Affect modulation, functioning, and depression






Koen DEMYTTENAERE, MD, PhD
University Psychiatric Center KU
Leuven, campus Gasthuisberg
Leuven, BELGIUM

Affect modulation, functioning, and depressionr


by K. Demyttenaere, Belgium



The DSM-5 criteria for a major depressive episode comprise two symptoms that represent impaired affect modulation (depressed mood and anhedonia) and require “a clinically significant distress or impairment in social, occupational, or other important areas of functioning.” The latter is often not taken into account but could be helpful in diagnosing and identifying “really” depressed patients. When looking at outcomes, standard scales mainly focus on changes in symptom severity, while changes in positive affect and changes in functioning or quality of life are poorly represented. Looking beyond symptoms could help clinicians in better assessing differences between different (classes of) antidepressants, and it has been shown that functioning predicts remission as well as relapse and recurrence independently from symptom severity. The relation between symptoms (including affect modulation) and functional recovery has been insufficiently investigated and mediating factors such as cognition or feelings of embarrassment (stigma) could play an important role. It has been shown that absenteeism (as a measure of occupational impairment) decreases during treatment with antidepressants but one should avoid violated expectations: in community samples, untreated depressed patients perform better than treated depressed patients, again suggesting that mediating variables should be taken into account.

Medicographia. 2014;36:441-445 (see French abstract on page 445)


Diagnosis of depression: the place of altered affect modulation and functional impairment

The Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) criteria for a major depressive episode (MDE) comprise two symptoms that represent impaired affect modulation: depressed mood and anhedonia, including lack of pleasure, and both are considered as core symptoms (Table I, page 442). The criteria further comprises two somatic symptoms (appetite, sleep), two cognitive symptoms (concentration, guilt/worthlessness), an affective-cognitive-somatic symptom (fatigue/loss of energy), a behavioral symptom (retardation or agitation), and a suicidality symptom.1 The emotion-based understanding of depression focuses on impaired affect modulation: an excess of negative affect (depressed mood) and a lack of positive affect (decreased pleasure in most activities).2 Impaired affect modulation in depression could also be seen as increased activation and/or duration of negative affect (sadness/irritability) or diminished activation and/or duration of positive affect. Some authors investigated the presence of positive and negative affect as two separate dimensions, while others investigated the ratio of positive over negative affect (resulting in a positivity index), while still others investigated these affects in a more dynamic way by looking at the time courses of both affects (eg, how much time is needed to experience positive affect after an increase in negative affect?).2-4 It has also been postulated that depression stems not only from inadequate engagement in pleasurable activity and excessive experience of aversive events, but also from the diminished reward value of potentially pleasant events and the heightened averseness of unpleasant events (Table II).5


Table I
Table I. DSM-5 diagnostic criteria for major depressive episode.

Adapted from reference 1: American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders (5th Ed). Arlington, VA: American Psychiatric
Publishing; 2013. © 2013, American Psychiatric association.



But positive affect and positive emotions can be divided in several subgroups. A first subgroup is achievement-based (the drive and/or pleasure of achieving): “energetic,” “lively,” “active.” A second subgroup of emotions is affiliative-based (safety): “feeling safe,” “feeling secure,” “warm.” And a third subgroup relates to well-being (soothing and calming): “contentment,” “peacefulness,” “relaxed,” “peaceful.” There is a link between positive affect and approach behavior and goal-directed behavior: it has actually been postulated that the expectation of reward (positive affect) engenders approach motivation and facilitates goal-directed behavior toward rewarding stimuli (achievement-based or affiliative-based) and that there hence is a link between sensitivity to signals of incentive reward and positive emotionality.6 Achievement-based or affiliative- based behavior has, by definition, a link with functioning.

The DSM definition also requires “a clinically significant distress or impairment in social, occupational, or other important areas of functioning.” This criterion was included to minimize false positive diagnoses, although its usefulness is debatable: many of these symptoms (decreased interest, concentration problems, fatigue or loss of energy, psychomotor retardation, or agitation) inherently result in significant functional impairment; this clinical significance criterion could therefore be at risk of being redundant or of creating false negative diagnoses.7 An example of this possible contradiction is a study in a primary care patient population fulfilling the DSM symptom criteria for major depression, where 28% of the patients did not have clinically significant impairment—defined as at least moderate impairment (a score of ≥4) in the three domains (occupational, social, and family functioning) of the Sheehan Disability Scale (SDS).8,9 About two-thirds of these outpatients had impairment scores between 5 and 8 (≥4 is mild impairment, ≥7 is severe impairment).

Measuring outcomes in antidepressant treatment: beyond symptom scales

It is difficult to demonstrate clinically relevant differences in efficacy between different antidepressants, perhaps because of the heterogeneity of patients with major depression but perhaps, also, because outcome measures are most often limited to observer-rated scales that focus only on symptoms. Self-rated scales or changes in positive affect, functioning, or quality of life are most often not assessed, and if they are assessed they are most often poorly reported in the literature. It is remarkable that anhedonia (lack of interest and pleasure in most activities)—despite being considered as a core diagnostic criterion—is only poorly represented in the most frequently used outcome scales (the HAMilton Depression rating scale [HAMD] and Montgomery-Asberg Depression Rating Scale [MADRS]).10,11


Table II
Table II. Affect dysregulation in depression: increased activation
and/or duration of negative affect (sadness/irritability) or diminished
activation and/or duration of positive affect and motivation.

After reference 5: Dimidjian et al. Annu Rev Clin Psychol. 2011;7:1-38. © 2011,
Annual Reviews.



Despite the acceptance of functioning as an important diagnostic and outcome criterion, many randomized clinical trials actually do not report functional outcomes: in a systematic review of 203 depression trials (77% drug therapy studies and 23% psychotherapy studies) functional outcome scales were used in fewer than 5% of trials.12 Moreover, it has been shown that the correlation between symptom scales and functioning scales is only moderately high, which suggests that they are largely independent dimensions that may need different treatment approaches.13

However, several findings support the use of outcome measures that go beyond symptom scales.

First, this approach could help the clinician to make a better assessment of the differences between different antidepressants. Indeed, 52.3% of psychiatrists take the presence of a specific symptom or symptom profile into account for prescribing a specific antidepressant.14 And although there is ongoing discussion regarding whether antidepressants with different mechanisms of action target different aspects of depression, it has been suggested that serotonergic and serotonergic/ noradrenergic agents have a stronger effect on guilt, fear, irritability, and anxiety, while noradrenergic and dopaminergic agents have a stronger effect on loss of pleasure and enjoyment, loss of motivation and energy, and loss of interest.15 For example, patients treated with the noradrenergic agent reboxetine were shown to be more socially adjusted than patients treated with fluoxetine: the reboxetine–fluoxetine comparison showed a significant association with reboxetine for several items, while the opposite—ie significant association with fluoxetine—was not seen.16 The largest difference was found in six items: community involvement, interest in hobbies, social compliance, rejection sensitivity, control of surroundings, and vainness. Among these items, community involvement and social compliance explore active social behavior, while most of the others—ie, rejection sensitivity, control of surroundings, and vainness—investigate self-perception aspects. A 24-week comparative trial between escitalopram and duloxetine did not show significant differences in MADRS scores and rates of response and remission at end point; however, escitalopram showed a significant advantage over duloxetine for both total SDS score and occupational impairment score.17 A study comparing agomelatine and venlafaxine did not show any significant difference in HAMD score, but agomelatine did significantly better than venlafaxine in improving hedonic function.18 Although it could be hypothesized that an increase in positive affect is more important than a decrease in negative affect for restoring functioning, more data are still needed to provide a final answer to this question.





Second, going beyond symptom scales scores could help in predicting remission. In a 6-month follow-up study of 1083 patients with a mood disorder that used a multiple regression model for clinical remission six months after enrollment, age, race, and gender were not found to be significant predictors of remission; however, being married was (odds ratio [OR], 1.323; confidence interval [CI],1.013-1.727; P=0.040) and patients with severe baseline functional impairment (the “extremely difficult” category) had a significantly lower chance of remission (OR, 0.610; CI, 0.392-0.945; P=0.028) at six months compared with patients with mild baseline functional impairment (the “somewhat difficult” group) even when controlled for baseline depression severity, anxiety level, and alcohol use.19 Similarly, another naturalistic study with 1359 patients showed that baseline occupational status (again in a multivariate analysis) was a highly significant predictor of symptomatic outcome 6 months later (using “unemployed” versus “working for pay” as reference category: OR, 0.52 (CI, 0.35- 0.75; P=0.001).20

Third, going beyond symptom scales scores could help in predicting relapse and recurrence. During a two-year maintenance treatment with citalopram, discriminant analysis correctly predicted the presence or absence of recurrence in 84.38% of subjects, suggesting that functional recovery is a powerful predictor of long-term outcome, even in patients with symptomatic remission.21 In a trial of cognitive-behavior therapy where patients were followed-up for 24 months, psychosocial dysfunction level predicted monthly changes in depressive symptoms and relapse (but depressive symptom severity did not predict functioning): deteriorations in psychosocial functioning may signal imminent major depressive relapse/recurrence and provide targets for change during treatments focused on relapse/recurrence prevention.22

Fourth, more data on functioning in patients with depression would result in a better understanding of the relation between symptomatic and functional recovery. In fact, multiple questions on this relation remain incompletely answered. A naturalistic study investigated the relation between symptomatic and functional remission in more detail by following patients with complete or partial remission for 6 months.23,24 Symptomatic improvement was assessed with the HAMD scale and improvement in functioning with the Social and Occupation- al Functioning Assessment Scale (SOFAS), with normal functioning being defined as a score ≥80. Again, the time course of symptomatic and functional improvement were comparable, hence challenging the idea that functional improvement lags behind symptomatic improvement. A high correlation was reported between the SOFAS and HAMD-17 scales throughout the study (Pearson correlations at baseline, 0.62, P<0.0001; at end point, 0.63, P<0.0001), which means that improvements in symptom severity and functional impairment from depression are significantly correlated. The HAMD score for complete remitters (HAMD≤7) was 4.3 at baseline and 4.0 after six months of follow up, and for partial remitters the HAMD-D score was 12.0 and 7.2 respectively; the SOFAS score for complete remitters was 80.4 at baseline and 84.6 at six-month follow-up, and for partial remitters the SOFAS score was 62.8 and 76.2, respectively. But these results also show that even in symptomatically remitted patients, functioning is still suboptimal even 6 months later (23% patients still not reaching normal functioning). Twentyfour percent of patients with a HAMD-17 score of ≤7 did not have normal levels of functioning at the end of the six-month follow-up period, and even when using a cutoff score of ≤5, 17% of the patients still had functional impairment. By plotting receiver operating characteristics (ROC) curves, the authors showed that a score of ≤5 on the HAMD scale maximized both sensitivity and specificity for identifying normal levels of functionality with respect to other scores, suggesting that the more frequently used score of ≤7 is too high.24 At baseline, partial remitters had lost 44 working days in the past 3 months (start of treatment) and at end point they had lost 63 days in the past 6 months (a decrease in work loss of about 30%). For complete remitters, this was 21 and 20 days, respectively (a decrease in work loss of about 50%). A review on the relations between depression and functioning (social, occupational, and physical) showed that these domains related moderately well with measures of depressive symptoms but not so well as to be seen as redundant: the authors concluded that the relationship between symptoms and functioning is complicated, and that functioning tends to be less responsive to treatment.25

Other studies have also showed that treatment of depression actually results in a dramatic decrease in absenteeism: the mean number of work days lost was 11.0 in the 3 months before initiation and 5.4 days in the 3 months following initiation of antidepressant treatment: the effect was largest for absences of 6 consecutive days of more.26 But one should stay cautious when trying to draw conclusions from depressed subjects seeking help and being treated as they may differ from those not seeking help (in the general population). In fact, a large epidemiological study has showed that 56% of depressed patients on treatment claimed to be “working as carefully as usual in the past 4 weeks” whereas for those not on treatment, the percentage was 66%; similarly, 45% of depressed patients on treatment said that they had “accomplished as much as usual in the past 4 weeks” while the figures was 56% for those not receiving treatment.27 A more recent replication of this study found similar results for ICD-10–confirmed depression, anxiety disorders, and schizophrenia: compared with not receiving treatment, receiving treatment was consistently associated with nonparticipation in the labor force (part-time employment, looking for work, or not being in the labor force), and was negatively associated with work performance (working as carefully as usual in the past 4 weeks and accomplishing as much as usual in the past 4 weeks).28 The latter studies illustrate the fact that depressed patients on treatment and those not on treatment differ not only in their help-seeking behavior, but probably also in their personality characteristics and psychosocial context.

A large European study focused on factors mediating the relation between depression and functioning and a path analysis found that approximately half of the impact of MDE on role functioning was not mediated by depression directly, but indirectly by problems with cognition (measured with five items that included questions about difficulties with concentration, memory, understanding, and ability to think clearly) and by feelings of embarrassment (measured with one item: “how much embarrassment did you experience because of your health problems during the past 30 days?”).29 Therefore, more specific interventions aimed at improving these mediating factors could be helpful in improving the societal effects of MDE on role functioning. Focusing on concentration and attention may lead to improved role functioning. Embarrassment is related to a negative evaluation of oneself and limits the ability to engage in effective social interaction. Patients with MDE are at risk of being embarrassed about their condition because of self-stigmatization. Moreover, it has been shown that stigma in MDE patients is associated with greater unmet mental health care needs and with antidepressant drug noncompliance.30,31

In conclusion, although the DSM criteria for major depression clearly comprise affect modulation items (depressed mood as well as loss of pleasure) and include a functional impairment criterion, the most frequently used observer rating scales used to assess change during treatment do not sufficiently cover changes in positive affect and changes in functioning, even though assessing these changes could help clinicians in better understanding the differences in efficacy between different (classes of) antidepressants. Moreover, functional impairment seems to be a predictor of remission, relapse, and recurrence even after controlling for symptom severity.


References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th Ed.). Arlington, VA: American Psychiatric Publishing; 2013.
2. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: The PANAS Scales. J Pers Soc Psychol. 1988; 54(6):1063-1070.
3. Fredrickson BL. What good are positive emotions? Review Gen Psychol. 1998;2:300-319.
4. Wichers M, Lothmann C, Simons CJP, Nicolson NA, Peeters F. The dynamic interplay between negative and positive emotions in daily life predicts response to treatment in depression: A momentary assessment study. Brit J Clin Psychol. 2012;51:206-222.
5. Dimidjian S, Barrera M Jr, Martell C, Munoz RF, Lewinsohn PM. The origins and current status of behavioral activation treatments for depression. Annu Rev Clin Psychol. 2011;7:1-38.
6. Depue RA, Luciana M, Arbisi P, Collins P, Leon A. Dopamine and the structure of personality: relation of agonist-induced dopamine activity to positive emotionality. J Pers Soc Psychol. 1994;67(3):485-498.
7. Spitzer RL,Wakefield JC.DSM-IVdiagnostic criterion for clinical significance:does it help solve the false positives problem? Am J Psychiatry. 1999;156:1856-1864.
8. Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 1996;11(suppl 3):89-95.
9. Demyttenaere K, Enzlin P, Dewe W, et al. Compliance with antidepressants in a primary care setting, 2: the influence of gender and type of impairment. J Clin Psychiatry. 2001;62(suppl 22):34-37.
10. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23:56-62.
11. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
12. Brockow T, Wohlfahrt K, Hillert A, et al. Identifying the concepts contained in outcome measures of clinical trials on depressive disorders using the International Classification of Functioning, Disability and Health as a reference. J Rehabil Med. 2004;44(suppl 1):49-55.
13. McKnight PE, Kashdan TB. The importance of functional impairment to mental health outcomes: a case for reassessing our goals in depression treatment research. Clin Psychol Rev. 2009;29:243-259.
14. Zimmerman M, Posternak M, Friedman M, et al. Which factors influence psychiatrists’ selection of antidepressants? Am J Psychiatry. 2004;161:1285-1289.
15. Nutt D, Demyttenaere K, Janka Z, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. 2007;21(5):461-471.
16. Dubini A, Bosc M, Polina V. Do noradrenaline and serotonin differentially affect social motivation and behavior ? Eur Neuropsychopharmacol. 1997;7(suppl 1): S49-S55.
17. Wade A, Gembert K, Florea I. A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder. Cur Med Res Opin. 2007;23(7):1605-1614.
18. Martinotti G, Sepede G, Gambi F, et al. Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder. J Clin Psychopharmacol. 2012;32:487-491.
19. Angstman KB, Rasmussen NH, MacLaughlin KL, Staab JP. Inter-relationship of the functional status question of the PHQ-9 and depression remission after six months of collaborative care management. J Psychiatr Res. 2013;47(3):418-422.
20. Demyttenaere K, Verhaeghen A, Dantchev N, et al. “Caseness” for depression and anxiety in a depressed outpatient population: symptomatic outcome as a function of baseline diagnostic categories. Prim Care Companion J Clin Psychiatry. 2009;11(6):307-315.
21. Franchini L, Zanardi R, Gasperini M, Smeraldi E. Two-year maintenance treatment with citalopram 20mg, in unipolar subjects with high recurrence rate. J Clin Psychiatry. 1999;60 (12):861-865.
22. Vittengl JR, Clark AL, Jarrett RB. Deterioration in Psychosocial Functioning Predicts Relapse/Recurrence After Cognitive Therapy for Depression. J Affect Disord. 2009;112(1-3):135-143.
23. Romera I, Perez V, Menchon JM, Delgado-Cohen H, Polavieja P, Gilaberte I. Social and occupational functioning impairment in patients in partial versus complete remission of a major depressive disorder episode: a six-month prospective epidemiological study. Eur Psychiatry. 2010;25:58-65.
24. Romera I, Perez V, Menchon JM, Polavieja P, Gilaberte I. Optimal cutoff point of the Hamilton Rating Scale for Depression according to normal levels of social and occupational functioning. Psychiatry Research. 2011;186:133-137.
25. McKnight PE, Kashdan TB. The importance of functional impairment to mental health outcomes: a case for reassessing our goals in depression treatment research. Clin Psychol Rev. 2009;29:243-259.
26. Winkler D, Pjrek E, Moser, Kasper S. Escitalopram in a working population: results from an observational study of 2378 outpatients in Austria. Hum Psychopharmacol Clin Exp. 2007;22:245-251.
27. Waghorn G, Chant D. Receiving treatment and labor force activity in a community survey of people with anxiety and affective disorders. J Occup Rehabil. 2007;17:623-640.
28. Waghorn G, Chant D. Receiving treatment, labor force activity, and work performance among people with psychiatric disorders: results from a population survey. J Occup Rehabil. 2011;21:547-558.
29. Buist-Bouwman MA, Ormel J, de Graaf R, de Jonge P, van Sonderen E, Alonso J, Bruffaerts R, Vollebergh WAM, the ESEMeD⁄MHEDEA 2000 investigators. Mediators of the association between depression and role functioning. Acta Psychiatr Scand. 2008;118:451-458.
30. Roeloffs C, Sherbourne C, Unutzer J, Fink A, Tang LQ, Wells KB. Stigma and depression among primary care patients. Gen Hosp Psychiatry. 2003;25:311-315.
31. Sirey JA, Bruce ML, Alexopoulos GS, Perlick DA, Friedman SJ, Meyers BS. Perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence. Psychiatr Serv. 2001;52:1615-1620.