Subthreshold and residual symptoms in depression and anxiety disorders: where next?

Department of Psychiatry
University of Cape Town

Subthreshold and residual symptoms in depression and anxiety disorders: where next?

by D. J. Stein, South Africa

While there is considerable consensus about first-line treatments of major depressive disorder and anxiety and related disorders, there is ongoing controversy about the nature of, and approach to, subsyndromal and residual symptoms of these conditions. Such symptoms deserve attention for a number of reasons, including their association with impairment and relapse, and in this paper, recent developments in this area of work are briefly reviewed. Conceptually, it makes good sense to regard depression and anxiety disorders as chronic disorders that are deserving of a staged and sequential approach to assessment and management. Further, several randomized controlled trials have been useful in showing that targeted pharmacotherapy or psychotherapy interventions are useful for specific residual symptoms. At the same time, there is a relative lack of data in this area, and clinicians should also exercise clinical judgment to ensure optimal diagnosis and management of subthreshold and residual symptoms.

Medicographia. 2014;36:452-457 (see French abstract on page 457)

While there is considerable consensus about first-line treatments of major depressive disorder and anxiety and related disorders (including trauma and stressor-related disorders), there is ongoing controversy about the nature of, and approach to, subsyndromal and residual symptoms of these conditions. Such symptoms deserve attention for a number of reasons. First, subthreshold symptoms of mood and anxiety disorders may be associated with considerable impairment. Second, residual symptoms of depression may predict clinical relapse. Third, there is ongoing debate about the neurobiology and treatment of subsyndromal and residual depressive and anxiety symptoms. In this paper, recent developments in this area are briefly reviewed.

Subthreshold and residual symptoms

It has long been recognized that in efficacy studies many patients with depression do not respond fully to pharmacotherapy, psychotherapy, or their combination,1 a fact underlined by recent effectiveness trials (Figure 1).2 Work in this area was given further impetus by the development of operational definitions for recovery, remission, relapse, and recurrence of depression.3 More recent contributions have further refined these concepts (Table I, page 454), and also extended them to other disorders.4,5 Subsequent studies have emphasized the impairment associated with subthreshold mood and anxiety symptoms.6-12 In particular, community studies, which allow rigorous investigation of a broad spectrum of symptomatology, have indicated that clinical thresholds may have a degree of arbitrariness, given that respondents with symptomatology that fails to meet diagnostic criteria, but that is severe and persistent, suffer significant impairment. Indicators of such impairment include a range of measures such as disability, suicidality, and use of health care resources.13

Figure 1
Figure 1. Overall STAR*D (Sequenced Treatment Alternatives to Relieve Depression Study) participant flow.

After reference 2: Rush et al. Am J Psychiatry. 2006;163(11):1905-1917. © 2006, American Psychiatric Association.

Clinical studies have complemented this work by emphasizing the significance of residual depressive and anxiety symptoms. First, residual symptoms are associated with worse psychosocial impairment.14,15 Second, residual symptoms of depression are associated with greater risk of relapse and a more chronic course of illness.16,17 There are fewer data addressing this issue in anxiety disorders, but some suggest that similar relationships may hold.18-20 There are also relatively few studies addressing whether residual symptoms predict recurrence of disorders, but again there are some data suggestive of a significant association.21

Subthreshold prodromal symptoms may be related to residual symptoms of treatment; the “roll-back phenomenon” refers to observations that as an illness begins to respond and remit, those symptoms that first appeared are also the last to disappear.22 The notion that residual symptoms reflect underlying neurobiological deficits that precede onset of the full disorder, is supported by work emphasizing that antidepressant response has a slower time course than placebo response.23 Furthermore, if prodromal symptoms of relapse mirror those of the initial episode, then early recognition of such symptoms may be particularly useful.24

Table I
Table I. Recommendations of the ACNP task force on the conceptualization
of remission.

Abbreviations: ACNP, American College of Neuropsychopharmacology; MDE,
major depressive episode.
After reference 5: Rush et al. Neuropsychopharmacology. 2006;31(9):1841-1853.
© 2006, Nature Publishing Group.

The literature on subthreshold and residual symptoms has made an important contribution to emphasizing that mood and anxiety disorders are chronic conditions, and so require both short- and long-term individual and public health interventions. Shorter-term treatment should clearly aim at response, remission, and relapse prevention.25 Longer-term management should likely aim at recovery, arguably at well-being, and certainly at recurrence prevention.24

Nature of residual symptoms

Various investigations have attempted to delineate the prevalence and type of residual mood and anxiety symptoms. One to two-thirds of patients with major depressive disorder fail to respond fully to antidepressant treatment of adequate dose and duration.26,27 Anxiety, sleep impairment, fatigue, and cognitive disturbances are particularly frequent residual symptoms of depression, and many patients with residual symptoms have multiple such symptoms (Figure 2).14 Residual symptoms include both core depressive symptoms (eg, suicide) as well as less classical symptoms of depression (eg, pain).27 Residual anxiety may be a particularly robust predictor of relapse.24

Some research has addressed the question of how best to assess residual symptoms. Assessment of recovery should arguably cover the domains of symptoms, psychosocial impairment, and pathophysiological changes.28 Depression rating scales, the Sheehan Disability Scale, and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire may be useful,29 as may the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER).30

It is also important, however, to differentiate treatment-emergent side effects from residual symptoms, and to address any comorbid psychiatric or medical disorders that may confound symptom assessment.26 Other relevant clinical and diagnostic issues to consider include antidepressant tachyphylaxis, inaccurate diagnosis (eg, missing bipolar disorder), and lack of adherence (Table II).29 It is also important to consider relevant psychosocial stressors; there is evidence that patients with residual symptoms are particularly vulnerable to depression when exposed to life stressors.24

A number of studies have contributed to understanding the neurobiology of residual symptoms.32,33 Several systems have been studied in patients in recovery from depression. First, such patients demonstrate alterations in the hypothalamicpituitary- adrenal axis. Second, some patients demonstrate abnormalities in the serotonergic system, with increased vulnerability to depressive symptoms after tryptophan depletion. Third, there may be persistent shortened rapid eye movement (REM) latency and evidence of decreases in cortical ϒ-aminobutyric acid (GABA). Finally, there may be persistent negative biases in the processing of emotional material. Several of these disturbances, including dexamethasone suppression, electroencephalographic sleep abnormalities, and cognitivebiases, have been associated with increased risk of relapse.24 Nevertheless, it should be noted that few studies directly link such abnormalities with residual symptoms.

Figure 2
Figure 2. Residual symptoms following acute
remission from major depressive disorder.

After reference 15: Nierenberg et al. J Clin Psychiatry. 1999;
60(4):221-225. © 1999, Physicians Postgraduate Press, Inc.

Treatment of residual symptoms Despite the clinical significance of residual depressive and anxiety symptoms, the evidence-based literature on the management of such symptoms is relatively sparse.34-37 Thus, expert consensus in this area continues to rely on clinical wisdom and anecdotal experience. A few randomized controlled studies have, however, addressed specific interventions for particular residual symptoms. Furthermore, there is a growing literature on the management of treatment-resistant depression and anxiety disorders, which may be relevant.38,39

A first approach to the management of residual depressive or anxiety symptoms is to target specific symptoms based on presumptive underlying neurobiology or known treatment approaches. Thus, for example, zolpidem augmentation may be useful in improving residual insomnia, and modafinil augmentation may be useful in improving residual fatigue in patients treated with antidepressants for major depressive disorder.40,41 Prazosin or cognitive-behavioral therapy augmentation may be useful for residual sleep impairment in posttraumatic stress disorder.42 Augmentation studies also demonstrate benefit for clonazepam augmentation of antidepressants for anxiety in depression, and of eszopiclone augmentation of antidepressants for insomnia in generalized anxiety disorder.43-45 While a range of other agents may be considered along these lines,46 only a few options are supported by data from randomized controlled trials addressing residual symptoms in treated patients.27

A second approach is to assume that residual symptoms represent incomplete treatment, and so to use the most robust possible augmentation and switch approaches. A range of evidence- based pharmacological augmentation options are now available for the management of treatment-resistant depression and anxiety disorders. Furthermore, augmentation with cognitive- behavioral therapy has also been shown to be effective in a range of these conditions.

Switching to a different pharmacological class has long been recognized as a valuable option, although success rates are not always as high as clinicians would like. This approach would seem particularly compelling when patients have a history of multiple relapse and recurrence with severe prodromal and residual symptomatology. It may also be particularly relevant when particular residual symptoms are thought to respond to specific pharmacological or psychotherapeutic interventions.

Indeed, it is important to differentiate subthreshold and residual symptoms. There are several different relevant considerations here. First, while residual symptoms may predict relapse, other well-known predictors including the number of previous episodes, stability of response, and adequacy of treatment should not be ignored.24 Second, data on antidepressant efficacy are more persuasive for severe symptoms of depression, while it is generally harder to differentiate medication from placebo in the management of mild symptoms.47 It is relevant to mention that only atypical antipsychotics and L-methylfolate are FDA-approved for use as adjunctive agents in depression, and that the former are associated with a significant adverse event burden. Third, while there is general agreement about the operationalization of response, remission, and even recovery, there is less agreement about the operationalization of constructs such as well-being. Sometimes, no treatment is the best form of management.48

Table II
able II. Differential diagnostic issues in evaluating new-onset or
residual symptoms in major depressive disorder.a

After reference 29: Zajecka. J Clin Psychiatry. 2013;74(suppl 2):9-13. © 2013,
Physicians Postgraduate Press, Inc.

As noted earlier, focusing on residual symptomatology may, however, be clinically useful in emphasizing that depression and anxiety disorders are chronic conditions that deserve both short- and long-term individual and public health interventions.

In particular, they raise the issue of a staged approach to the assessment and management of these conditions. Anecdotal experience, for example, suggests that for many patients a two-stage sequential approach may be useful, with pharmacotherapy for acute depression being followed by cognitive behavioral therapy for residual symptoms and relapse prevention.24 There is a need for additional rigorous work in this area, following along the lines of that which has already been undertaken for treatment-resistant mood and anxiety disorders.


Subthreshold and residual symptoms are important clinical phenomena insofar as they are associated with significant impairment and predict relapse and recurrence. A body of literature has emphasized ongoing neurobiological abnormalities in patients in recovery from depression, but further work is needed to relate such abnormalities to residual symptoms. Conceptually, it makes good sense to regard depression and anxiety disorders as chronic disorders that are deserving of a staged and sequential approach to assessment and management. Certainly, several randomized controlled trials have been useful in showing that targeted pharmacotherapy or psychotherapy interventions are useful for specific residual symptoms. At the same time, there is a relative lack of data in this area, and clinicians should also exercise clinical judgment to ensure optimal diagnosis and management of subthreshold and residual symptoms.

Acknowledgment: Prof Stein is supported by the Medical Research Council of South Africa.

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Keywords: anxiety; depression; neurobiology; residual; subthreshold; symptom; treatment