I n t e r v i e w w i t h W. C h o u c h a a n d J . – F. A l l i l a i r e , F r a n c e

Left. Jean-François ALLILAIRE, MD, PhD
Right. Walid CHOUCHA, MD
CHU Pitié Salpêtrière, Service de Psychiatrie Adulte

For how long should an antidepressant be prescribed following achievement of remission, and at what dosage?

Continuation or consolidation therapy is systematically indicated once a patient has responded to acute antidepressant treatment, whatever the severity, nature, or number of depressive episodes. However, recommendations for the length of this therapy vary widely from 4 to 12 months, according to different authors. Some consider 4 to 9 months of continuation antidepressant treatment to be sufficient. Others recommend approximately 6 months of continuation therapy if there are residual symptoms, and 4 months if there is complete remission with no residual symptoms. More recently, prudent authors have recommended 9 to 12 months of continuation therapy whether residual symptoms are present or not.1 During this phase, the antidepressant should be continued at the same dose that induced remission. All studies have shown considerable benefit from continuation therapy, with relapse rates at least halved. Continuation psychotherapy can be added to continuation medication following an acute phase response, whether to a single medication or a combination. In certain situations, there is no need for continuation antidepressant treatment to be followed by maintenance therapy: (i) patients presenting with a first nonsevere depressive episode and aged <55 years old (for some authors <50 years old and for others <60 years old). Some authors recommend continuation treatment for 4 to 6 months in this group of patients; and (ii) patients presenting with a second nonsevere depressive episode after >3 years of remission (for some authors, more than 5 years). Some authors recommend continuation treatment for 6 to 12 months in this group of patients. There is a 30% to 80% chance that these two groups of patients will not show relapse or recurrence during 5 years of follow-up after their last depressive exacerbation. After a full continuation phase, antidepressant treatment discontinuation should then be gradual, and if there is a return of the depressive symptoms, one should revert to the effective dose with a further attempt at withdrawal after at least a further 4 to 6 months of continuation treatment (a further 9-12 months according to some authors). Clinical experience indicates that this phenomenon usually reflects impending relapse. If such patients relapse again during a later drug withdrawal trial, a period of maintenance treatment then becomes appropriate.

Acontinuation phase of antidepressant treatment is systematically indicated once a patient has responded to acute-phase antidepressant treatment, and this should be followed by a maintenance treatment phase in certain clinical situations. The length of such phases remains controversial. However, the antidepressant dose during the continuation and maintenance phases should be the same as that which induced remission. Full remission means that the patient no longer meets the criteria for a depressive disorder and has minimal symptoms at most during 2 months or more. We generally consider that full remission has occurred when the Hamilton Rating Scale for Depression score is less than 8. Consequently, residual symptoms may persist even after the patient has achieved full remission, and they are considered as an important risk factor for relapse and long-term social dysfunction. The prevalence of residual symptoms in remitted patients is estimated to be 30% to 50%. They mainly include insomnia, anxiety, cognitive disturbances, apathy, and fatigue/somnolence. Management of these symptoms includes optimizing the antidepressant dose and duration, assessing and enhancing adherence to treatment, adding psychotherapies like interpersonal or cognitive therapy (with better evidence for the latter), and augmenting current antidepressant treatment with adjunctive pharmacotherapy. Other important risk factors for relapse may include comorbid personality, somatic or social disorders, and recurrent depression. Lifestyle recommendations for maintaining remission may include regular physical exercise, more balanced dietary habits, more healthy sleep, as well as better planning and organization of different daily life activities.
Medicographia. 2009;31:182-185. (see French abstract on page 185)

Keywords: depression; continuation therapy; maintenance therapy; remission; relapse; recurrence; residual symptom; adjunctive psychotherapy; adjunctive pharmacotherapy; lifestyle recommendation

Maintenance, prophylactic, or preventive therapy is either of lifetime duration or for at least 5 years.2 Lifetime maintenance treatment is indicated in the following situations: (i) patients presenting with three or more depressive episodes; (ii) patients presenting with their first depressive episode over the age of 55 years (for some authors this is >60 years of age); and (iii) patients presenting with a second depressive episode when over the age of 40 years.
In the following situations, treatment should be maintained for at least 5 years (3 years for some authors and 4 years for others): (i) patients presenting with a second depressive episode while aged less than 40 years; (ii) patients presenting with a second depressive episode after less than 3 years (for some authors <5 years) of maintained remission; (iii) patients presenting with a second depressive episode after more than 3 years of remission (for some authors >5 years) but experiencing a severe episode (presence of marked suicidal thoughts/actions, psychotic, melancholic or catatonic features, etc); and (iv) patients presenting with a severe first depressive episode. A total of 70% to 90% of these 4 groups of patients are at risk of relapse or recurrence within 5 years if medication is stopped.
In all cases of maintenance therapy, the antidepressant should be maintained at the same dosage that induced remission.3

What results should a clinician expect in terms of remission?

Complete or full remission4 means that the patient no longer meets the criteria for a depressive disorder and has minimal symptoms at most during 2 months or more. We generally consider that full remission has occurred either when the Hamilton Rating Scale for Depression (HAM-D) score is less than 8, the 9-item Patient Health Questionnaire (PHQ-9) score is less than 5, or the Beck Depression Inventory (BDI) score is less than 9.
The three items most frequently judged by patients to be very important in determining remission are the presence of features of positive mental health such as optimism and self-confidence, a return to one’s usual, normal self, and a return to usual levels of functioning.
A patient is considered to be in recovery when remission is maintained for beyond 6 months. The term partial remission means either that the patient no longer meets the criteria for a depressive disorder and has minimal symptoms at most for less than 2 months, or has more than just minimal symptoms for 2 months or more. We generally consider that partial remission has occurred when the HAM-D score is over 7 (between 8 and 17 or 18).
Response means that there is a robust improvement in depressive symptoms with treatment (a reduction of 50% or more in HAM-D or Montgomery–Åsberg Depression Rating Scale [MADRS] scores). Partial response means an improvement in depressive symptoms with treatment, but without reaching response (only 25%-49% reduction in symptoms).
Nonresponse means a relative lack of symptom improvement (less than 25% reduction in symptoms). As we can see, residual symptoms may persist even after the patient has achieved full remission, as defined by even the most conservative criteria. Their prevalence in remitted patients is estimated to be 30% to 50%.
Relapse occurs when depressive symptoms fulfilling the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for a major depressive disorder arise during either partial or full remission. Recurrence occurs when depressive symptoms fulfilling the DSM criteria for a major depressive disorder arise during the period of recovery. Rebound means a return of the original depressive symptoms but with greater intensity, and withdrawal refers to the development of different symptoms that are related to the stopping of a drug treatment.

When is adjunctive therapy such as psychotherapy needed?

The two main recommended adjunctive psychotherapies in depression are interpersonal therapy and cognitive therapy. Their indication in managing residual symptoms and preventing relapse and recurrence is, however, less well established. Trials of interpersonal therapy for the prevention of recurrence have shown some benefits, but the effects are weaker than those of drugs, and any additional benefit in combination with drugs is limited.
There is better evidence for the effects of cognitive therapy in preventing relapse and recurrence, and there is an emerging indication for its addition to antidepressants, particularly when residual symptoms are present. One randomized, controlled study of cognitive therapy5 involved 158 patients with recent major depression who were partially remitted with antidepressant treatment but who had residual symptoms of 2 to 18 months’ duration. Patients randomized to continue antidepressant therapy with the addition of cognitive therapy (16 sessions during 20 weeks with 2 subsequent booster sessions) showed significantly reduced relapse rates at 68 weeks compared with those who continued pharmacotherapy alone (29% vs 47%).
Although the cognitive therapy group showed a more significant increase in remission rates at 20 weeks, the increase was comparatively small and not reflected in the mean symptom ratings, particularly on ratings of worthlessness and hopelessness.
It seems that the preventive effects of cognitive therapy on relapse are more powerful than the immediate effects on residual symptoms. In a longitudinal study,6 a total of 40 subjects with residual symptoms were randomized either to modified cognitive therapy targeting anxiety and irritability, or to clinical management. Modified cognitive therapy significantly reduced residual symptoms, as well as relapse and recurrence rates at 4 and 6 years, compared with the clinical management group (35% vs 70%).
In a subsequent study of recurrent depression,7 a total of 40 patients were randomized either to a therapeutic strategy that included cognitive therapy, lifestyle modification, and well-being therapy, or to a control group. Modified cognitive therapy significantly reduced recurrence from 80% to 20% during 2 years.

What kinds of lifestyle recommendations are helpful for maintaining
remission in patients?

The first recommendation is regular physical exercise. When prescribing exercise, several caveats apply:
◆ Anticipate barriers, as hopelessness and fatigue can make physical exercise difficult.
◆ Keep expectations realistic, as some patients are vulnerable to guilt and self-blame if they fail to carry out the regimen.
◆ Introduce a feasible plan: walking, alone or in a group, is often a good option. Paying attention while walking to colors, smells, shapes, sounds, and people may be ideal.
◆ Accentuate the pleasurable aspects of exercise: the specific choice of exercise should be guided by the patient’s preferences, and must be pleasurable.
◆ A goal of 30 minutes of moderate-intensity aerobic exercise, 3-5 times a week is recommended for otherwise healthy adults.
◆ Encourage adherence, as greater antidepressant effects are seen when training continues beyond 16 weeks.
◆ Relaxation exercises, whenever possible, are recommended, including meditation and even yoga!
Another lifestyle recommendation concerns dietary habits. Less of a caloric and more of a balanced diet is recommended. It is better to have more meals rather than bigger meals.
Recommendations regarding sleep habits are also important. Activities including sport, television, and even reading should ideally be avoided before going to sleep. A steady sleep routine that involves always trying to go to bed early and at the same time everyday is recommended. The sleeping room should be as uncluttered as possible, with no office or work equipment in it, and should be dedicated only for sleeping. The bed mattress for sleeping should be comfortable. Siestas, if possible, may be very beneficial.
Finally, daily life activities should be planned in such a way as to minimize or avoid “hurrying.” Multiple activities should not be performed simultaneously. Rest after every activity is recommended. As residual symptoms affect those parts of the brain responsible for high concentration activities, planning, and organization, patients should therefore try to avoid activities that demand too much of this, such as reading, writing, the Internet, or watching the news, and encourage activities like gardening, painting, or bird-watching.

What therapeutic approach should be used for residual symptoms?

We should first try to address treatment-emergent side effects. Indeed, significant overlap exists between the residual symptoms of a depressive episode and the side effects of antidepressants. A systematic assessment of symptoms prior to beginning pharmacological treatment can help to distinguish between residual symptoms and treatment side effects. If dose optimization improves a patient’s symptoms, one may assume that they are likely to have been residual. On the other hand, if op- timization has no effect or worsens symptoms, clinicians may assume that these symptoms probably represent side effects of pharmacologic therapy, as the intensity of the side effects is typically dosedependent. Second, we should diagnose and treat any comorbid medical or psychiatric conditions, such as substance abuse, since these conditions may cloud the assessment of symptoms, whether related to the underlying depressive disorder or antidepressant treatment.
If it is decided that symptoms are likely to be residual, clinicians may want to optimize the antidepressant dose and duration, assess and enhance adherence to treatment, add psychotherapy (cognitive or interpersonal therapy), and augment current therapy with adjunctive pharmacological treatment. By contrast, if symptoms are likely to be side effects of pharmacological treatment, clinicians may want to decrease the antidepressant doses or switch the patient to another antidepressant. Adjunctive treatment, however, may improve such symptoms regardless of the underlying etiology. Such adjunctive treatment includes the following8: (i) for anxiety, either a benzodiazepine (like lorazepam, alprazolam, or clonazepam), buspirone, gabapentin, or even an antipsychotic (olanzapine, quetiapine); (ii) for insomnia, we can add either an hypnotic (like zolpidem or zopiclone), or lorazepam, or sedative antidepressants (like mirtazapine, mianserine, or trazodone); (iii) for fatigue and somnolence, we can add either methylphenidate, modafinil, bupropion, or reboxetine; (iv) for apathy, we can also add either methylphenidate, modafinil, bupropion, or reboxetine; and (v) for cognitive disturbances, we can add either anticholinesterase medications (like donepezil), methylphenidate, modafinil, bupropion, reboxetine, or memantine. It seems that the risk and severity of residual symptoms is significantly less with serotonin and norepinephrine reuptake inhibitors than with selective serotonin reuptake inhibitors9; the ideal scenario would be an antidepressant that addressed residual symptoms at the same time as other symptoms, thus removing the need for adjunctive therapy.

When should the clinician and the patient suspect a relapse?

Patients at risk of relapse are those who present with: (i) three or more depressive episodes; (ii) a second depressive episode occurring after the age of 40 years or one that is associated with severe symptoms, or one that occurs less than 3 years after remission from their first episode (for some authors, less than 5 years); (iii) a first depressive episode occurring after the age of 50 to 60 years (or before 20 years of age according to certain authors); (iv) a longer depressive episode; (v) residual symptoms at remission10: their presence appears to affect early short-term relapse rather than overall long-term risk of recurrence or number of recurrences, and to be responsible for impaired long-term social functioning. There is some conflict in the literature concerning factors like initial severity of depression, life stressors, and personality as predictors of residual symptoms. In addition, residual symptoms are prevalent both in patients who have received psychotherapy, as well as those treated with pharmacotherapy; (vi) relapse at medication withdrawal11; (vii) family history of bipolar disorder or recurrent depression; (viii) associated disorders on axis 1 or 2; and (ix) bad social adjustment, persistent stressful life events, or absence of social support. _

1. Reimherr FW, Amsterdam JD, Quitkin FM, et al. Optimal length of continuation therapy in depression: a prospective assessment during long-term fluoxetine treatment. Am J Psychiatry. 1998;155:1247- 1253.
2. Kupfer DJ, Frank E, Perel JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry. 1992;49:769-773.
3. Franck E, Kupfer DJ, Perel JM, et al. Comparison of full-dose versus half-dose pharmacotherapy in the maintenance treatment of recurrent depression. J Affect Dis. 1993;27:139-145.
4. Frank E, Prien RE, Jarrett RB, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse and recurrence. Arch Gen Psychiatry. 1991;48: 287-297.
5. Paykel E, Scott J, Teasdale J, et al. Prevention of relapse in residual depression by cognitive therapy. Arch Gen Psychiatry. 1999;56:829-835.
6. Fava GA, Grandi S, Rafanelli C, Canestrari R, Morphy MA. Six-year outcome for cognitive behavioral treatment of residual symptoms in major depression. 1998;155:1443-1445.
7. Fava GA, Rafanelli C, Grandi S, Conti S, Belluardo P. Prevention of recurrent depression with cognitive behavioral therapy: preliminary findings. Arch Gen Psychiatry. 1998;55:816-820.
8. Fava M. Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology. 2006;20:29-34.
9. Stahl SM. Essential Psychopharmacology.<./em> 2nd ed. New York, NY: Cambridge University Press; 2000.
10. Kennedy N, Paykel ES. Residual symptoms at remission from depression: impact on long-term outcome. J Affect Dis. 2004;80:135-144.
11. Paykel ES. Continuation and maintenance therapy in depression. Br Med Bull. 2001;157:145-159.


Lorsqu’un patient a répondu à un traitement antidépresseur d’attaque, une phase de consolidation est systématiquement indiquée et doit, dans certaines situations cliniques, être poursuivie par une phase d’entretien. Si la durée de ces différentes phases ne fait pas l’objet d’un consensus, la posologie du traitement antidépresseur, quant à elle, doit être la même pendant les phases de consolidation et d’entretien que celle qui a permis la rémission. Une rémission complète signifie que le patient ne remplit plus les critères d’un trouble dépressif et ne présente que des symptômes minimaux, pendant 2 mois ou plus ; elle correspond généralement à un score inférieur à 8 à l’échelle HDRS (Hamilton Rating Scale for Depression). Les symptômes résiduels, qui peuvent donc persister même après la rémission complète, sont considérés comme un facteur de risque important de rechutes et de handicap social à long terme. La prévalence des symptômes résiduels chez les patients en rémission est estimée entre 30 et 50 %. On y trouve principalement l’insomnie, l’anxiété, les troubles cognitifs, l’apathie, la fatigue et la somnolence. Leur prise en charge comporte l’optimisation de la dose et de la durée du traitement antidépresseur, l’évaluation et l’amélioration de l’observance du traitement, l’ajout de psychothérapies interpersonnelles ou cognitives (l’efficacité de ces dernières étant mieux prouvée) et l’association au traitement antidépresseur en cours d’un traitement pharmacologique adjuvant. La personnalité comorbide, les troubles somatiques et sociaux et la dépression récurrente sont également des facteurs de risque important de rechute. Pour contribuer au maintien de la rémission, on peut recommander un exercice physique régulier, de meilleures habitudes alimentaires, un sommeil plus équilibré ainsi qu’une meilleure planification et organisation des activités de la vie quotidienne.