The arrival of tricyclic antidepressants and monoamine oxidase inhibitors during the late 1950s brought a lot of hope and enthusiasm about the possibility of treating an illness that was, till then, considered difficult to treat and amenable mostly to electroconvulsive therapy. The focus of the new treatments was on the acute episode of depression. However, over the next couple of decades, it became clear that, as Frank and colleagues wrote, “unipolar depression cannot be viewed as a single episode of illness but rather as a chronic disabling condition” and that “the longitudinal nature of the illness must be considered when evaluating the effectiveness of treatment strategies” [1, p. 1093]. They [1] also noted that the dosage of antidepressants in the maintenance phase of treatment should not be tapered but should be maintained at the original effective dose. Finally, they suggested that a patient who cannot continue pharmacotherapy (e.g., due to medical illness or pregnancy) may be helped by interpersonal therapy to extend the time between episodes. Frank, Kupfer, and Perel [2] also found that interpersonal therapy continued only once a month had a significant effect on the survival time to recurrence and raised the question of whether more frequent therapy sessions might provide additional protection to patients with recurrent depression. They [3] also advocated for early treatment intervention in subsequent episodes of depression as the early intervention significantly shortened the overall length of the second episode. However, they raised an important question, i.e., whether this finding could be generalized beyond the effect of combined psychopharmacotherapy/psychotherapy intervention to early intervention with either medications or psychotherapy alone. Prien and colleagues [4], in reporting the results of their study on using lithium, imipramine, or a combination of lithium and imipramine in the prevention of recurrences in unipolar and bipolar disorders, recommended that psychotherapeutic approaches in conjunction with medications warrant investigation. Thus, the stage was set for inquiry and study of various therapeutic interventions in recurrent depression: what intervention, when, and how?

Around the time these studies were published, G. Fava started with his observations and studies of treatment response in depression, e.g., [5, 6]. He also started to examine various symptomatology during the course of major depression, such as prodromal symptoms [7]. In a special review article on prodromal symptoms, G. Fava and Kellner [8] raised several important issues that impact the course of depression, such as premorbid personality traits that are impacted by stress at times and chronic subclinical fluctuations in chronic affective disorder. Finally, after an acute episode of affective illness, there is a possible persistence of residual symptomatology after the acute episode of affective illness; despite apparent recovery, residual symptoms may persist. The symptoms that may be interpreted as prodromes of a depressive relapse may thus be residual symptoms from the previous episode. They [8] raised the importance of these observations for treatment planning and for informing the patients and their families about the chronic nature and course of affective disorder.

G. Fava and Kellner [8] also noted that the presence of residual symptomatology after completing medication treatment correlated with a poor long-term outcome. Thus, G. Fava and colleagues [9] studied the effects of cognitive-behavioral therapy (CBT) on residual symptomatology and the course of the illness. Forty patients in their study were first successfully treated with antidepressants and then assigned to either CBT or clinical management of behavioral symptoms, while antidepressants were gradually discontinued. In both the CBT and the clinical management groups, the treatment consisted of ten 40-min sessions. Patients were followed for 2 years. The CBT group had a significantly lower level of residual symptoms after medication discontinuation than the clinical management group. Interestingly, the CBT group also had a lower relapse rate (15%) than the clinical management group (35%), though this difference was not statistically significant. Nevertheless, the results led the authors to the suggestion that “a sequential use of pharmacotherapy and cognitive-behavioral treatment is feasible, and the addition of psychotherapy does not appear to be redundant. Indeed, by deferring the psychotherapeutic intervention, we were able to provide a less intensive course of therapy.” Interestingly, the difference in relapse rates became larger if a 4-year follow-up (35% vs. 70%) [10] yet started to fade in a 6-year follow-up (50% vs. 75%) [11]. It is important to note that the numbers of subjects in both follow-ups were small. Nonetheless, CBT seemed to improve the long-term outcome of major depression. A similar study [12] conducted on patients with recurrent major depression (≥3 episodes of depression) yielded similar but significant results in terms of relapse (25% vs. 80%). Patients receiving CBT (vs. clinical management) also had a significantly lower level of residual symptoms after discontinuation of medication.

These and other findings led G. Fava to the development of various concepts ultimately pertinent to his framing of the long-term treatment of depression, such as the sequential model, treatment of recovery in major depression, use of clinimetric approach, rational use of antidepressants, and the new model of the mental health clinic. In 1999, he [13] expounded the issues involved in the common practice in clinical medicine – administration of treatments in sequential order. He noted that the sequential model introduced a conceptual shift in psychotherapy research and practice, stating that the target of psychotherapy is not “predetermined and therapy-driven” [13, p. 228] but rather depends on the type and severity of residual symptomatology. He also outlined four potential applications of the sequential model in affective disorders: use of psychotherapy after pharmacological treatment; use of pharmacotherapy after psychological treatment; sequential use of two psychotherapeutic techniques; and use of two pharmacological strategies. His article with E. Tomba [14] further explained a number of issues regarding the sequential model and its clinical application. Some of the points made were the advantages of applying treatments sequentially versus simultaneously (consideration of side effects, greater adherence with monotherapy, and loss of efficacy over time and possible antagonistic effect of two concurrent treatments); the importance of staging and the role of comorbidity; the need for repeated assessment (at least three assessment phases: initial screening, reassessment after the first phase of treatment, and final assessment after the completion of the second phase); consideration of subclinical symptomatology; the use of macro-analysis; and the need for individualized treatment. They [14] also emphasized that the clinical assessment of patients should focus on attainment of individual goals and treatment of all modifiable and nonbiological factors rather than solely focusing on the diagnosis and treatment of individual disease (important concept proposed by Tinetti and Fried [15] in their article, “The End of the Disease Era”).

Interestingly, in one of his latest treatises on sequential treatment of depression, G. Fava [16] reviewed again the permutations of sequential approaches and discussed the possibly least noted and explored permutation – sequential use of two different pharmacological strategies. He questioned whether the same medications that are used in the acute treatment of depression are the most suitable for preventing relapse. He entertained an interesting notion that some antidepressants with one mechanism of action may be more suitable for treatment of the acute phase of depression, while antidepressants with another mechanism of action may be more suitable for long-term treatment. He suggested that, for instance, selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors may not be suitable for long-term treatment because of their major side effects and the likelihood of behavioral toxicity. He felt that antidepressants acting primarily as 5-HT2 antagonists may be more suitable for long-term treatment and gave an example of ritanserin being possibly such an antidepressant. There are other antidepressants with a similar mechanism of action, such as mirtazapine, trazodone, and nefazodone. It would be interesting to examine the sequential approach of using SSRI antidepressant in the acute phase of depression, followed by treatment with one of these antidepressants in the maintenance phase.

In their review on the concept of recovery in major depression, G. Fava, Ruini, and Belaise [17] noted again the role of residual effects of treatment and emphasized that “monotherapy is likely to be insufficient in most of the cases” [17, p. 311]. They raised the issue of well-being and the fact that we know very little about well-being in the residual phase of the illness. They also asserted that the scales used for assessment of depressive symptomatology do not adequately capture the wide spectrum of residual symptomatology and that a therapeutic response is frequently mistakenly equated with remission.

The article on the clinimetric approach [18] expanded the concept originally developed by Alvan Feinstein according to which clinimetrics is concerned with “the measurements of clinical issues that do not find room in customary clinical taxonomy. Such issues include the types, severity, and sequence of symptoms; rate of progression in illness (staging); severity of comorbidity; problems of functional capacity; reasons for medical decisions (e.g., treatment choices); and many other aspects of daily life, such as well-being and distress” [18, p. 177].

As antidepressants are the mainstay treatment of depression, especially severe depression, it is important to consider the pros and cons of their use in long-term treatment of depression and their place in the sequential model. In the discussion of the rational use of antidepressants [19], Fava summarized tolerance to antidepressants and its different expressions. Those include loss of antidepressant efficacy, resistance to the antidepressants’ paradoxical effects (e.g., increase in depression after using imipramine in subjects with the lowest scores of depression), worsening of the course of depression [20], switching to bipolar disorder, and withdrawal reaction following discontinuation of antidepressants [19]. He pointed out that, at times, “withdrawal symptoms are likely to be misunderstood as indicators of impending relapse and may lead to reinstitution of treatment” [19, p. 199]. He then delved into the treatment of a major episode, discussing its assessment, when to use antidepressants, the choice of antidepressants (tricyclics may be more efficacious than SSRIs in melancholic depression), psychotherapeutic management, and duration of treatment. He noted that “there is a tendency to protract drug treatment for long periods of time, with the assumption that it may be protective against relapse” [19, p. 200]. However, there is some evidence that prolonged use of antidepressants (over 1 year) may increase the risk of developing a second episode of depression. Summarizing all his thinking on the use of antidepressants, Fava suggested that considering all the antidepressants’ benefits and harms, their use should be limited “to only the most severe and persistent cases of depression, limiting their use to the shortest possible duration, reducing their utilization in anxiety disorders (unless a major depressive disorder is present or treatments have been ineffective)” [19, p. 201]. He added that the better tolerability of newer antidepressants has stretched their original indications and that “currently, the prescribing physician is driven by an overestimated consideration of potential benefits, little attention to the likelihood of responsiveness and neglect of potential vulnerabilities to the adverse effects of treatment.” [19, p. 202]. Interestingly, an analysis of the data from the longitudinal Zurich Cohort Study [21], that are not without limitations, raises the possibility that antidepressants may worsen the long-term course of depression.

The discussion of clinimetrics and rational use of antidepressants in the context of sequential treatment of depression underscores the importance of careful clinical approaches to the treatment of depression based not just on the so-called evidence-based use of treatments but mainly on repeated assessments, rational use of antidepressants, implementation of psychotherapeutic approaches, careful reassessments, and individualization of treatment that does not address just the diagnosis but also various other factors such as functionality, well-being, cognitive abilities, and others. The concerns about the proper application of these factors and sequential treatment led G. Fava and colleagues [22] to propose a new model of mental health clinic where the core team (a psychiatrist, an internist, and four clinical psychotherapists) would assure proper implementation of sequential treatment with repeated assessments and other mentioned “ingredients.”

A properly constructed theory or model of treatment requires confirmation in terms of its applicability in clinical practice. A full and detailed review of the confirmatory works of the sequential model of treatment is beyond the scope of this editorial. Thus, I will summarize four major reviews [23‒26] that summarize and critically evaluate the sequential model of treatment and its use.

In 2005, G. Fava, Ruini, and Rafanelli [23] synthetized data from studies on the use of the sequential approach in mood and anxiety disorders. They found that the sequential approach reduced relapse in unipolar recurrent depression and that psychotherapy had some beneficial effects in bipolar patients who were already on mood stabilizers. However, the sequential use of pharmacotherapy and psychotherapy did not improve outcomes in anxiety disorders, mostly obsessive-compulsive disorder and panic disorder with agoraphobia. However, at that time, the sequential approach was not applied to generalized anxiety disorder, social phobia, and posttraumatic disorder. They concluded that the sequential approach represents a conceptual shift in clinical practice as “therapeutic targets are not predetermined but depend on the response of patients to the first course of treatment” [23, p. 1398].

Subsequently, G. Fava and colleagues conducted two major meta-analyses of high-quality studies on the sequential approach use in the treatment of recurrent major depressive disorder [24, 25]. In the first one, Guidi, Tomba, and G. Fava [24] reported a significant effect of CBT during continuation of antidepressants when compared to antidepressants alone or treatment as usual – patients receiving both CBT and medication relapsed less frequently. Patients treated with CBT during the discontinuation of antidepressants were less likely to experience relapse/recurrence than those continuing antidepressants or receiving treatment as usual. The authors noted a number of important clinical points established either on the basis of their critical review of the literature or on their findings. These include, for instance, the report that patients receiving their preferred treatment (either pharmacotherapy or psychotherapy) respond better than those not receiving their preferred treatment, or it is possible that “psychotherapy may generate skills that patients can continue to use after treatment ends to manage their own affective states, reducing internal and external risks for relapse or recurrence” [24, p. 134]. They also outlined the indications for the use of the sequential approach as follows: (a) recurrent depression, (b) the presence of residual symptomatology despite response to pharmacotherapy, and (c) situations when the physician or the patient or both intend to stop drug treatment. However, as they pointed out, the sequential model does not seem to be suitable for mild major depression or minor depression, as initial treatment with antidepressants may not be warranted, and psychotherapy would be more suitable.

The second meta-analysis [25] published 5 years later expanded the number of analyzed studies from the original 13–17. The findings were similar – that a sequential approach after acute treatment with either antidepressants alone or a combination of pharmacotherapy and psychotherapy reduced the risk of relapse or recurrence; and that the prevention effect of this approach relies on diminishing the residual symptoms and/or increasing psychological well-being. Finally, a clinically oriented review of different treatment options in relapse prevention in major depression by Cosci, Mansueto, and G. Fava [26] again made a number of important and practical recommendations. Those included providing patients with adequate information about the prognosis; about the fact that depression is treatable yet likely to reoccur if antidepressants are discontinued without proper follow-up treatment; and the need of the patient’s active role in achieving recovery. These three reviews provide solid evidence of the effectiveness of the sequential approach and its important place among treatment options for chronic recurrent major depressive disorder.

Over several decades, Giovanni Fava, first alone and later with a team of collaborators, doggedly pursued the establishment and validation of the sequential approach to the management of recurrent major depressive disorder. They succeeded in demonstrating that the sequential approach to the management of depression is clearly a very valuable tool that enriches our treatment armamentarium. G. Fava’s and his collaborators’ work on the sequential approach is an excellent example of a determined concept development from original ideas to model testing and validation that also includes the work of others.

The seminal contributions also include testing of this model’s clinical applicability; use of clinimetrics; careful attention to the course of illness with consideration of residual and prodromal symptomatology and its impact on treatment and its selection; individualization of treatment; consideration of nonbiological factors such as functionality and well-being; restrain in relying solely on diagnosis as treatment guidance; and creativity and originality in treatment modalities selection and application. G. Fava’s and his collaborators’ technique is a very rich one that emphasizes the importance of a complex clinical approach to treatment of chronic recurrent depression (and possibly other disorders) rather than using the guidance of “evidence-based” treatments alone. Sadly, such an approach is rare in present-day clinical practice. Some may disagree with certain elements of the sequential approach, but most clinicians would agree that this “is the way to go.”

The work on sequential approach to treatment of depression is not finished. There are understandable limitations of the work completed so far. For instance, the present model does not go beyond two episodes of depression, though we may assume that the sequentiality of treatments (pharmacotherapy and psychotherapy in various permutations) could be repeated through numerous episodes. However, that remains to be tested. The various permutations of the sequential model, e.g., the interesting notion of using sequentially two antidepressants with different mechanisms of action (one for the acute phase of the illness and the other one for maintenance) or the sequential use of various psychotherapies merit to be properly tested, as well. Nevertheless, the sequential model deserves full attention of the clinicians treating the chronically mentally ill, not only because it intuitively makes sense and has been (partially) validated, but also because it enriches our clinical thinking and therapeutic decision-making, which will ultimately help our patients.

The author has no conflict of interest to declare.

The author has no funding sources to declare.

Richard Balon is the sole author of this editorial.

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