The Incentive Salience Hypothesis: A Novel Treatment Strategy for Depression

Author: David Soskin, M.D.
Mentor: Maurizio Fava, M.D.

Title: The Incentive Salience Hypothesis: A Novel Treatment Strategy for Depression

(a) Abstract
Given that dopamine effects on reward processing appear to be more specific to salience/"wanting" than to hedonics/"liking," we have hypothesized that stimulants may have a more robust antidepressant effect in combination with well-being therapy (WBT), a cognitively and behaviorally based psychotherapy, which targets the incentive processing and associative learning of reward. We propose to test this hypothesis by randomizing 40 subjects with major depressive disorder (MDD) and residual depressive symptoms on SSRI monotherapy to 8 weeks of treatment with either WBT in combination with a stimulant or WBT with pill placebo. Similar to augmentation studies with D-cycloserine, this proof-of-concept study could help us to provide further evidence for enhancement between combined psychotherapy and pharmacologic interventions. The study also constitutes a novel clinical translation of the incentive salience model to target impaired reward processing in human subjects with MDD.

(b) Specific Aims
This study aims to identify a novel medication-therapy combination strategy for residual symptoms of MDD.

Specific Aim (1): To assess the efficacy of lisdexamfetamine in combination with WBT on symptom remission and response.

Hypothesis 1a: Partial SSRI responders assigned to treatment with WBT in combination with lisdexamfetamine will demonstrate higher rates of remission (HAM-D-17, HAM-D-31) compared to controls.
Hypothesis 1b: Partial SSRI responders assigned to treatment with WBT in combination with lisdexamfetamine will demonstrate higher rates of response (HAM-D-17, HAM-D-31) compared to controls.

Specific Aim (2): To assess the effects of lisdexamfetamine in combination with WBT on functioning, well-being, and positive affectivity.

Hypothesis 2a: Partial SSRI responders assigned to treatment with WBT in combination with a stimulant will demonstrate greater improvement in functioning (FS-12) compared to controls.

Hypothesis 2b: Partial SSRI responders assigned to treatment with WBT in combination with a stimulant will demonstrate greater improvement in well-being (PWB) compared to controls.

Hypothesis 2c: Partial SSRI responders assigned to treatment with WBT in combination with a stimulant will demonstrate greater improvement in positive affectivity (SHAPS, PANAS, BAS) compared to controls.

(c) Background and Significance
MDD is a highly prevalent psychiatric disorder associated with significant medical co-morbidity and functional disability (Kessler, 2003). Current pharmacologic treatments are considered to be suboptimal (American Psychiatric Association, 2000): only approximately 50% of outpatients starting treatment with an SSRI will respond (Agency for Healthcare and Policy Research, 1993) and fewer will remit (Trivedi, 2006). Perhaps more problematic, between 40% (Ramana, 1995) and 60% (Rush, 2006) of responders will relapse within one year.

There is continuing clinical urgency to identify more effective augmentation strategies (Fleurence, 2009). Stimulants have a promising mechanism of action by altering dopamine kinetics in the ventral striatum (VS). As a class, they also have historical importance in the treatment of MDD. There have been five positive open-label augmentation trials using stimulants with MAOIs or TCAs for refractory depression (Nelson, 2000). Two recent studies adding stimulants to SSRIs showed improvement for specific symptoms of fatigue and apathy (Fava et al., 2005; Ravindran et al., 2008). However, controlled studies have failed to demonstrate significant changes in response or remission (Candy, 2008).

The factors contributing to high failure rates in the modern antidepressant era are reviewed by Gelenberg and colleagues (Gelenberg, 2008). In addition to these broad historic and systemic factors, previous stimulant augmentation studies may have been limited by the hypothesis that their pro-dopaminergic effects are mediated through hedonic reward. First proposed by Wise (1982), dopamine has been viewed as a candidate "pleasure neurotransmitter" (Pecina, 2008) for over 30 years. Yet recent data from animal models suggest that dopamine has greater effects on two other subsytems of reward – incentive salience and reward learning. Microinjection of amphetamine (AMPH), an indirect dopamine agonist, into the nucleus accumbens (NAcc) shell in rodents has been shown to increase the incentive impact of reward cues ("wanting" or incentive salience), as well as secondary reinforcement when response reinforcement contingencies exist (reward learning), without enhancing the hedonic impact of rewards ("liking") (Kelley, 1991; Wyvell, 2000). Using event-related MRI and a monetary incentive delay paradigm, Knutson found related evidence that AMPH modulates both psychological and physiological aspects of incentive processing in humans (Knutson, 2004). Healthy subjects receiving AMPH demonstrated increased positive arousal for anticipating gain and avoiding loss as measured by increased cue-related excitement and duration of ventral striatum (VS) activity. Additionally, AMPH subjects displayed increased right NAcc activation during loss anticipation, prompting the investigators to conclude that AMPH treatment "may also promote tonic VS activity during anticipation of loss, which might facilitate increased positive arousal and concomitant affective reframing of potential loss as potential gain." There are also increasing human data that dopamine neuronal activation in the basal ganglia contributes to the coding of predictive reward signals and can amplify the incentive impact of learned signals (McClure, 2003).

Given that dopamine effects on reward processing appear to be more specific to salience/"wanting" than to hedonics/"liking" (Berridge, 2007), we have hypothesized that stimulants may have a more robust antidepressant effect in combination with WBT, a cognitively and behaviorally based psychotherapy which targets the incentive processing and associative learning of reward. WBT has been demonstrated to be effective for the treatment of the residual phase of affective disorders (Fava, 1998). It is also unique in that its focus of treatment is anhedonia – a core feature of depression, a potential endophenotype (Pizzagalli, 2005), and the symptom domain, which neurobiologically links mesolimbic dopaminergic dysfunction in MDD (Hasler, 2009) to the putative functional (Burgdorf, 2001) and mechanistic (Schmitz, 2001) action of stimulants.

(d, e) Design and Methods
1. Recruitment: participants to be recruited by referral or local advertisements.
2. Subject selection: subjects will be selected from outpatients between 18 and 55 years of age, who are experiencing residual symptoms after 8 weeks of SSRI therapy, with at least 4 weeks at a stable dose of the current agent.
3. Design: subjects will be randomized to eight weeks of double blind treatment with stimulant or pill placebo added to well-being therapy.
4. Inclusion criteria: subjects must meet DSM-IV diagnostic criteria for MDD during the present episode of illness with continuing residual symptoms; subjects must have a 31-item HAM-D score of 14 to 26 at screening and randomization; subjects must have a score of 3 or 4 on the CGI-S at screening and randomization; subjects must have undergone 8 weeks of SSRI therapy, with at least 4 weeks at a stable dose of the current agent.
5. Exclusion criteria: treatment within 4 weeks of randomization with any non-SSRI antidepressant, antipsychotic, mood stabilizer, standing benzodiazepine, stimulant, or stimulant-like agent; current treatment-resistant episode of MDD; a primary diagnosis of an Axis I disorder other than MDD; history of a psychotic disorder, dysthymia, antisocial personality disorder, BPD, or mental retardation; initial insomnia at screening that is not adequately controlled by medications; co-morbid medical conditions including a structural heart defect or rhythm abnormality that might be exacerbated by stimulant therapy; hypertension as measured by a resting sitting systolic blood pressure of > 149mmHg or diastolic blood pressure > 95mmHg; tachycardia as measured by a sitting pulse rate of >100 bpm or <50 bpm after resting for 5 minutes; significant suicide risk; allergy, hypersensitivity, intolerance, or history of non-responsivity to stimulant medications; history of non-responsivity to CBT or well-being therapy; history of a substance use disorder, with the exception of nicotine dependence, within 12 months prior to screening; women who are pregnant or breastfeeding.
6. Treatment assignment and randomization: treatment assignment will be made at the time of the baseline visit; subjects will be randomized on the basis of a random numbers list.
7. Safety: physical exam will be performed at initiation and completion of study; side effects will be evaluated with ratings of frequency, intensity, and burden at follow-up. Vital signs will be monitored at screening, baseline, and weeks 1, 2, 4, 6, and 8. Urine drug testing will be conducted at screening to ensure that patients are not using prohibited agents.
8. Dosing: subjects will have received 8 weeks of SSRI therapy prior to randomization. If the SSRI dosage is considered to be suboptimal by the study physician on the basis of clinical history and diagnostic interview at intake, the dosage will be optimized at least 4 weeks prior to randomization. SSRI dosage will be fixed after randomization. Subjects will receive treatment with the stimulant, lisdexamfetamine, or matched placebo. Lisdexamfetamine has been selected given its lower risk for abuse and diversion (Heal, 2009), and will be flexibly dosed between 20 and 50 mg/d. The initial dose of 20 mg/d may be increased by 10 mg/d at each interval study visit based on clinician judgment of relative efficacy and side effect burden.
9. Concomitant medications: concomitant medications for medical conditions will be continued as long as they are kept stable during the course of the study. The treating physician may prescribe and/or uptitrate zolpidem for patients with insomnia. The addition of other psychotropics is prohibited.
10. Well-being therapy: 4 licensed therapists, who will have been trained in WBT, will provide weekly sessions of 30 to 50 minutes duration. Therapists will follow the procedures outlined in the WBT manual. The initial sessions (weeks 0-2) will be focused on identifying and contextualizing episodes of well-being. The intermediate sessions (weeks 3-5) will be focused on modifying cognitions and behaviors, which lead to premature interruption of well-being, and optimizing cognitions and behaviors, which have been idiographically linked to enhanced well-being. Final sessions (weeks 6-8) will apply the Psychological Well-Being scales (PWB) to refine treatment according to Ryﬀ’s dimensions of well-being. Additional principles and techniques of WBT include reappraisal, mood-charting, scheduling of activities, shaping, problem-solving, and assertiveness training.
11. Assessment: diagnosis of MDD established at screening using DSM-IV criteria, confirmed by Mini-International Neuropsychiatric Interview (MINI). Primary efficacy measures to include the 17-item and 31-item Hamilton Depression Rating Scale (HAM-D). Secondary measures to include Clinical Global Impressions-Severity of Illness (CGI-S) and (CGI-I) scales, 12-item Short-Form Health Survey (FS-12), Positive and Negative Affect Schedule (PANAS), Behavioral Inhibition and Activation scales (BIS/BAS), Snaith-Hamilton Pleasure Scale (SHAPS), and Psychological Well-Being scales (PWB). Primary measures to be administered at screening and once weekly for weeks 0 to 8. Secondary measures to be administered twice weekly for weeks 0 to 2, once weekly for weeks 2 to 8.
12. Mentors and consultants: primary research mentor, Dr. Maurizio Fava; psychotherapy mentor, Dr. Amy Farabaugh; WBT consultant, Dr. Giovanni Fava.

(f) Proposed Analyses
Assuming a standard deviation of 5 for the change from randomization to week 8 in the HAM-D-31, a total sample size of 40 subjects (20 per treatment group) will provide 80% power to detect a difference of 4.5 units between the active and placebo treatment groups at a two-sided 0.05 significance level. Chi squared tests will be used to compare the percentage of subjects in remission, as defined by a HAM-D score of < 8. Interval changes on measures of depression, functioning, well-being, and affectivity will be analyzed with mixed effects growth curve models (Raudendbush, 2002). Data from all subjects randomized to treatment, including subsequent withdrawal or deviation from the protocol, will be accounted for with mixed model repeated measures (Gueorguieva, 2004).

(e) Timeline
Consultant, Dr. Giovanni Fava, will provide 2 weeks of WBT training to DCRP therapists prior to the study's start date. 1 to 2 months will likely be required for processing of the application by the IRB. Based on enrollment rates of augmentation trials recently performed at the DCRP, we estimate that 2-3 patients will be enrolled per month. Given a timeline of 2 months per patient between baseline and endpoint visits, we expect the project to be completed in 2 years.

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