British Medical Bulletin

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British Medical Bulletin 57:145-159 (2001)
© 2001 Oxford University Press

Continuation and maintenance therapy in depression

E S Paykel

Department of Psychiatry, University of Cambridge, Cambridge, UK

	Abstract

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
This paper reviews longer term treatment for unipolar depression. Antidepressant continuation for prevention of early relapse has been routine for many years. Recent evidence supports a longer period of 9 months to 1 year after remission. Antidepressants are also effective in maintenance treatment for recurrent depression, and are indicated where there is clear risk of further episodes. Antidepressant withdrawal after continuation and maintenance should always be gradual, over a minimum of 3 months and longer after longer maintenance periods, to avoid withdrawal symptoms or rebound relapse. Trials of interpersonal therapy in the prevention of recurrence show some benefit, but effects are weaker than those of drug and additional benefit in combination is limited. There is better evidence for effects of cognitive therapy in preventing relapse and an emerging indication for its addition to antidepressants, particularly where residual symptoms are present.

	Longer term outcome in depression

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
This paper will review the use of medication, principally antidepressants, and of psychological treatments in the longer term treatment of unipolar depression.

Most modern treatments for depression are comparatively recent in development. Tricyclic and MAO inhibitor antidepressants were introduced at the end of the 1950s, other medications, and modern specific psychological and psychotherapeutic treatments tailored to depression, later. Prior to the modern antidepressant era many follow-up studies of depression were published. Robins and Guze¹, in reviewing these, found a wide range of outcomes in different studies. There was some consistency in the proportion of deaths due to suicide, which spanned a narrow range of 13–17%. Scott² obtained a reasonably consistent proportion of 15% for chronic depression in earlier studies.

The advent of antidepressants produced optimism regarding the treatment of depression, but in fact relatively few long-term follow-up studies of depression were published in the 1960s and 1970s. There was also a tendency to label depression with poor outcome as ‘characterological depression’ or ‘depressive personality’, implying a disturbance of personality rather than an illness. More recent studies have made it clear that, although the immediate outcome of depression following treatment is good in terms of improvement, there are continuing problems in the longer term.

When the first antidepressants were introduced, it was assumed that only short-term treatment of about 3 months was usually required. By the mid 1960s, it was becoming apparent that this was often too short and by the early 1970s antidepressants were usually continued longer. Problems in spite of this pattern of treatment became evident with follow-up studies reported by Keller and colleagues from the US^3–6. Although most patients reached remission moderately rapidly, 30% of those who had remitted relapsed within a year. Later extension of the study⁷ showed that over 15 years 85% of recovered subjects experienced a recurrence, although only 58% of those who remained well for at least 5 years did so. Two 16 year British and Australian follow-up studies of patients admitted to university hospitals during the late 1960s⁸,⁹ showed that approximately 60% of patients had been re-admitted at least once, reducing to 50% in those for whom the index episode was the first admission. Only 20% had recovered fully with no further episodes, while just under 20% were incapacitated throughout or died of suicide. The remainder had courses characterised by recovery and recurrences.

More recent studies have found similar outcomes¹⁰,¹¹. A further problem which has become increasingly clear is occurrence of residual symptoms after partial remission¹², which occurs in up to one-third of depressed patients, and is associated with very high risk of relapse.

Data are still lacking on depression treated in primary care, the common setting for treatment of depression in most countries, and on patients presenting with index episodes requiring psychiatric out-patient rather than in-patient treatment. These groups, more mildly ill than hospitalised subjects, might have better outcome.

The renewed attention to longer term outcome has led to a more precise terminology¹³. The term remission is now used to describe the earlier part of the time when symptoms have subsided. It may be complete or incomplete with residual symptoms and it may be followed by subsequent problems. The term recovery is used by contrast to describe a state of freedom from symptoms which is both complete and persistent. The word relapse has been reserved for an early return of symptoms which can be regarded as return of the original episode, and the term recurrence for a later occurrence of symptoms which can be regarded as a new episode. There is no precise separation between these two, but there is evidence that rates of symptom return are highest in the first 6–12 months after remission and then diminish¹¹.

In parallel, a new terminology has developed in relation to drug treatment. The term continuation therapy has been applied to the continuation of antidepressants following acute treatment which ought to be routine for some months, with the purpose of preventing relapse. The term maintenance treatment is applied to longer treatment aimed at preventing recurrence in those at high risk.

	Continuation therapy with antidepressants

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
Since the 1970s, good evidence has accumulated regarding the efficacy of longer term antidepressant treatment¹⁴,¹⁵. The earliest studies were of tricyclic antidepressants and MAO inhibitors, but there are now increasing studies of SSRIs and newer drugs. It would appear that all drugs which have substantial acute antidepressant effects have some effects in prevention of relapse and recurrence.

Table 1 shows results of randomised controlled trials (RCTs) of continuation in relapse prevention. These have usually been withdrawal studies comparing effects of treatment for 6–9 months in responders to acute treatment, with withdrawal to placebo after 2–3 months.

View this table: [in this window] [in a new window]   Table 1. Controlled trials of antidepressant continuation in prevention of relapse

 
All the studies showed considerable benefit from continuation, with relapse rates at least halved. The absolute rates vary among studies because of sample characteristics. Relapse rates were particularly high after discontinuation of MAO inhibitors, although it is unclear whether this indicates a particular effect of the drugs, or something about the kinds of patients likely to respond to them. Two further studies, not shown in the table, examined effects of administering antidepressants or placebo after ECT¹⁶,¹⁷. Both found relapse rates lowered on antidepressants. A controlled trial of antidepressant augmentation by lithium found significantly higher relapse rates after early lithium withdrawal than continuation¹⁸.

A recent study¹⁹ employed a staged randomised design, with withdrawal to placebo after 3 months, 6 months or one year. Relapse rates in the next 3 months on fluoxetine or after withdrawal to placebo were 26% versus 49%, 9% versus 23%, and 11% versus 16%, respectively.

It is recommended that where response to acute antidepressant treatment has occurred, there should routinely be a following continuation period. Recommendations for its length have been for approximately 6 months after response²⁰ or for 4 months after complete remission with no residual symptoms²¹. In view of the Reimherr study, a longer period of 9–12 months after complete remission would now appear more prudent. Withdrawal should always be slow over at least 3 months. Relapse is particularly likely to follow drug withdrawal in patients with residual symptoms²²,²³.

In some patients, withdrawal will be followed by return of depressive symptoms. Where withdrawal has been slow, this may occur while the patient is still on a low dose. Clinical experience indicates that this phenomenon usually reflects impending relapse, and if the symptoms persist, full dose should be resumed followed by continuation for a further 9–12 months. Some of these patients relapse again on later drug withdrawal and a period of maintenance treatment then becomes appropriate.

ECT continuation after acute treatment has not been tested in controlled trials but one is now under way in the US. Occasionally patients are encountered clinically who respond to ECT but relapse repeatedly when it is stopped, in spite of vigorous treatment with antidepressants and lithium. There may be a limited place for continuing it with a reduced frequency of 1–4 per month for up to 6 months. In the author's view, longer continuation or maintenance is best avoided, in view of effects on memory and anaesthetic risks in out-patients.

	Maintenance therapy

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
There have also been many controlled trials of antidepressants versus placebo in longer term maintenance of 2 years or more in prevention of recurrences. These are summarised in Table 2. The most common design is again a withdrawal one, after acute treatment of recurrent depression, and response. The more recent studies have also required a symptom-free continuation period before randomised assignment to the maintenance phase has commenced. A few studies have started maintenance treatment de novo, following acute treatment with a variety of antidepressants or ECT.

View this table: [in this window] [in a new window]   Table 2. Controlled trials of antidepressant maintenance in prevention of recurrence in unipolar depression

 
Maintenance studies also show benefit from long-term antidepressants although differences between drug and placebo treated groups are not as marked as for continuation therapy, and a few studies have been negative.

The US Agency for Health Care Policy and Research clinical guidelines for unipolar depression²⁴ recommended maintenance treatment very strongly if there had been three or more episodes of major depression prior to the inception episode and recommended it strongly if there had been two episodes of major depression in the past, or one or more in addition to the index episode in the last 2 years, together with recurrence within 1 year of previous medication discontinuation, family history of bipolar disorder, onset before 20 years of age, or a severe, sudden or life threatening episode in the past 3 years. The last three indications are not well established.

Treatment length required for maintenance is not yet fully determined. Kupfer et al²⁵, in an extension of the study of Frank et al²⁶ found that even after 3 years' maintenance in recurrent depressives who remained well on imipramine, there was a high rate of recurrence (67%) in the next 2 years on imipramine withdrawal, compared with 5 years' maintenance (9%). Regarding dose, a comparison of full dose and half dose maintenance found a substantially higher recurrence rate on the latter²⁷.

Clinically, it is reasonable to employ a combination of indications for maintenance, and for its length. Three years maintenance is appropriate almost as a routine for recurrent patients, particularly where an episode prior to the present one has occurred in the last 5 years or where remission has been difficult to achieve. Maintenance for 5 years or more is appropriate for those at greater risk, and indefinite or life-long maintenance where two or three attempts to withdraw medication have been followed by another episode within a year.

Generally, as in continuation therapy, the antidepressant used will be that to which the patient has already responded in acute treatment. If side effects are a problem, including the weight gain that can develop on tricyclics²⁸, change to an antidepressant with fewer side effects is indicated. Unnecessary change should be avoided since the patient may be unresponsive to the new drug. Doses may be lowered slightly from acute treatment, but only to a limited degree.

Reliable predictors of relapse and recurrence would be of value in focusing treatment. Relapse has been found related to occurrence of stressful life events and absence of social support in the follow-up period²⁹, to expressed emotion, particularly hostility, in key relatives³⁰,³¹, to older age of onset and more previous episodes¹¹,³². The social factors appear more important in milder depression and earlier episodes and relatively unimportant in severe recurrent disorder^33–35. Residual symptoms consistently predict higher relapse rates¹². In longer follow-up studies, higher recurrence rates have been found where there have been more previous episodes, and less consistently with endogenous or psychotic depression³⁶.

There are not yet biological markers of incomplete recovery and risk of relapse which are useful in practice. Persistent dexamethasone non-suppression after antidepressant treatment predicts a greater risk of early relapse³⁷, but no more than 50% of depressives overall show non-suppression even when depressed.

	Lithium in maintenance treatment of unipolar depression

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
The place of lithium in bipolar disorder is discussed elsewhere in this issue. There is also evidence from controlled trials that lithium is effective in the long-term prevention of unipolar recurrent depression^38–44. Coppen et al⁴⁵ also found it superior to placebo after ECT in a one year study which was intermediate between continuation and maintenance. In direct comparisons, lithium has sometimes been found superior to antidepressant⁴³,^46–48, sometimes equal⁴⁰,⁴⁴, sometimes inferior⁴¹,⁴⁹. Two studies have also found lithium-tricyclic combinations superior to either drug alone⁴¹,⁴³, although a third study failed to do so⁵⁰.

This might seem to render choice of maintenance treatment in unipolar depression equivocal. In practice, many more unipolar patients are managed long-term on antidepressants alone than on lithium alone, reflecting continuing use of the regimen successful in acute treatment. Also the trials of lithium in long-term treatment of unipolars have predominantly been in severe and recurrent disorder, and some of them have been in subjects who have already had long periods on lithium and may be prone to recurrence on its withdrawal.

There is little long-term evidence regarding anticonvulsant mood stabilisers in unipolars. Use of lithium and other mood stabilisers in bipolar disorder is outside the scope of this paper.

There have only been a small number of controlled trials of antidepressants in long treatment of bipolars. They suggest that tricyclics are not of benefit alone, and may precipitate mania⁴⁰,⁴¹,⁴³. There is some evidence for the value of antidepressant-lithium combinations⁴³,⁵¹, but also evidence of risk of mania⁵². In practice, most clinicians do have some patients who remain well on antidepressant alone. Tricyclics appear more likely to precipitate rapid cycling and are preferably avoided. Evidence is not clear for SSRIs. Clinically, I have found MAO inhibitors easier than re-uptake inhibitors for stabilisation of bipolars.

	Mode of withdrawal

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
Findings of controlled trials show good benefit from continuation and maintenance treatment, but findings of naturalistic follow-up studies show high rates of relapse and recurrence. There are several possible explanations for this discrepancy⁵³.

First, some key published follow-up studies have been based on samples treated in special university centres, which tend to have referred to them the more severe, resistant and recurrent patients with poorer outcome.

Secondly, modern maintenance studies require subjects to be recurrent on inclusion, to respond well to the study antidepressant, and to remain well during continuation treatment, before being included in the randomised maintenance phase. Such samples, with poor spontaneous long-term outcome without maintenance, and good response to the particular study antidepressant, may get much greater long-term benefit from it than the average patient.

Thirdly, treatment delivered in practice may fail to conform to recommendations. This is known to occur in acute depression. A British study of hospitalised depressives did not find major deficiencies in long-term medication treatment or compliance in the 18 months after discharge, and recurrences did not appear to be related primarily to deficient treatment⁵³. However American studies have suggested some deficiencies and that these may be associated with worse outcome^54–56.

An important possibility concerns mode of withdrawal. In long-term trials withdrawal has often been rapid, over 2–4 weeks. Rapid drug withdrawal might increase relapse and recurrence rates. There is accumulating evidence pointing to the need for slow withdrawal of psychotropic drugs. A naturalistic study of lithium in bipolars found high and rapid rates of recurrence of mania after stopping⁵⁷. A further report found lower recurrence rates when withdrawal was slow rather than abrupt⁵⁸.

Three phenomena need to be distinguished: relapse (return of the original symptoms), rebound (return of original symptoms but with greater intensity or more likelihood), withdrawal (development of different symptoms related to drug stoppage). There is clear evidence of withdrawal symptoms on abrupt stoppage, particularly from high dose or longer treatment, both after tricyclics⁵⁹, and SSRIs⁶⁰. Symptoms are particularly gastrointestinal and influenza-like. This is a true withdrawal phenomenon, easily avoided by slower withdrawal over a month or so. It now appears probable that there is also rebound relapse if withdrawal is too rapid, even if slow enough to avoid withdrawal symptoms.

In clinical practice, antidepressants should always be withdrawn slowly after continuation or maintenance therapy, over a minimum of 3 months in gradual steps. If treatment has been over several years, dose reduction and stopping should take longer.

	Interpersonal therapy

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
Although psychotherapy has been widely used in depression for many years, most approaches have been little evaluated in controlled trials. However, the last 20 years has seen the advent of more specific therapies, tailored to specific disorders, often with detailed treatment manuals, and evaluation in controlled trials.

Among psychotherapies for depression, interpersonal therapy (IPT) has been the best studied and the only one to be evaluated in longer term designs. One controlled trial, carried out in the late 1960s and early 1970s, examined relapse prevention in a factorial design with continuation antidepressant^61–63. Patients responding to amitriptyline were randomised to six groups: drug continuation for a further 8 months, withdrawal to placebo double blind after 2 months continuation, withdrawal openly to no medication; in each drug group either with or without what later became codified as IPT. As shown in Table 1, antidepressant continuation halved the relapse rate compared to early withdrawal; results were the same, whether this was double blind or open. IPT had no effect on relapse rates or symptoms, although it was superior to low contact in effects on measures of social adjustment and interpersonal relationships.

Two more recent studies have examined effects of IPT on recurrence, again in factorial designs. Frank et al²⁶ treated recurrent major depressives with both imipramine and IPT to remission and for 4 months continuation followed by randomisation to a maintenance design for 3 years. Recurrence rates on placebo alone were very high (around 90%), on imipramine around 20%, with no further benefit from combination with IPT; on IPT without imipramine, recurrence was reduced but only by a small amount. The preferred treatment from this study was antidepressant.

Reynolds et al⁶⁴ treated elderly patients with recurrent non-psychotic major depression acutely with nortriptyline plus weekly IPT. After a 16 week continuation phase, responders were randomised to maintenance treatment for the next 3 years. Recurrence rates were: placebo and medication clinic 90%, placebo plus IPT 64%, nortriptyline plus medication clinic 43%, nortriptyline and IPT 20%. Thus there were stronger effects for nortriptyline than for IPT, but an additive effect of combination with a further worthwhile benefit.

Unfortunately, the recurrence studies have not reported on social adjustment, where there might be improvement due to IPT not achieved by medication. At present, it is still difficult to make a strong argument that IPT offers sufficient advantage for relapse and recurrence prevention in clinical practice to outweigh its additional cost, compared with medication alone, but further studies are under way.

	Cognitive behavioural therapy

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
The second well-evaluated psychological therapy specifically tailored to depression is cognitive-behavioural therapy (CBT). The first evidence suggesting relapse prevention emerged in follow-up studies from acute controlled trials of antidepressants against cognitive therapy in depression. Three studies showed significantly lower relapse rates after cognitive therapy^65–67, with non-significant trends in the same direction were found in three other studies^68–70. However, naturalistic follow-up studies of acute trials cannot be definitive. Different kinds of patients with different prognoses for relapse may respond initially to cognitive therapy and to antidepressant acute treatment. Also, antidepressant continuation was not always undertaken or well controlled in the follow-up studies. In one study in which it was⁶⁷, a relapse rate of 52% after antidepressant withdrawal was reduced to 32% with one year's continuation, not significantly different from the 21% relapse after cognitive therapy, although still suggestive.

Fava and colleagues^71–73 undertook a small trial of 40 patients with residual depressive symptoms after acute antidepressants, who were randomised to a modified form of cognitive therapy or clinical management. Relapse and recurrence were significantly reduced at 4 years. In a second 40 patient trial in recurrent depression, there was significant prevention of recurrence⁷⁴. In both these studies, the cognitive therapy was much modified from standard, and antidepressants were withdrawn, rendering patients highly at risk of symptom return and maximising the possible effects of the cognitive therapy. Usually these patients will be continued on antidepressants, and the relevant question is what cognitive therapy adds to the drug therapy.

More recently, a larger controlled trial of cognitive therapy has been carried out in 158 patients with residual symptoms after major depression⁷⁵,⁷⁶. Antidepressants were continued in moderately high dose throughout the 17 months of the treatment trial and controlled follow-up. Subjects were randomised to receive clinical management alone or clinical management with 5 months' cognitive therapy. Cognitive therapy significantly reduced relapse rates from 47% in the clinical management group to 29% in the cognitive therapy group⁷⁵. There were also significant differences in the proportions reaching full remission, but only a relatively small proportion of subjects in either group remitted fully. Symptom ratings showed limited significant effects particularly on ratings of worthlessness and hopelessness, key targets for cognitive therapy⁷⁶. Cognitive therapy also produced some significant benefit in social adjustment. Relapse prevention appeared to be the principal effect of cognitive therapy in this study.

This study showed major benefit by adding cognitive therapy to drug treatment which had produced only partial improvement, in a group of subjects highly at risk of relapse. CBT, like IPT, is costly, but prevention of further episodes in patients at higher risk of these is emerging as a specific indication for it, particularly in combination with medication. Further studies of psychological therapies used in this way are needed. Conventional cognitive therapy requires the presence of negative cognitions, at least at residual symptom level, to be feasible, but modifications for recovered previously depressed subjects are currently being evaluated, as are cognitive approaches in bipolar disorder.

	Key points for clinical practice

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 

• Antidepressant continuation following acute treatment and response should be routine. Doses should be the same or only a little lower than for acute treatment. Recent evidence suggests duration of 9–12 months after remission, rather than shorter periods. Where symptoms return during or after withdrawal, full dose continuation for a further similar period should be initiated
  
• For depressives with already recurrent histories, particularly with recent recurrences, longer term maintenance is indicated. Duration may vary from 3 years to life-time, but in general the more adverse the prognosis, the longer the maintenance treatment
  
• Adverse prognostic indicators for relapse and recurrence, strengthening treatment indications, include residual symptoms at remission, longer episode, more previous episodes, previous chronicity, more severe episodes, previous episode in the last year, relapse after medication withdrawal, onset early in life
  
• Withdrawal of antidepressants and lithium after longer term use should always be gradual, with dose reductions over at least 3 months. Probably the longer the duration of treatment the slower the reduction. Abrupt cessation of antidepressants after longer term use can lead to withdrawal syndromes; rapid although not abrupt withdrawal to rebound relapse and recurrence
  
• The indications for psychological therapies in relapse and recurrence are less well established, but cognitive therapy appears to have a specific indication when added to medication where there is high risk of relapse and recurrence, particularly in presence of residual symptoms
  

	Footnotes

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 
Correspondence to: Prof. E S Paykel, Department of Psychiatry, University of Cambridge, Douglas House, 18E Trumpington Road, Cambridge CB2 2QQ, UK

	References

Top Footnotes Abstract Longer term outcome in... Continuation therapy with... Maintenance therapy Lithium in maintenance treatment... Mode of withdrawal Interpersonal therapy Cognitive behavioural therapy Key points for clinical... References

 

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