“Engage” Therapy: Behavioral Activation and Improvement of Late-Life Major Depression

Abstract

Objective

Engage is a treatment for late-life depression developed to match the skills of community clinicians. It is based on the theory that dysfunction in the RDoC positive valence systems (PVS) is a critical mechanism of late life depression. Accordingly, it uses “reward exposure” (engagement in meaningful, rewarding activities) as its principal intervention. This study tests the hypothesis that change in behavioral activation, an index of PVS function, during successive treatment periods with Engage and during follow-up predicts depression at the end of each period.

Methods

Forty-eight non-demented, older adults with unipolar major depression were treated openly with 9 weekly sessions of Engage and assessed 36 weeks after entry. Depression severity was assessed with the 24-item Hamilton Depression Rating Scale (HAM-D) and behavioral activation with the Behavioral Activation for Depression Scale (BAS) at baseline, 6 weeks (mid-treatment), 9 weeks (end of treatment), and 36 weeks.

Results

A mixed effects model examined whether change in BAS in successive periods occurring during Engage treatment and during follow-up predicts depression at the end of each period. Both BAS change (F_{1, 52}=18.63, p<0.0001) and time (F_{2, 52}=7.68, p=0.0012) predicted HAM-D scores at the end of each observation period. For every point of increase in BAS change, there was a reduction of HAM-D by 0.105 points. HAM-D at each point did not predict subsequent change in BAS (F_{1, 52}=2.17, p = 0.146).

Conclusion

During Engage treatment and follow-up, change in behavioral activation is followed by improvement of depressive symptoms and signs.

INTRODUCTION

Engage is a streamlined behavioral intervention for late-life major depression developed to match the skill level of community clinicians.(1) The principal assumption of Engage is that late-life depression is mediated by brain circuit abnormalities and targeting these abnormalities with a behavioral intervention can improve its symptoms and signs. This assumption is consistent with the Research Domain Criteria (RDoC) Project, which asserts that biosignatures of neural systems can augment the management of behavioral disorders.(2)

Starting from the above assumption, we theorized that dysfunction in the RDoC positive valence systems is fundamental to the pathogenesis of late life depression.(1) The positive valence system comprises networks processing reward related functions. The best characterized reward circuit consists of dopaminergic neurons of the ventral tegmental area (VTA) that project to the nucleus accumbens (NAcc), which contains mainly GABAergic inhibitory neurons.(3) VTA dopamine neurons also innervate regions of the prefrontal cortex, the amygdala, and the hippocampus. The NAcc receives glutamatergic innervation from the prefrontal cortex, amygdala and hippocampus; these structures also have glutamatergic connections with one another. The VTA-NAcc complex is critical for the recognition of rewards and for initiating consumption behavior but also for responses to aversive stimuli.

The centrality of the positive valence system in late-life depression is based on rodent and human studies. Stress-based animal models of depression have been developed, e.g. chronic social defeat, chronic mild stress, and learned helplessness. In these models, stress induces changes in structural plasticity of dendrites and dendritic spines within the reward regions.(3) In the NAcc, stress leads to loss of inhibitory synapses and reduces its inhibitory tone. Human studies also suggest that depression is accompanied by disturbances in several domains of the positive valence system. Depressed patients are impulsive and time-inconsistent in intertemporal choice action for gain and loss in control delay discounting tasks,(4) suggesting a dysfunction in the reward valuation domain of the positive valence systems. Depressive symptoms are accompanied by a reward-based decision making deficit and higher levels of variability and more random action selection suggesting an impairment in the domain of action selection/preference-based decision-making. Activity in the NAcc and the ventral striatum is reduced in major depression. In a monetary incentive delay task, subjects with major depression showed weaker responses to gains in the left nucleus accumbens and the caudate bilaterally than non-depressed individuals.(5) Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes. In a reward and punishment reversal paradigm, subjects with major depression had both impaired reward reversal accuracy and attenuated activation of the anterior ventral striatum in response to unexpected rewards.(6) Aging influences the action selection/preference-based decision-making domain of the positive valence system. Aging impairs reward-related learning and decision making, especially when reward information is uncertain or the task requires flexible adaptations to changing stimulus-reward contingencies,(7) and also increases sensitivity to punishment.(8)

Based on the view that abnormal function of the positive valence systems is a mechanism fueling depression, Engage uses “reward exposure” to reignite the positive valence systems. “Reward exposure” is the principal intervention of Engage and consists of engagement in meaningful to the patient social and physical activities. “Reward exposure” is informed by Behavioral Activation Therapy (BAT)(9), a treatment with strong evidence of efficacy in depressed younger adults. (10-12) In addition to encouraging patients to re-engage in rewarding activities, Engage incorporates simplified strategies for ease of training community-based clinicians of varying educational levels and older adults of varying backgrounds and cognitive function. Accordingly, Engage relies on graduated re-engagement by proscriptively starting with easy to implement social and physical activities and moving to more complex social and physical activities. If patients fail to engage in activities leading to “reward exposure”, therapists seek to identify and address barriers to reward exposure (e.g. negativity bias, apathy, or emotional dysregulation) so that “reward exposure” can proceed unimpeded. Thus, Engage uses a structured, stepped approach focusing on “reward exposure” and uses simplified interventions. A proof of concept study comparing Engage with historical comparison group receiving problem solving therapy (PST), showed that Engage is non-inferior to PST in reducing depression in older adults.(13)

This study examines whether improvement in a behavioral expression of positive valence system function predicts subsequent reduction of depressive symptoms and signs. Consistent with the RDoC Consensus Workshop,(14) it uses the Behavioral Activation for Depression Scale (BAS) as a behavioral proxy of positive valence system function. This study tests the hypothesis that increase in BAS during successive periods of treatment with Engage and during post-treatment follow-up predicts depression severity at the end of each period.

METHODS

Subjects

The subjects were older adults recruited by the Weill Cornell Institute of Geriatric Psychiatry and the University of California San Francisco by advertisement for an open treatment trial of Engage therapy approved by the Institutional Review Boards of both institutions. The inclusion criteria were: 1) Age≥ 60 years; 2) unipolar, non-psychotic major depression (by SCID(15), DSM-IV); 3) Mini-Mental State Examination (MMSE) ≥ 24; 4) off antidepressants or have been on a stable dose of an antidepressant for 12 weeks and do not intend to change the dose in the next 10 weeks; and 5) capacity to consent. Exclusion Criteria were: 1) Intent or plan to attempt suicide in the near future; 2) history or presence of psychiatric diagnoses other than unipolar, non-psychotic major depression or generalized anxiety disorder; 3) use of psychotropic drugs or cholinesterase inhibitors other than mild doses of benzodiazepines.

Assessment

All instruments were administered by trained interviewers. Diagnosis and age at the onset of the first depressive episode was assigned in research conferences by agreement of two clinician investigators after review of a narrative of the subjects’ psychiatric history, the SCID-R(15) and other rating scales.

Severity of depression was quantified with the 24-item Hamilton Depression Rating Scale (HAM-D).(16) Behavioral activation was rated with the Behavioral Activation for Depression Scale (BAS).(17) BAS, the assessment instrument of behavioral activation, was generated through an exploratory factor analysis of a rationally derived set of items followed by a confirmatory factor analysis.(17, 18) This factor structure was replicated in community samples with elevated depressive symptoms (19, 20) and in depressed outpatients (21). Adequate reliability and validity were reported for the BAS in all the above studies, with BAS scores showing predicted associations with depressive symptoms. The BAS consists of 25 items. However, one of the items (Item 22: My work/schoolwork suffered because I was not as active as I needed to be) was not relevant to most of our depressed older adults. For this reason, we used 24 out of the 25 items of the BAS. HAM-D and BAS were administered at baseline, week 6, week 9 (end of Engage treatment), and week 36 (27 weeks after completion of Engage).

Medical burden was assessed with the Charlson Comorbidity Index.(22) Disability was quantified by the interviewer-administered World Health Organization Disability Assessment Schedule II-12 item (WHODAS).(23) The WHODAS yields a composite score of disability after assessing the domains of: Understanding and communicating, getting around, self-care, getting along with others, household and work activities, and participation in society.

Overall cognitive impairment was rated with the Mini Mental State Examination (MMSE).(24) Executive functions were assessed with the Stroop Color Word Interference Test (25), a response inhibition test, and the Dementia Rating Scale, Initiation/Perseveration Scale (DRS-IP), which consists of tasks of semantic fluency, visual planning, and verbal and motor perseveration.(26) Memory was rated with the Hopkins Verbal Learning Test (HVLT-R), a test of recall and retention.(27)

All scales were administered at baseline. The HAM-D and BAS were also administered 6, 9, and 36 weeks later.

Engage

The principal intervention of Engage is “reward exposure”, offered in all 9 sessions of 40-45 minute duration. Assisted by therapists, patients develop a list of rewarding activity goals and select 2-3 goals to pursue between sessions. In each session, patients select two or three activities with rewarding value, develop a list of ideas of how to pursue each, select the most feasible and rewarding among these ideas, and make action plans with concrete steps to address obstacles to implementation. In patients who do not adequately pursue planned rewarding activities during the initial three sessions, therapists identify “barriers” to reward exposure, i.e. negativity bias, apathy, or emotional dysregulation.

Therapists add interventions only when barriers detract from pursuing and valuing meaningful, rewarding activities. Interventions for negativity bias include practicing using a positive focus related to reward engagement, playing devil’s advocate for thoughts interfering with engagement, weighing the evidence to motivate patients to pursue activities, writing alternative positive explanations to negative thoughts interfering with engagement in rewarding activities, and learning how positive people respond. Strategies for apathy consist of prompts to initiate action plans for reward exposure. These include checklists, reminders, labels, tape recorders, electronic instructions to start tasks, calls to prompt action plans, and family and friends acting as prompts. Strategies for emotional dysregulation consist of distraction, meditation, relaxation exercises, deep breathing, and imagery. Patients practice the selected strategy in session and then on their own, so that they can use it when they sense difficulties while pursuing plans for reward exposure.

Therapist Training

The therapists were 6 social workers (MSW) practicing in the community and 7 (4 MSW and 3 Ph.D.) members of the research team. Therapists were asked to read the Engage Manual and two trainers (PA or PR) offered two 45-minute didactic sessions. Then, therapists had one-to-one role-play sessions in which a trainer first role-played, and after role-reversal, evaluated each trainee’s fidelity to Engage with the Engage Adherence Scale (E-AS). Therapists were assigned “practice cases” and required to achieve E-AS scores≥ 4 (good) on two consecutive sessions to be certified.

Analysis of Data

Mixed-effects linear regression analyses(28) were used to analyze HAM-D and BAS progression with a subject-specific random intercept and fixed effects for time. To test the hypothesis that improvement in BAS is followed by a reduction of HAM-D, a mixed effects model with BAS change from baseline to week 6 (week 6 – baseline), from week 6 to week 9 (week 9 – week 6) and from week 9 to week 36 (week 36 – week 9) was used as independent variables with HAM-D at week 6, week 9 and week 36 as the dependent variable. We also used a mixed effects analysis to examine whether severity of depression influences change in behavioral activation. To this end, we examined whether HAM-D at baseline, week 6 and week 9 predicted BAS improvement from baseline to week 6, from week 6 to week 9 and from week 9 to week 36. We used time (weeks) as a categorical variable in all analyses. We report estimates and their 95% confidence intervals.

RESULTS

Forty-eight older adults were studied. Thirty-nine of these subjects comprised the sample of the proof of concept study reported earlier (13) and 9 were subjects recruited later. They met DSM-IV criteria for major depression. The severity of their depressive symptoms (HAM-D) and their disability (WHODAS II) were within the mild to moderate range severity (Table 1). No subject met DSM-IV criteria for dementia and their MMSE scores were above the dementia range (≥24). There was a wide range in the subjects’ performance on executive functions (Stroop Color Word and DRS-IP) and memory (HVLT-R learning and delayed recall) tasks. At baseline, the correlation of BAS and HAM-D at baseline was r= −0.501, df=47, p<0.0001.

Table 1.

Baseline Demographic and Clinical Data of 48 Older Adults Treated with Engage Therapy Over 9 Weeks.

VARIABLE	Median	Mean	Standard Deviation
Gender (F:M)	2:1
Age	71.4	71.7	8.2
Education (Years)	16.0	16.2	5.6
Age Of Depression Onset	46.0	45.8	23.9
HAM-D*	22.0	22.8	4.0
BAS**	80.0	80.3	25.3
Charlson Comorbidity Index	2.0	2.6	2.1
WHODAS II***	28.5	29.1	8.1
Mini-Mental State Examination	29.0	28.8	1.2
Age Corrected T-Scores:
Stroop Color Word Score	46.0	48.7	12.2
DRS-IP+	54.0	51.7	6.1
HVLT-R++ Learning Trials	46.0	45.5	12.1
HVLT-R++ Delayed Recall	46.5	45.7	12.3

^*Hamilton Depression Rating Scale-24 items

^**Behavioral Activation for Depression Scale

^***World Health Organization Disability Assessment Schedule II

⁺Dementia Rating Scale- Initiation/Perseveration Subtest

⁺⁺Hopkins Verbal Learning Test-Revised

All subjects were treated with 9 sessions of Engage and all received “reward exposure”. Approximately, 44.4% of participants received reward exposure alone. But 28.9% required additional interventions for negativity bias, 17.8% required additional interventions for apathy, and 8.9% required additional interventions for emotional dysregulation in order to help them focus on reward exposure.

Behavioral activation (BAS) (F_3,140=5.13, p=0.002) and depressive symptoms and signs (HAM-D) (F_3,142=23.98, p<0.0001) both changed significantly with time during the 36-week observation period. There was a sharp increase (19.1 points, 95% CI: 8.8-29.4, t₁₄₀=3.66, p= 0.004) in BAS and a sharp decrease (10.5 points, 95% CI: 7.9-13.2, t₁₄₂=7.82, p < 0.0001) in HAM-D during the 9 weeks of treatment with Engage (Figure 1). During the post treatment period (week 9 to 36), there was a mild decline in BAS and a mild increase in HAM-D.

Figure 1.

Change in 24-item Hamilton Depression Rating Scale (HAM-D) (left vertical axis) and change in Behavioral Activation in Depression Scale (BAS) (right vertical axis) in 48 non-demented older adults with major depression treated with Engage (9 weekly sessions) and assessed over 36 weeks.

To test the hypothesis that increase in BAS is followed by reduction in HAM-D, we constructed a mixed effects model with severity of depression as the overtime outcome, i.e. HAM-D at weeks 6, 9 and 36. The predictors were BAS change from baseline to week 6, from week 6 to week 9, and from week 9 to week 36 as well as time (weeks). Both BAS change (F_{1, 52}=18.63, p<0.0001) and time (F_{2, 52}=7.68, p=0.0012) were significant predictors of HAM-D. For every point of change in BAS change, there was a change of HAM-D by 0.105 points.

We investigated whether severity of depression (BAS) influences change in behavioral activation (BAS) during the next assessment period. A mixed effects model showed that HAM-D scores was not significantly associated with subsequent change in BAS (F_{1, 52}=2.17, p = 0.1463).

DISCUSSION

The principal finding of this study is that change in behavioral activation at various periods during and even after termination of Engage predicts depression severity at the end of these periods. Severity of depression did not significantly influence change in behavioral activation during Engage treatment. Assuming that increased behavioral activation reflects improvement in positive valence systems function,(14) this finding supports the basic premise of Engage, implicating the positive valence system in the mechanism of antidepressant response of Engage.

This is the first study to examine the relationship between change in behavioral activation and severity of depression in depressed older adults treated with Engage. The relationship of behavioral activation change to depression is consistent with brain imaging findings related to behavioral activation. Response of major depression to behavioral activation was predicted by pretreatment connectivity of the right insula with the right middle temporal gyrus and the left intraparietal sulcus with the orbital frontal cortex.(29) Behavioral activation therapy was followed by activation changes in reward structures, including the paracingulate gyrus during reward selection, the right caudate nucleus during reward anticipation, and the paracingulate and orbital frontal gyri during reward feedback.(30) A paradigm requiring cognitive control in both sad and neutral contexts resulted in decreased activation in prefrontal structures (paracingulate gyrus, the right orbital frontal cortex, and the right frontal pole) during responses to cognitive control stimuli presented within a sad context in prefrontal structures.(31) The magnitude of pretreatment activation in the paracingulate gyrus cluster predicted the magnitude of depressive symptom change after behavioral activation therapy.

In this sample, the BAS related change in depression severity was approximately 1.06 HAM-D points. Viewed in the context of antidepressants vs. placebo trials, where the mean end-point difference is about 2.5 HAM-D points, the BAS related change in depression appears clinically meaningful. However, non-specific therapeutic factors account for the rest of improvement in depression.

The findings of this study have to be considered in the context of its limitations. First, the study had no comparison group treated with another therapy or receiving no treatment. Therefore, it is unclear whether the relationship of behavioral activation and depressive symptoms is specifically related to Engage. However, even if behavioral activation is associated with reduction of depression during a treatment other than Engage, one may argue that behavioral activation is a common final pathway of effective psychotherapies for depression. Second, it is possible that behavioral activation assessed by BAS and classical depression scales measure the same construct. While overlap cannot be excluded, the BAS explained only 18.4% of the variance in depressive symptomatology in depressed outpatients.(21)

This study is the first attempt to examine the impact of Engage on the positive valence system and on depressive symptoms and signs. While BAS is viewed by the RDoC consensus workshop as a behavioral proxy for positive valence systems function (14), self-report is one of several ways to study these relationships. Additional methods include study of performance in paradigms engaging the positive valence system as well as structural and functional neuroimaging indices of this system’s functions. Beyond confirming the effect of Engage on the positive valence system, such studies may identify changes in specific constructs of this system and clarify the mechanisms of response to behavioral treatment of depression.