Management of Recurrent Depression in Primary Care
Authors: Giovanni A. Fava, Chiara Ruini, Nicoletta Sonino
Journal: Psychotherapy and Psychosomatics (2002)

The patient is a 37-year-old woman with a major depressive episode of recent onset. She had 2 previous episodes 1 and 3 years earlier, which had been treated by her primary care physician with fluoxetine for 6 months each time. There is no evidence of bipolar illness. She wants to know which treatment is right for her at this point.Major depressive disorder is a highly prevalent condition in the general population. Its chronic and recurrent nature is getting increasing attention [1]. Approximately 8 of 10 people experiencing a major depressive disorder will have 1 or more episodes during their lifetime, i.e., a recurrent major depressive disorder [2]. In some patients, the episodes are separated by many symptom-free years of normal functioning. For others, the episodes become increasingly frequent [3]. This latter course appears to be the more prevalent, both in psychiatric and primary care settings [4, 5, 6, 7, 8, 9].Partial remission between episodes, not full recovery, appears to be the rule and is associated with residual disability [7]. At least 1 patient out of 3 is likely to relapse within a year [4, 5, 6]. Two major risk factors associated with relapse appear to be persistence of subthreshold or subclinical symptoms and number of episodes of major depression [4, 5, 6, 7]. As a result, for most people, depression is a life-long episodic disorder with multiple recurrences (averaging 1 episode in every 5-year period) [8].The adverse economic, interpersonal and medical consequences (e.g. work impairment, and family dysfunction) of the course of unipolar depression are considerable [1]. The case vignette thus highlights a common clinical problem faced by clinicians, whether in primary care or specialty settings. As our patient meets the criteria for recurrent depression developed by Frank et al. [10](≥3 episodes of unipolar depression, with the immediately preceding episode being no more than 2.5 years before the onset of the present episode), there is an 80–90% chance of relapse within 2 years from remission of depression and discontinuation of antidepressant treatment [10, 11].Since the chances of relapse are so high, the primary care physician would think of referral to a psychiatric specialist as the next logical step, relying on his/her clinical judgment for further therapeutic strategies. There is very little empirical support, however, that this choice, per se, entails substantial benefits for the patient. An impressive series of studies point to this conclusion.Simon et al. [12]compared the 6-month outcome in depressed patients receiving antidepressant prescriptions either from psychiatrists or primary care physicians. The proportion receiving antidepressant medication at an adequate dose for 90 days or more was similar in both cases (about 50%). The two groups showed similar rates of improvement in all measures of symptom severity and functioning [12]. Even collaboration between primary care physicians and mental health consultants [13]or implementation of clinical-practice guidelines and practice-based education [14]did not yield any significant advantage over usual care in long-term outcome.Three hundred eighty-six patients with recurrent major depression or dysthymia who had recovered after 8 weeks of antidepressant treatment by their primary care physicians were randomized to a relapse prevention program (involving a depression specialist) or usual primary care [15]. There were no significant differences in the relapse rate over a 12-month follow-up period.What emerges from these studies is the failure of the mental health specialist to improve the outcome of major depression in the primary care setting [16]. The introduction of more tolerable and easy-to-use antidepressant drugs, compared with the traditional tricyclics (which required dosages that nonpsychiatric physicians were reluctant to use), has blurred the difference among physicians in prescribing antidepressant drugs. At the same time, an impressive amount of pharmaceutical propaganda has clouded the evidence which underlies clinical decisions [17]. The main therapeutic strategies are now described, taking into consideration the most reliable findings available.Maintenance pharmacotherapy has been advocated as an effective tool for reducing relapses and recurrences in major depression [18, 19, 20]. A number of studies have demonstrated the superiority of antidepressant drugs (mostly tricyclics) against placebo in protecting the patient from relapsing [18, 19, 20]. Their average duration was 17 months [21]and only one small trial of imipramine reached 5 years [22]. Viguera et al. [23]analyzed 27 studies with variable length of antidepressant treatment which reported follow-up on drug discontinuation. Duration of drug treatment did not seem to affect long-term prognosis once the drug was discontinued. In clinical terms, this means that it does not matter whether you have treated a depressed patient for 3 months or 3 years, when you stop the drug. Indeed, there was a statistical trend which suggested that the longer the drug treatment, the higher was the likelihood of relapse [23]. An observational study on 236 unipolar patients, who had received antidepressants during recovery and were followed for an affective recurrence for up to 5 years, showed that the rate of recurrence for patients with fewer than 5 previous episodes was not affected by medication after the initial 8 months [24]. While benefits of long-term drug treatment have been clearly shown only in outpatients with major depression, we cannot assume that these can be achieved in the milder, heterogeneous forms of depression in primary care [19, 25].If we then consider the case vignette in light of the evidence we have summarized, we reach the following conclusions. One might judge the time of treatment with an antidepressant used by the primary care physician (6 months) in the previous 2 episodes as being too short and expect a more favorable outcome with a longer course of treatment (1 or 2 years). Certainly, during that time, the patient would be more protected from relapse than being drug free, but this would not affect the outcome after discontinuation of the antidepressant drug [23]. The problem would simply be postponed (table 1). One might expect this strategy to be valuable at a time when the patient is particularly exposed to stressful life circumstances. In a controlled study [26], however, maintenance pharmacotherapy was not found to be protective against life stress.Another option would be lifelong pharmacotherapy with antidepressant drugs. This, however, is not easy to communicate to the patient. Not infrequently, the physician starts with a gradual approach (telling the patient it will be for 1 or 2 years, while meaning indefinitely). Andrews [27]raised the issue of being more honest with people with recurrent depression and the need of long-term pharmacotherapy. However, if 'people have a right to the truth' [27], they are also entitled to the full story [28].Even though lifelong pharmacotherapy is chosen (table 2), there is the common and vexing problem of relapse during pharmacotherapy [29]. The return of depressive symptoms during long-term antidepressant treatment was found to occur in 9–57% of patients in published trials [30]. Possible explanations include pharmacological tolerance, loss of placebo effect, increase in disease severity, change in disease pathogenesis, accumulation of a detrimental metabolite, unrecognized rapid cycling, and prophylactic inefficacy [30]. A number of pharmacological strategies have been suggested in uncontrolled and often small trials for addressing this loss of efficacy (increase or decrease in dose, augmentation, change to a different drug), but specific guidelines do not exist [30]. In the first and only large-scale controlled trial [31], about 1 patient out of 3 relapsed during a 3.5-month maintenance treatment with fluoxetine. Two of the 3 patients relapsing while on fluoxetine responded to a blindly determined double dose of fluoxetine. However, part of these patients (11% of the initial ones) relapsed again while on doubled fluoxetine, despite the relatively short follow-up [31]. The patient should thus be warned that loss of clinical effects during long-term pharmacotherapy does occur, despite adequate compliance. Increasing the dose could be effective (at least temporarily), but depression can also become treatment resistant. Results from one study [32]suggest that full doses are superior to lower doses in the maintenance phase. Lower doses, however, are less likely to produce side effects [32]and more likely to allow a successful response by increasing the dosage when there is a loss of clinical effect [29]. The occurrence of side effects such as weight gain or sexual dysfunctions [21]may undermine compliance and quality of life.Lithium has been found to reduce relapses in unipolar depression [33]. However, also with lithium, progressive loss of clinical effect has been reported [34, 35]. Certainly reemergence of depressive symptoms in allegedly unipolar depressed patient treated with antidepressants calls for reconsideration of differential diagnosis, with particular reference to milder forms of bipolar disorder [29].Recurrence of depression in the case vignette can also be managed by treatment of the new episode with the same or other antidepressant and discontinuation when remission ensues [36]. The appearance of prodromal symptoms generally precedes the full syndrome by weeks or months [36]. An early intervention upon relapse was found to significantly shorten the length of the depressive episode [37]. As a result, relatively frequent follow-up visits and education of patients and their family members to recognize the patient's characteristic prodromal symptoms (which appear to be similar across episodes of the same patient) may potentially increase the efficacy of this approach [36]. This treatment, which is in line with approaches to recurrent disorders in clinical medicine, requires the establishment of a good patient-doctor relationship and a lower degree of compliance compared with the long-term pharmacotherapy. It should also be observed that a substantial proportion of patients discontinue antidepressant therapy after responding to the initial acute phase of treatment, regardless of the physician's advise [38, 39, 40, 41].Two main disadvantages may, however, be present (table 1). One is given by the phenomenon of resistance [29]: the likelihood that a drug treatment may be associated with a diminished chance of response in those patients who successfully responded to it but discontinued it. This phenomenon was considered to be relatively rare. In a naturalistic 6-year follow-up of depressed patients where the intermittent pharmacotherapy was used and patients were treated with the same antidepressant of the initial episode, it was found to take place only in 4% of instances [42]. However, the first study which assessed the efficacy prospectively of reinitiating exactly the same treatment (fluoxetine) in patients who had a depressive relapse upon drug discontinuation [43], provided a different picture. Thirty-eight percent of patients either did not respond or initially responded but again relapsed after reinitiation of fluoxetine. The second disadvantage has to do with discontinuation syndromes which may occur, particularly with SSRI, despite tapering [44, 45].The presence of residual symptoms, despite drug or psychotherapeutic treatment, has been strongly correlated with poor long-term outcome [7]. Further, some residual symptoms of major depression may progress to become prodromal symptoms of relapse [7]. This has led to the development of a sequential strategy based on the use of pharmacotherapy in the acute phase of depression and cognitive behavioral therapy in its residual phase [46]. In randomized controlled trials [11, 42, 47, 48, 49, 50], the various applications of this model have been found to yield a lower relapse rate in recurrent depression. Preliminary studies have suggested its usefulness also in atypical depression [51], bipolar disorder [52], and when loss of clinical effects occurs during long-term antidepressant treatment [53]. Its preventive effects appeared to be related to abatement of residual symptoms and/or increase in psychological well-being and coping skills. The practical steps for implementing this approach are described in table 2 and detailed elsewhere [46]. It may include discontinuation of antidepressant drug treatment, as outlined in table 2, or its maintenance. It may offer the advantage of yielding enduring effects while limiting the exposure to and costs of drug therapy. There are two main disadvantages (table 1). One is given by the fact that patients should be motivated to undergo a short-term (10–20 sessions) psychotherapeutic treatment while they are apparently well. The other is the fact that, while the other strategies may be pursued by a nonspecialist physician, implementation of the sequential approach requires referral to a specialized psychotherapist.Information is needed about several clinical issues surrounding recurrent depression.Attention has been called to the arbitrary nature of the distinction between treatment response associated with residual symptomatology and refractory depression [54]. At present, we do not know whether different antidepressant drugs may entail different rates of residual symptoms. What we know is that there may be differential remission rates, as was found to be the case for amitriptyline [55]and venlafaxine [56]. The question would be crucial in view of the role of residual symptoms in recurrent depression [54]. Similarly, we do not know whether combinations of antidepressant drugs, as they are used in treatment resistant depression [57], may yield a more pervasive recovery than a single antidepressant.Whether different antidepressant drugs or different dosages of the same antidepressant drug may engender different rates of loss of clinical effects is another crucial, unanswered clinical question [29]. At present, we have only one, large-scale, controlled study [31]on the effects of increasing the dosage of antidepressants. Other strategies, such as switching to a different type of antidepressant, have not been investigated in controlled studies [30]. We also need to know more about the pathophysiological mechanisms underlying tolerance to antidepressant drugs [58].Similarly, we do not know whether lack of response to an antidepressant which is reinstituted after a drug-free period in the same patient and which was found to be effective, may differ among drugs [54]. We also need to compare intermittent and continuation pharmacotherapy in controlled studies.Adding cognitive behavioral psychotherapy to the treatment package of recurrent depression was found to yield long-term benefits in terms of relapse rate [11, 42, 47, 48, 49, 50]. Both discontinuation and maintenance of pharmacotherapy have been used in the sequential approach, but have not been directly compared in controlled studies. Is there an advantage in keeping drug treatment after psychotherapy?Guidelines for the treatment of depression are available to clinicians. Both those developed by the American Psychiatric Association [59]and the Agency for Health Care Policy and Research Practice Guidelines [60], while providing evidence-based data on the management of the acute phase of depression, do not provide adequate discussion of the different strategies that recurrent depression entails. Evidence indicates that both antidepressant pharmacotherapy and time-limited depression-targeted psychotherapies are efficacious in primary care settings [59]. The Primary Care Guideline Panel recommended maintenance pharmacotherapy for patients with histories of 3 or more depressive episodes and vulnerability to future recurrences because of associated risk factors [60]. Guidelines for treating depression in primary care were developed also in Australia and New Zealand [61]. They suggested at least 2 years of continuation of pharmacotherapy for repeated episodes or where there were other risk factors for relapse [61].Hollon and Shelton [62]show how treatment guidelines for major depressive disorders understate the case for the empirically supported psychosocial interventions. Another important aspect in the development of guidelines is the issue of conflict of interest of those involved in them [63, 64, 65], which disclosure fails to correct [66].The World Health Organization ranked major depression as the fourth most disabling medical disorder by disability-adjusted life years, a measure of burden [67]. By 2010, World Health Organization projected, major depression will be ranked second unless meaningful improvements occur in prevention, diagnosis and treatment. The case illustrated in the vignette outlines the difficulties that prevention of depressive recurrences entails. On the basis of evidence available, the following approach is outlined.First, the patient should be offered adequate information about the prognosis of her depressive illness. It is unlikely that a new course of treatment with the same or similar antidepressant will favorably affect her condition. Andrews [27]remarks that many doctors are concerned that telling people the true prognosis will cause their depression to worsen. However, this very much depends on the content and modalities of the communication. In our Affective Disorders Program, we share with our patients that depression is likely to recur [28]. In the case vignette, we would tell her that depression is very likely to ensue again once antidepressant drugs are stopped. So, one option would be to continue with an antidepressant drug indefinitely. We would tell her, however, that also this option is not completely risk free, since loss of clinical effect may occur. The other option would be to start working on prevention of the next episode. For doing this, we would need to view depression not as something coming 'out of a clear sky', but as a result of a maladaptive lifestyle. Depressed patients are often unaware of the consequences of long-term minor life stresses, interpersonal friction, prolonged anxiety, excessive work, and inadequate rest [11]. It is ironic that, while psychiatrists tend to view prevention of relapse of depression purely in pharmacological terms, as if it were a disease such as diabetes [27], diabetologists, as other medical specialists, emphasize the importance of nonpharmacological strategies [68]. This second option is more difficult to pursue, but is likely to yield enduring effects. We would also explain to the patient that a longer course of treatment with an antidepressant drug this time would be unlikely to yield a better prognosis once the drug is discontinued [23]. In our clinical experience, patients generally look favorably to pursuing a treatment strategy that may provide long-term effects.If the patient described in the vignette accepted to try to pursue a sequential approach, we would treat her with the same drug that was used in the previous 2 episodes. If resistance occurs, we would switch her to a different type of antidepressant (a drug affecting both serotonin and noradrenaline, such as a tricyclic). After 3 months of treatment, we would reassess the patient carefully (table 2). Is she well or simply better? What is the level of residual symptomatology? Such an assessment may require both structured interviews and self-observation (diary). A helpful example which we make is the following. 'When we first saw you, you were very depressed. Driving the way you did, you went off the road. With antidepressant drugs, we did put you back on the road. Things are much better now. However, if you keep on driving the way you used to, you may end up off the road again, sooner or later' [46]. The example outlines the need for lifestyle modification and introduces a sense of control in the patient as to his or her depressive illness. This psychological preparation paves the way for subsequent psychotherapeutic approaches.The clinician could then refer the patient for a short-term (10–20 sessions) course of cognitive-behavioral therapy. This would be the psychotherapeutic approach of choice, since it has been specifically studied for its preventive effects [46]. We would be inclined to taper antidepressant drugs during the course of psychotherapeutic treatment (table 2). Tapering should be performed at the slowest possible pace, to minimize the risk of antidepressant medication discontinuation syndromes [21, 59]. There are no significant differences in relapse rates off medication between studies involving rapid discontinuation and those in which tapering was more gradual [23]. Slow tapering, however, may allow the detection of emerging symptoms in their prodromal phases, which may become the target of psychotherapeutic strategy [54]. Interventions that bring the person out of a negative functioning are one form of success, but facilitating progression toward psychological well-being is quite another [69]. This is an emerging area for psychotherapeutic research and practice [46, 69]. The advantages of maintaining the patient on antidepressant drugs are not clear, unless one aims to keep pharmacotherapy indefinitely and to use the addition of a psychotherapy only as a boosting strategy.A final aspect of the sequential approach lies in a careful assessment of the patient once both pharmacotherapy and psychotherapy have been terminated. If improvement appears to have occurred, the patient can be seen at regular follow-up visits, geared not only to verify the presence of depressive relapses, but also to assess the subclinical symptomatology [7]. If substantial residual symptomatology persists despite clinical response or minimal or no benefits have been achieved by psychotherapeutic approach, then indefinite drug treatment can be discussed with the patient. In our clinical experience, however, the patient has gained a better psychological acceptance of a pharmacological approach. Whether this should be indefinite or intermittent (table 1), very much depends on the patient's preferences and the patient-doctor relationship (with ensuing opportunities for monitoring the patient). Clinical indicators for indefinite, instead of intermittent, drug therapy could be rapid onset of depression with suicidal ideations and the likelihood of severe discontinuation syndromes in a specific patient.Prevention of recurrence in major depression cannot simply be based on prolongation of ongoing pharmacological treatment. The evidence available suggests that the active collaboration of the patient (in choosing a treatment option, in lifestyle modification, in seeking treatment again when needed) is a crucial, and yet neglected variable. This can lead to a more rational use of antidepressant drugs and to therapeutic efforts of more enduring quality than those prevailing today [70].This paper was supported in part by grants from the Ministero dell' Università e della Ricerca Scientifica e Tecnologica (MURST, Roma, Italy) to G.A.F. and N.S. and by a grant from the 'Mental Health Evaluation Project' (Istituto Superiore di Sanità, Roma, Italy) to G.A.F. There are no conflicts of interest.'Case management' is a section which addresses biopsychosocial management of cases in clinical medicine. It integrates research evidence with clinical experience. Full disclosure of conflict of interest is required. However, clinicians with substantial conflicts of interest (owing a patent, being a stockholder or executive or serving in the board of directors or being a regular consultant in a company with commercial interests tied to the research discussed) cannot contribute.