b y G . A . F a v a a n d D . V i s a n i , I t a l y

Several investigations have suggested the usefulness of a sequential way of integrating pharmacotherapy and psychotherapy in depression. 1 Administration of treatments in sequential order is a common practice in clinical medicine, particularly when treatment fails. This sequential administration of treatments also occurs in clinical psychiatry. It may involve switches to different types of drugs, as is often the case in drug-refractory depression, an increase or decrease in dose, augmentation, or change to a different drug.2 There are also examples of changes of types of treatment: use of antidepressants after unsuccessful cognitive behavioral therapy (CBT) in depression,3 and of CBT in the management of drug-resistant major depressive illness.4
The recent findings of the largest depression trial, Sequenced Treatment Alternatives to Relieve Depression (STAR*D), have provided a dramatic illustration of the difficulties in achieving recovery from depressive illness by using pharmacological strategies. 5 The aim of the trial was to apply the best pharmacological strategies to obtain remission in major depression. A sample of 3671 patients was treated with citalopram in an open fashion: only 36.8% of patients remitted. Those who did not recover were submitted to four sequential steps involving switching, augmentation, and combination strategies, based on available literature. The recovery rate was low and difficult to attribute to specific effects of citalopram, since there was a variety of nonspecific therapeutic ingredients, as in other major trials.5-8 Because of the type of randomization that was chosen (equipoise-stratified randomization strategy), the role of cognitive therapy could not be established, since the patients who opted for it were too few (less than one third of participants).9 TheSTAR*D results were rather disappointing. The cumulative rate of remission after 4 sequential steps was 67%.5 However, when sustained recovery was considered (taking into account relapse rates while on treatment), the cumulative rate was 43%.10 This means that the strenuous efforts after step one (open treatment with citalopram) yielded an additional 6% of sustained recovery.11
In clinical medicine, there is also, however, another type of sequential treatment, which is not related to the partial remission or failure associated with a specific therapy (sequence is performed regardless of the outcome of the first component, as a preplanned strategy). This type of approach is based on the awareness that one course of treatment is unlikely to yield full disappearance of symptomatology. A related assessment strategy is the staging method, whereby a disorder is characterized according to seriousness, extension, and features.1,12,13

There is increasing literature on the bleak long-term outcome of depression in terms of relapse and recurrence. This unsatisfactory outcome seems to be associated with the presence of substantial residual symptomatology. If residual symptoms are the rule after completion of drug or psychotherapeutic treatment, and their presence has been correlated with poor outcome—as residual symptoms upon recovery may progress to become prodromal symptoms of relapse—then treatment directed toward residual symptoms may yield long-term benefits. Treatments that are aimed at potentially different symptoms, such as pharmacotherapy and psychotherapy, may thus be used in a sequential order. One type of treatment (eg, psychotherapy) may be employed to improve symptoms that the other type of treatment (eg, pharmacotherapy) was unable to affect. Several studies substantiate the clinical advantages of the sequential use of psychotherapy after pharmacological treatment. There has been little research on other forms of sequential treatment in depression. It has also been suggested that the most effective drugs in treating acute depression may not be the most suitable for postacute or continuation treatment. The sequential treatment of depressive illness does not fall within the realm of maintenance strategies. It is an intensive two-stage approach, which is based on the fact that one course of treatment with a specific tool (whether pharmacotherapy or psychotherapy) is unlikely to hold a solution to the complex array of symptoms in patients with depression. The sequential model entails considerable implications for assessment and treatment planning.
Medicographia. 2009;31:186-191. (see French abstract on page 191)

Keywords: depression; recovery; staging; sequential model; cognitive behavioral therapy; wellbeing therapy

Instead of administering different therapies together, their sequential administration is planned, based on some specific effects induced by each of them that provide additional benefits in the course of time. Staging has the potential to improve the logic and timing of interventions.11 The phenomenological development of unipolar depression may be categorized according to stages (Table I).14 A drug that may be effective in stage 2 major depressive episode (previously untreated) may not be as effective in a patient with stage 4 recurrent major depression who has been submitted to previous trials. Most of the patients in STAR*D were in stages 4 or 5 of Table I. Pharmacological manipulations, either by switching or augmentation (steps 1 and 2), may propel depressive illness into a refractory phase, characterized by low remission, high relapse, and high intolerance (steps 3 and 4).11

Table I
Table I. Stages of primary unipolar depression.14

Rationale for sequential treatment

Standard treatment of depression, even in specialized settings, seems to yield modest and temporary benefits and to leave a large amount of residual symptomatology, which appears to be one of the strongest predictors of an unfavorable outcome.15,16 These findings have led to the hypothesis that residual symptoms upon recovery may progress to become prodromal symptoms of relapse, and that treatment directed toward residual symptoms may yield long-term benefits.17 Treatment that is potentially aimed at producing different effects (eg, pharmacotherapy and psychotherapy) may thus be used in a sequential order. One type of treatment (eg, psychotherapy) may be employed to improve symptoms that the other type of treatment (eg, pharmacotherapy) was unable to affect. This may be particularly important when treatments provide different modulations of cortical-limbic pathways, such as CBT and antidepressant drugs in major depression.18
Even though psychotherapy-pharmacotherapy combinations have been shown to be more effective than monotherapy in a number of psychiatric disorders, the effect size observed favoring combined treatment has been generally rather modest in mood and anxiety disorders.19-22 Another line of evidence potentially support- ing the sequential model in affective disorders is the increasing awareness of the role of comorbidity. 23,24 In major depression, two thirds of patients meet the criteria for another axis I disorder (particularly anxiety disorders), and one third has two or more disorders.25 It is thus unlikely that monotherapy will entail a solution to such complex disturbances, additionally because some forms of comorbidity may be covered by the acute manifestations of the disorder and become evident only when the most severe symptoms have abated.26

Use of psychotherapy
after pharmacological treatment

In a controlled therapeutic trial,27 40 patients with major depressive disorder who had been successfully treated with antidepressant drugs were randomly assigned to either CBT or clinical management of residual symptoms. In both groups, antidepressant drugs were tapered and discontinued. The group that received CBT treatment had a significantly lower level of residual symptoms after drug discontinuation in comparison with the clinical management group. CBT also resulted in a lower rate of relapse, with achievement of statistical significance at a 4- year follow-up.28 These differences faded at a 6-year follow-up.29 However, when multiple relapses were considered, patients in the CBT group had a significantly lower number of depressive episodes than those in the standard clinical management group.29 The aim of this approach was to spend CBT resources when they are most likely to make a unique and separate contribution to patient wellbeing and to achieve a more pervasive recovery. This sequential approach was also applied to 40 patients with recurrent major depression (according to the criteria outlined by Frank et al30) by the same group of investigators.31 Patients were randomly assigned to either CBT for residual symptoms—supplemented by lifestyle modification and wellbeing therapy32,33— or clinical management. In both groups, antidepressant drugs were tapered and discontinued. At a 2-year follow-up, CBT resulted in a significantly lower relapse rate (25%) than did clinical management (80%). The differential relapse rate was found to be significantly related to the abatement of residual symptoms. 34 At a 6-year follow-up, CBT still resulted in a significantly lower relapse rate (40%) compared with clinical management (90%).35
Other groups of investigators lent support to the sequential use of pharmacotherapy and psychotherapy for relapse prevention in unipolar depression. Paykel et al36 randomized 158 patients with recent major depression, partially remitted with antidepressant treatment but with residual symptoms, to clinical management or clinical management associated with cognitive therapy. Patients received continuation and maintenance antidepressants during a 1-year follow-up period. The relapse rate was 47% in the clin- ical management group and 29% with CBT. There was a small but statistically significant effect on residual symptom levels.37 Cost effectiveness analyses showed substantial benefits with the CBT approach. 38 At a 6-year follow-up,39 the effects on prevention of relapse and recurrence were found to persist up to 3 and a half years after the end of CBT.
Similar results were obtained with mindfulnessbased cognitive therapy (MBCT).Teasdale et al40 randomized 145 patients in remission or recovery from major depression to treatment as usual (TAU) or TAU supplemented by MBCT. For patients with 3 or more previous episodes of depression, who constituted 77% of the sample, relapse rates were 66% for the TAU controls and 37% for the patients also receiving MBCT.40 However, there were no significant differences in outcome for patients with only two previous episodes of depression. Since MBCT was administered in groups, this study provided the first demonstration that the sequential model may yield beneficial results also in the group format. The favorable results concerning MBCT were replicated in a subsequent study.41
In another randomized controlled trial,42 187 patients were randomized to TAU including continuation of pharmacotherapy, or to TAU associated with group cognitive therapy. During a 2-year follow- up period, cognitive therapy resulted in a significant protective effect, which increased with the previous number of depressive episodes experienced. Bockting et al43 identified a significant protective effect of cognitive therapy in patients with at least two previous episodes who remitted on various types of treatments (n=172). Preventive cognitive therapy protected against the influence of a consistently found risk factor for relapse/recurrence (the number of depressive episodes). This result underlines the potential of psychological preventive interventions.
One study, however, has failed to substantiate the clinical advantages of the sequential model in unipolar depression.44 A total of 132 patients with major depression who achieved remission with fluoxetine were randomized to receive CBT and medication or medication management alone, and were followed for up to 28 weeks. Relapse rates did not differ between the two groups, even though the addition of CBT was associated with attributional style gains.45 A major limitation of this study, however, was the duration of follow-up (in previous studies, maximal gains tended to occur at a later point).
The results of the randomized controlled trials therefore lend support to the use of a sequential treatment model (pharmacotherapy followed by psychotherapy) for preventing relapse in unipolar depression. This approach appears to be particularly important in recurrent depression. However, since incomplete recovery from the first lifetime major depressive episode was found to predict a chronic course of illness during a 12-year prospective naturalistic follow-up study,46 this sequential approach may be indicated whenever substantial residual symptomatology is present.
The advantages of keeping patients on their medication during psychotherapy, versus tapering and discontinuation, have not been directly compared in sequential studies. Some inferential indications may come from a study by Blackburn and Moore.47 A total of 75 outpatients with recurrent major depression were allocated to 3 groups: short-term and maintenance (2 years) treatment with antidepressant drugs, CBT in the short-term and maintenance phases, and antidepressant use in the short-term phase with CBT for maintenance. CBT displayed a similar prophylactic effect to maintenance medication. There were no significant differences among treatments. These results have been confirmed in a trial by Hollon et al48 involving 104 patients who responded to treatment (either CBT or medication). Patients who responded to CBT were withdrawn from treatment and compared with medication responders who had been randomly assigned to either continuation medication or placebo withdrawal during a 12-month period. Patients who survived the continuation phase without relapse were withdrawn from all treatment and monitored during a 12- month naturalistic follow-up period. Patients who completed CBT were significantly less likely to relapse (31%) than patients on placebo (76%) and no more likely to relapse than those who carried on taking continuation medication (47%). Survival analysis of the naturalistic follow-up indicated that CBT, unlike antidepressant drugs, had an enduring effect extending beyond the end of treatment.48 The results of these two studies47,48 therefore suggest that discontinuation of antidepressant drugs may be feasible in subgroups of patients when CBT is provided.
A novel indication for the sequential model was provided by a very small pilot study, which concerned 10 patients with recurrent depression who relapsed while taking maintenance antidepressant drugs.49 They were randomly assigned to a dose increase and clinical management, or to CBT and maintenance of the antidepressant drug at the same dose. Four of five patients responded to a larger dose, but all had relapsed again at that dose by a 1-year follow-up. Four of five patients responded to CBT, but only one relapsed during follow-up. In another recent investigation,50 the feasibility of a family intervention approach to the loss of clinical effect during long-term antidepressant therapy was explored. A total of 20 outpatients with recurrent major depressive disorder who lived with a partner and had relapsed while taking antidepressant drugs were randomly assigned to (i) family intervention approach according to the McMaster Model and maintenance of the antidepressant drug at the same dosage or (ii) dose increase and clinical management. Seven out of 10 patients responded to an increased dosage; all but 1 relapsed again on that dosage during follow-up. Seven out of 10 patients responded to family intervention, but only 1 relapsed during follow-up. The data from these pilot studies49,50 have to be confirmed with large-scale controlled studies, but may suggest that the application of a sequential model is feasible when there is a loss of clinical effect during long-term antidepressant treatment.2 Treatment for patients with psychotic depression is urgently needed due to the increased risk of morbidity and mortality associated with this population.51 Patients with psychotic depression show a poorer response to antidepressant treatment with tricyclics or selective serotonin reuptake inhibitors alone compared with nonpsychotic depressed individuals.52,53
Pilot data by Gaudiano et al51 recently suggested that patients with psychotic depression can benefit from modified CBT approaches (acceptance and commitment therapy, ACT). In this pilot trial, 40 patients were randomly assigned to enhanced treatment as usual (ETAU) or ETAU plus individual ACT sessions. ACT was associated with clinically significant reductions in acute symptom severity and impairment compared with treatment as usual. Gaudiano et al51 found it appropriate to begin therapy with most hospitalized patients once they were able to participate in other group therapy on the unit, after initial psychiatric stabilization with medications. After acute psychotic symptoms dissipate and antipsychotic medication is withdrawn, psychotherapy can be started to help patients monitor residual symptoms and learn to cope more effectively with stressors to prevent symptom recurrence.

Use of pharmacotherapy
after psychological treatment

There is little research on the sequential use of psychotherapy and pharmacotherapy, despite the fact that successful psychotherapy is also associated with substantial residual symptomatology.15 Frank et al54 used a successive cohort approach to compare two similar groups of female patients with recurrent unipolar depression: one in which the combination of interpersonal psychotherapy (IPT) and pharmacotherapy was initiated at the beginning (n=180), and a second in which IPT alone was first provided, with only those not remitting being given the combination treatment (n=159). The remission rate was significantly higher in the latter group. The results thus suggest that the strategy of offering IPT to women with recurrent depression, adding pharmacotherapy only in the case of incomplete remission, might be advantageous.

Sequential use of
two pharmacological strategies

The sequential use of pharmacological strategies in affective disorders has been traditionally limited to instances of treatment resistance.2 A notable exception has been the use of lithium to reduce relapse in unipolar depression.55
It has also been suggested56 that the most effective drugs in treating acute depression may not be the most suitable for post-acute or continuation treatment. During a 6-year follow-up in a randomized trial comparing the sequential use of pharmacotherapy and cognitive behavioral treatment versus clinical management in patients with recurrent depression,35 no antidepressant drugs were used unless a relapse ensued. Patients were then treated with the same antidepressant drug that had been used in the previous episode. Clonazepam was added to the treatment regimen and continued when the antidepressant drug was stopped. The mean survival time after introduction of clonazepam was significantly longer than that before the first relapse.

Implications for assessment
and treatment planning

The literature that has been reviewed here has potential implications for clinical practice, but it should be interpreted with caution in view of several issues. First of all, there are insufficient studies exploring the various types of sequential approach in unipolar depression, with the exception of pharmacotherapy followed by psychotherapy. Further, the sequential design is exposed to the risk that one treatment is provided in a more expert manner than another (eg, the use of psychotropic drugs compared with psychotherapy). Third, certain types of treatment that have been used, such as mindfulness therapy and wellbeing therapy, may not be widely available, and there are difficulties entailed in their translation from the “expert” site to clinical practice. Fourth, when the results of a sequential treatment are compared with those of a minimal intervention control group (such as clinical management or TAU), there is the possibility that the treatment effect may have been achievable with any active treatment and may not be specific to the treatment at hand. Finally, several of the aforementioned studies were based around patients who had responded to initial treatment, and this might have led to an undervaluation of the fact that patients at high risk may have dropped out early.
Nonetheless, there are considerable implications for assessment and treatment planning that are worthy of clinical attention. The sequential model calls in fact for a substantial modification of the flat, cross-sectional approach based on DSM-IV (Diagnostic and Statistical Manual of Mental Disorders– Fourth Edition) criteria only, which ignores the longitudinal development of depressive illness, previous episodes, and responses to previous treatments. 3 A satisfactory assessment requires multiple points of observation during the course of affective illnesses. Such observations may disclose psychopathological features that are overshadowed by the acute manifestations of the affective disorder. As a result, three assessment phases are required, with modalities that depart from those commonly used in psychiatric practice. The key issue is in fact to match treatment ingredients with psychopathological findings.

Initial assessment
The majority of patients with mood and anxiety disorders do not qualify for one, but for several axis I and axis II disorders.23,24 However, there is comorbidity that wanes upon successful treatment of depression and comorbidity that persists, in syndromic or subsyndromic forms (residual symptoms). Clinical differentiation of such morbidity requires a shift from the current psychometric model (where severity is determined by the number of symptoms and not by intensity or quality) to a clinimetric model, 57 which may allow a definition of the progression, extent, and severity of depressive illness.
As a response to the current flat diagnostic evaluation, Emmelkamp et al58 have introduced the concept of macro-analysis (a relationship between co-occurring syndromes is established on the basis of where treatment should commence first). The planning of sequential treatment thus requires determination of the symptomatic target of the firstline approach (eg, pharmacotherapy), and tentative identification of other areas of concern to be addressed by subsequent treatment (eg, psychotherapy). Organization of different DSM syndromes by macro-analysis is thus the key to successful implementation of the sequential model.1

◆ Re-assessment after the first line of treatment has been completed
It is of the utmost importance that the patient be reassessed after the first line of treatment has been completed, in order to establish the level of remission in the patient and whether residual symptoms are occurring and further treatment is necessary.59 In two studies27,31 concerned with the sequential treatment of depression, reassessment was performed after 3 months of drug treatment, when maximal benefits were likely to be present.60 There are several major obstacles to a satisfactory assessment of the patient at this stage. The first lies in the exploration of only a few target symptoms, instead of the full spectrum of psychopathology (as if he or she were a new patient). The second pitfall derives from the fact that the hidden conceptual model in clinical assessment is psychometric, in which sever- ity is determined by the number of symptoms, not by their intensity or quality. Further, the assessment of subclinical symptomatology, as frequently occurs in the setting of remitted or partially remitted disorders,16,18 cannot exclude consideration of the symptoms’ longitudinal development (prodromal phase, the fully developed disorder, and residual states). Detre and Jarecki61 provided a model for relating prodromal and residual symptomatology in psychiatric illness, defined as the rollback phenomenon: as the illness remits, it progressively recapitulates (though in a reverse order) many of the stages and symptoms that were seen during the time it developed. Finally, in clinical practice as well as in research, collection of symptom information is performed during a clinical interview. However, selfobservation, in which the patient is instructed to report in a diary the most important episodes of distress that may have ensued in a specific time period, such as a couple of weeks, is an important source of information concerned with allostatic load.33

◆ Final assessment after the second line of treatment has been completed
Final assessment should take place after the second line of treatment has been completed; for instance, in a depressed patient when psychotherapy following pharmacotherapy has been performed and medications have been discontinued.59 If substantial residual symptomatology persists despite clinical response, then new treatment strategies, such as long-term, indefinite drug therapy, should be discussed with the patient.


The sequential treatment of mood and anxiety disorders does not fall within the realm of maintenance strategies, which have the aim of prolonging clinical responses obtained with treatments.62 It is an intensive, two-stage approach, which derives from the awareness that one course of treatment with a specific tool (whether pharmacotherapy or psychotherapy) is unlikely to entail a solution to the affective disturbances of patients. The aim of the sequential approach is to add therapeutic ingredients as long as they are needed. Therapeutic targets are not predetermined, but depend on the response of patients to the first course of treatment. _

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Le sombre avenir à long terme de la dépression en termes de rechute et de récidive est de plus en plus documenté. Cette évolution insatisfaisante semble liée à l’existence d’une symptomatologie résiduelle importante. Si les symptômes résiduels sont la règle à la conclusion d’un traitement pharmacologique ou psychothérapeutique et que leur présence est corrélée à un mauvais pronostic (du fait qu’ils peuvent évoluer après la guérison en symptômes prodromiques d’une rechute), les traiter peut s’avérer bénéfique à long terme. Les traitements visant des symptômes potentiellement différents, comme la pharmacothérapie et la psychothérapie, pourraient être utilisés dans un ordre séquentiel, l’un (par exemple la psychothérapie) employé pour améliorer les symptômes que l’autre (par exemple la pharmacothérapie) ne peut soigner. Plusieurs études étayent les avantages cliniques de l’utilisation séquentielle de la psychothérapie après la pharmacothérapie. Peu de recherches ont été faites sur les autres formes de traitement séquentiel de la dépression. Les médicaments les plus efficaces dans le traitement d’attaque de la dépression ne sont pas nécessairement les plus appropriés pour le traitement de la phase de consolidation ou d’entretien. Le traitement séquentiel de la maladie dépressive n’appartient pas aux stratégies de maintenance. Il s’agit d’une approche intensive en deux étapes basée sur le fait qu’un type de traitement spécifique (pharmacothérapie ou psychothérapie) ne peut détenir la solution de l’ensemble complexe des symptômes présentés par les patients dépressifs. Le modèle séquentiel a des implications considérables pour l’évaluation et la planification du traitement.