depression than were hitherto thought to occur, did not use a criterion for partial remission. Residual symptoms also comprise one aspect of the subthreshold depressive symptoms described in a number of long-term longitudinal studies.
There is also another meaning of the term, to refer to minor symptoms occurring below the level of partial remission. For example, one or more residual symptoms were found to be present in 82% of elderly depression remitters who achieved a score of below 8 on the Hamilton depression scale.14 Among responders to fluoxetine scoring 7 or less on the Hamilton scale in another study,15 residual symptoms were frequent, particularly sleep disturbance, fatigue, loss of interest, and guilt. At these severity levels, the subjects would be below the usual threshold for partial remission. Possibly the majority of recovered depressives have these symptoms, but they overlap, probably to a considerable but so far ill-explored extent, with what is experienced in normality. These minor symptoms are not the subject of this paper, which concerns more definite incomplete remission.

The treatment of residual symptoms and prevention of relapse

The most important implications of residual symptoms are the impaired future prognosis and the need for treatment. There are two aspects to the latter: treatment of the residual symptoms themselves and prophylactic treatment to prevent relapse.

Figure 1
Figure 1. Proportion of patients with ( ) and without ( ) residual symptoms relapsing after remission from depression.
After reference 8: Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25:1171-1180. Copyright © 1995, Cambridge University Press.

The association with relapse argues strongly that residual symptoms should be treated vigorously in order to abolish them, although there is not conclusive proof from controlled trials that abolishing or diminishing them in vulnerable subjects will lower the risk of relapse. In any case, these are distressing symptoms, associated with poor role function and impact on families, and they need treatment in their own right. However, converting partial remission in these subjects into complete remission may not be easy. There is often a history of treatment with a variety of antidepressants in succession in the current and previous episodes, with only partial improvement, and with side effects limiting the doses that can be achieved.
There is little randomized controlled trial evidence regarding the efficacy of different antidepressants and other treatments for residual symptoms, and tentative recommendations therefore depend on general principles. As always, when response is limited, there should be a process of reassessment.
A careful history will often reveal the antidepressant that helped most in this episode or previous episodes, and that might be used in an increased dose. Care should be taken before concluding that a dependent personality is preventing full remission; chronic illness can create a misleading impression about a personality, which once full remission is achieved, is revealed to be robust. Assessment of the current situation may reveal perpetuating factors, such as family that has adjusted to the chronic illness by substituting for the patient’s roles, so that these are not available for the patient to return to without therapeutic work to change family expectations; or a spouse who needs the patient to be ill; or elements of secondary gain in the patient, such as compensation or insurance payments.

Figure 2
Figure 2. Relapse prevention to 18 months, with and without 20 weeks’ cognitive
therapy in patients with residual depression maintained on antidepressants.
CT, cognitive therapy.
After reference 35: Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy. A controlled trial. Arch Gen Psychiatry. 1999;56:829-835. Copyright © 1999, American Medical Association.

If the patient is currently receiving submaximal doses of an antidepressant, the dose should be increased as far as can be tolerated, up to maximum permissible levels. If this fails on its own, augmentation with lithium or other augmentation approaches may be useful. If this too fails, a change of antidepressant may be considered, to a potent one shown in controlled trials to produce good remission, without side effects. This should be undertaken with caution, since there is a risk of worsening symptoms or failing to achieve the previous level of remission, so addition of a second antidepressant rather than substitution is often better, if it can be achieved without any limiting side effects. If there are clear personal or family issues pointing to psychotherapy, this should be added. For cognitive therapy, there is plentiful controlled trial evidence of a prophylactic effect, lessening relapse rates. The evidence that it lessens residual symptoms themselves is less good, but at the least it provides a useful framework helping the patient to manage the symptoms, and it will often be indicated in any case, when residual symptoms do not respond to antidepressant treatment alone, for its prophylactic effect.
The second treatment aspect is the prevention of relapse and recurrence in these patients, whose risk is substantial. Here the evidence base is strong. A key aspect is continuation and maintenance medication, the general value of which is supported by many controlled trials.32 Earlier, a recommendation was made that continuation treatment should not be withdrawn until the patient had experienced 4 months free of all symptoms.21 This recommendation for routine circumstances may in fact be too short in the light of later evidence that the risk of relapse extends longer than previously thought.33 Nine to 12 months now seems a better length for routine continuation. However, the presence of residual symptoms sufficient to indicate incomplete remission indicates a need for longer continuation. Treatment should be continued if possible until they have become of minor degree or completely subsided, probably for at least 18 months. This may entail quite long-term continuation or maintenance. When treatment is withdrawn, withdrawal should be slow. If symptoms return or worsen as doses are reduced, the full dose should be resumed for a longer period. If breakthrough symptoms recur as the dose is reduced, this may argue for indefinite maintenance.
There is also good evidence for the efficacy of cognitive therapy in reducing relapse rates,34 particularly in the situation of residual symptoms. Seven controlled trials have shown reduced relapse rates, including two studies in residual depression.11,35 Our own study35 specifically targeted subjects with residual symptoms in spite of antidepressant treatment as being a relapse-prone group that needed treatment additional to antidepressants. We found that adding cognitive therapy to full doses of antidepressant continuation and maintenance lowered relapse rates (Figure 2), and the effect lasted for 3 and a half years after the end of the cognitive therapy.36 This appeared to be a specific effect on relapse: residual symptom levels themselves were not lowered. The evidence is now sufficiently strong that cognitive therapy should routinely be used as adjunctive treatment to medication when partial remission persists without conversion to full remission.

Other residual phenomena

Israel37 suggested that recovery from depression should be determined in three domains: symptoms, psychosocial function, and pathophysiological changes. Social dysfunction and disability are additional important consequences of a depressive episode. Social adjustment was evaluated longitudinally in the late 1960s in a sample of depressed women in New Haven, Connecticut, USA, comparing them with a matched group of normal subjects in the general population.38,39 Widespread impairment was found in the depressed group compared with normal subjects, extending across all the domains studied, including work, social and leisure activities, relationships with extended family, marital relationships, and parental function. These deficits remitted more slowly than did depressive symptoms, and in the 2-month time period that included response and remission, these deficits were still severe. Improvement in some aspects was incomplete even at 8 months. Work impairment translates to decreased productivity and absence from employment, producing some indirect economic costs of depression. The problems associated with parental role are particularly important, since problems in parenting and parent-child relationships impact on development and later adaptation of the next generation.
Residual social dysfunction has since been reported by many other investigators and has been found to correlate with symptom outcome. Some of the many studies40-47 have been reviewed by Fava et al.11 Residual symptoms are associated with increased social dysfunction. In unpublished data derived from our controlled trial of cognitive therapy in patients with residual symptoms,35 we examined mean total scores on the Social Adjustment Scale at 20 weeks. Subjects with residual symptoms at 20 weeks and subjects who had relapsed by 20 weeks both showed worse social adjustment than those with neither adverse outcome at this point. Whether impaired social adjustment makes an independent contribution to prediction of subsequent relapse has not so far been reported.
A number of biological and neurocognitive measures, reviewed by Bhagwagar and Cowen,48 have been found to be abnormal in recovered depressives. Most prominent have been abnormalities of the hypothalamic- pituitary-adrenal axis, including waking salivary cortisol49 and dexamethasone non-suppression. The latter has been found to predict relapse. Several studies that followed up patients treated with tricyclic antidepressants found that dexamethasone non-suppression at the time of discharge predicted a greater risk of early relapse.50-57 One study of outpatients58 and two of patients treated with electroconvulsive therapy59,60 failed to find this. The enhanced dexamethasone–corticotropinreleasing- hormone test has also been found to predict relapse.61
A second set of persistent biological abnormalities is related to serotonin. The most prominent of these is a return of depressive symptoms on depletion of tryptophan by a high amino acid drink low in tryptophan.62 A third group of abnormalities is sleep-related, specifically, persistent shortened rapid eye movement (REM) latency.63 Another group of abnormalities is neurocognitive. Particularly prominent are the dysfunctional attitudes and attributions that occur in depression and that have also been found to persist after symptomatic recovery.64,65
The relation of these biological and neurocognitive abnormalities to residual symptoms has not been well studied, although they do appear to occur with full remission. Neither is there good evidence that they predict relapse, other than for dexamethasone suppression and REM sleep latency.

Bipolar disorder

This review primarily concerns unipolar disorder. However, there is a smaller but growing parallel literature regarding bipolar disorder. Two large pros- pective follow-up studies have found subthreshold symptoms present for substantial periods between episodes,66,67 as have a number of smaller earlier studies reviewed by Morriss,68 who also noted that these were most commonly residual after an episode. Two recent studies69,70 found residual symptoms early after remission to be common. Keller et al71 had earlier described subsyndromal symptoms in about half of a sample of bipolar patients in a controlled trial of high- or low-dose maintenance lithium. Both of the large studies found these present for much longer than the periods of major disorder, and found that depressive symptoms predominated over hypomania. There has been less examination of the prediction of major relapses by these symptoms, but three studies69,70,72 found that, when present, these residual or inter-episode symptoms are strong predictors of relapse and recurrence.

Conclusions: the nature and significance of residual symptoms

What can we say regarding the nature of residual symptoms in depression and their significance? There are various possibilities. Residual symptoms might represent persisting illness, the original illness continuing in milder form. Alternatively they might represent the phenomena preceding and underlying the depressive episode. Two possible aspects of the latter can substantially be discounted: subjects with residual symptoms are neither liable to be diagnosed as dysthymic nor, except to a minor degree, to show more personality abnormality than those who remit fully.
A third possible underlying phenomenon is that the residual symptoms could reflect the cognitive vulnerability of dysfunctional attitudes. However, the symptoms shown by residual depressives, although they include negative cognitions, are not limited to these, but include core mood and functional symptoms of depression. These are too wide to be related easily to a single abnormality of low self-esteem.
It thus seems likely, given these findings and the relative lack of association of residual symptoms with anything else except subsequent relapse, that the explanation is the first of those given above, persistence of the original disorder and its underlying neurobiological substrates. The most likely conclusion is that residual symptoms are a manifestation of a disorder that, in spite of improvement, is still present—they are evidence that the disorder continues. This is also supported by the tendency of relapses following residual symptoms to occur early. It reinforces the important practical treatment message: incomplete remission with residual symptoms indicates a high risk of relapse and a strong need for continuing treatment. _

: This paper is adapted and updated from Paykel ES. Partial remission, residual symptoms, and relapse in depression. Dialogues in Clinical Neuroscience. 2008;10:431-437. With permission from the author and Les Laboratoires Servier.

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Les symptômes résiduels, signe d’une rémission incomplète de la dépression, sont un important problème clinique. Ils surviennent chez environ un tiers des patients déprimés après un traitement aigu et ils englobent les symptômes typiques de la dépression à l’exception de ceux des troubles dépressifs majeurs. Leur conséquence la plus importante est une augmentation du risque de récidive, surtout la première année. Les symptômes résiduels sont révélateurs de la nécessité de poursuivre le traitement aigu pour davantage d’amélioration, si possible, de façon plus prolongée et à une posologie appropriée afin de prévenir une rechute. La thérapie cognitive est maintenant reconnue comme un traitement adjuvant efficace. D’autres anomalies persistantes sont retrouvées après une dépression comme l’inadaptation sociale, les comportements dysfonctionnels, l’hyperactivité de l’axe hypothalamo-hypophyso-surrénalien (HHS), le raccourcissement du temps de latence du sommeil paradoxal et la baisse de l’humeur après déplétion en tryptophane. On ne sait pas encore exactement jusqu’à quel point certaines de ces anomalies sont le reflet de symptômes résiduels ou des manifestations indépendantes, mais l’ hyperactivité de l’axe HHS et le raccourcissement du temps de latence du sommeil paradoxal semblent bien être associés à l’augmentation du risque de récidive. Par ailleurs, on met de plus en plus en évidence l’existence de symptômes résiduels dans les troubles bipolaires, en particulier la dépression bipolaire, et leur présence témoigne également de l’augmentation du risque de récidive.