Hostname: page-component-74656f9884-rdgjk Total loading time: 0 Render date: 2026-11-08T04:02:56.038Z Has data issue: false hasContentIssue false
  • English
  • Français

Incentive salience: novel treatment strategies for major depression

Published online by Cambridge University Press:  01 August 2013

David P. Soskin ,
Daphne J. Holt ,
Garret R. Sacco  and
Maurizio Fava
David P. Soskin*
Affiliation:
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
Daphne J. Holt
Affiliation:
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA
Garret R. Sacco
Affiliation:
Department of Psychology, University of Delaware, Newark, Delaware, USA
Maurizio Fava
Affiliation:
Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts, USA
*
*Address for correspondence: Dr. D. Soskin, Center for Treatment-Resistant Depression, Department of Psychiatry, Massachusetts General Hospital, 1 Bowdoin Square, Boston, MA 02114, USA. (Email dsoskin@partners.org)
Rights & Permissions [Opens in a new window]

Abstract

This article proposes that a recent shift in our understanding of dopamine function may support translational research to target deficits in positive emotions and reward processing in individuals with major depressive disorder (MDD). We review how dopamine functions to modulate approach behaviors in response to positive incentives, and we describe the incentive salience hypothesis, which posits that dopamine primarily modulates “wanting,” or anticipatory reward, rather than “liking,” or subjective pleasure. Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or “liking,” it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it provides a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD.

Keywords

Behavioral activation therapycognitive behavioral therapydopamineincentive salience hypothesismajor depressive disordernovel treatment strategiespsychopharmacologywell-being therapy

Information

Type
Review Articles
Information
CNS Spectrums , Volume 18 , Issue 6 , December 2013 , pp. 307 - 314
Copyright
Copyright © Cambridge University Press 2013 

Introduction

Advances in the pharmacological treatment of major depression have often been the result of serendipity. Imipramine was first observed to have mood effects in a pilot study testing the molecule, G 22355, an analog of chlorpromazine, as an antipsychotic. In a perhaps apocryphal story, Roland Kuhn, a principle investigator for the study, was impressed by the molecule's mood elevating properties, after a patient with schizophrenia absconded from a large, state hospital in Switzerland, and was found singing elatedly, as he bicycled through the streets of the surrounding town.Reference Healy1 Similarly, the impetus for studying monoamine oxidase inhibitors (MAOIs) as antidepressants can be traced to observations of patients with tuberculosis evincing more positive emotions when taking the antibiotic, iproniziad. Morris Solotorovsky, then Head of Bacteriology at the Merck Institute and an expert on the tuberculosis, quipped “but they are dancing with holes in their lungs.”2

Since the discovery of antidepressants affecting monoamine systems in the 1950s and 1960s, pharmacological advances have been fewer and the rate of antidepressant development has slowed.Reference Shorter and Tyrer3 This may reflect the rise in placebo responseReference Papakostas and Fava4; the systemic limitations of large, multisite trialsReference Gelenberg, Thase and Meyer5; the difficulty of generating rational hypotheses for drug development, given our incomplete understanding of the neural processes underlying emotions, cognitions, and behaviors; and the phenotype problem, defined here as the inclusion of heterogeneous samples in antidepressant trials, likely dampening signal detection.

As we learn more about the biology of neural networks and signaling cascades, as well as processes of synaptic plasticity and environmental transduction, there is a greater need for research, which moves us from insights into neural mechanisms toward innovative treatment strategies. Modern pharmacotherapies for depression have not produced significant gains in efficacy. For example, in trials with selective serotonin reuptake inhibitors (SSRIs), approximately 29–46% of depressed patients fail to respond or achieve only partial response,Reference Fava and Davidson6 between 40% and 60% of responders will relapse within one year,Reference Ramana, Paykel and Cooper7, Reference Rush, Trivedi and Wisniewski8 and rates of remission have been estimated to be about 37%.Reference Thase, Nierenberg and Vrijland9

This article proposes that a recent shift in our understanding of dopamine function may support translational research to improve care for individuals with major depressive disorder (MDD). We will briefly review how dopamine functions to modulate approach behaviors in response to positive incentives; discuss the incentive salience hypothesis of dopamine function and its potential relevance to MDD; and explore a translational treatment approach, which combines behavioral activation therapy and pro-dopaminergic medications to target the incentive processing and associative learning of reward.

The Role of Dopamine in Reward

Dopamine in healthy subjects

Historically, the use of dopaminergic stimulants can be traced to their performance-enhancing effects in military personnel during World War II.Reference Rasmussen10 Consistent with these initial empirical observations, Taneja etal. Reference Taneja, Haman, Shelton and Robertson11 found that healthy subjects randomized to treatment with the pro-dopaminergic agent, modafinil, reported significantly increased positive emotionality—a dimensional construct that includes positive arousal, motivation, and hedonic components—compared to controls. Recent neuroimaging findings also indicate that dopaminergic processes modulate motivational drives and approach behaviors in response to positive incentives.Reference Depue and Iacono12, Reference Depue and Collins13 For example, radioligand-based positron-emission tomographic (PET) studies have found increased metabolic activity within the ventral striatum following exposure to rewarding stimuli, including music and monetary gains,Reference Blood and Zatorre14–Reference Martin-Solch, Magyar and Kunig16 and amphetamine-induced increased release of dopamine in the ventral striatum has been linked to increased energy, arousal, and positive emotionality.Reference Drevets, Gautier and Price17

Dopamine in MDD

There is now strong evidence that the pathophysiology of depression involves abnormal functioning of cortico-basal ganglia reward circuitry, which is highly innervated by dopaminergic projections from the midbrain and may be targeted by pro-dopaminergic medications. Findings of dopamine dysregulation in MDD populations include reduced concentrations of the dopamine metabolite homovanillic acid (HVA) in cerebrospinal fluid,Reference Roy, Agren and Pickar18, Reference Lambert, Johansson, Agren and Friberg19 reduced L-dopa uptake across the blood–brain barrier,Reference Agren and Reibring20 reduced density of striatal dopamine transporters,Reference Klimek, Schenck, Han, Stockmeier and Ordway21 and increased striatal binding to D2/D3 receptors,Reference Di Mascio, Di Giovanni, Di Matteo, Prisco and Esposito22, Reference Meyer, McNeely and Sagrati23 with several conflicting studies also reported.Reference Parsey, Oquendo and Zea-Ponce24, Reference Hirvonen, Karlsson and Kajander25

Additionally, in rodent models, depressive phenotypes have been linked to the dysregulation of dopaminergic transmission through the ventral tegmental area (VTA) and nucleus accumbens (NAcc) under stress conditions.Reference Krishnan and Nestler26, Reference Nestler and Carlezon27 Acutely, upregulation of this pathway may promote adaptive arousal; however, chronic desensitization, overstimulation of cAMP binding protein (CREB), and abnormal expression of BDNF and the protein kinase AKT in the ventral striatum are associated with increased immobility times on the forced swim test.Reference Krishnan and Nestler26 Abnormal expression of circadian rhythm-modulating genes, such as CLOCK and DAT, distributed throughout the reward circuit, and concentrated in the NAcc, are associated with MDD-like behaviors, while CLOCK and DAT-knockdown mutant mice demonstrate increased positive arousal, motivation, and incentive processing.Reference Roybal, Theobold and Graham28

Dopaminergic treatments for MDD

Stimulants have a promising mechanism of action by altering dopamine (DA) kinetics in the ventral striatum (VS) and prefrontal cortex (PFC). 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.Reference Nelson29 Two recent studies on adding stimulants to SSRIs showed improvement for specific symptoms of fatigue and apathy.Reference Fava, Thase and DeBattista30, Reference Ravindran, Kennedy and O'Donovan31 However, controlled studies have failed to demonstrate significant changes in response or remission.Reference Candy, Jones, Williams, Tookman and King32

In contrast, dopamine antagonists, such as Seroquel and Zyprexa, and the mixed agonist-antagonist Abilify, have stronger evidence bases for MDD. Though it is plausible that individuals with biologically heterogeneous forms of depression could respond differentially to stimulants and antipsychotics, there remains a striking discrepancy between basic science research supporting the hypothesis that stimulants have therapeutic properties, specifically targeting motivational drives and approach behaviors impaired in MDD, and the paucity of controlled trials demonstrating antidepressant effects. However, recent findings of studies conducted in animals (see below) may provide a viable explanation for this discrepancy and a rationale for revisiting the use of stimulants in the treatment of MDD.

Incentive Salience Hypothesis

Dopamine deconstructed

Dopamine has been viewed as a candidate “pleasure neurotransmitter” for over 30 years.Reference Pecina, Smith and Berridge33 Yet data from animal studies of the NAcc and ventral pallidum (VP) suggest that, rather than impacting the experience of pleasure or hedonic processing, dopamine has its greatest effects on two types of reward processing—incentive salience and reward learning.Reference Salamone and Correa34, Reference McClure, Daw and Montague35 Microinjection of amphetamine (AMPH), an indirect dopamine agonist, into the NAcc shell in rodents has been shown to increase the incentive impact of reward cues (the degree to which they elicit “wanting” or their “incentive salience”), as well as secondary reinforcement when response reinforcement contingencies exist (reward learning), without enhancing the hedonic impact of rewards (“liking”) (see Figure 1).Reference Kelley and Delfs36–Reference Berridge, Robinson and Aldridge38 Using event-related MRI and a monetary incentive delay paradigm, Knutson etal. Reference Knutson, Bjork and Fong39 found related evidence that AMPH modulates both psychological and physiological aspects of incentive processing in humans. Healthy subjects receiving AMPH demonstrated increased positive arousal for anticipating gain and avoiding loss, as measured by increased cue-related excitement and changes in 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.”

Figure 1

NAc amphetamine amplification of cue-triggered “wanting.” Transient peaks of “wanting” for sucrose reward are triggered by 30-s appearances of a Pavlovian sucrose cue in a Pavlovian-Instrumental Transfer test (CS+; right). Amphetamine microinjection in nucleus accumbens magnifies “wanting” for sugar reward—only in the presence of the reward cue (CS+), indicating magnification of the cue's incentive salience. Only cue-triggered “wanting” was enhanced by this dopamine-related stimulation. By contrast, “liking” reactions to sucrose were not amplified by amphetamine microinjections in NAc (not shown). Drug-induced sensitization of NAc-related systems produces a similar pattern of effects that lasts much longer. Reprinted from Current Opinion in Pharmacology, Volume 9, Berridge, KC, Robinson, TE & Aldridge, JW. Dissecting components of reward: ‘liking’, ‘wanting’, and learning, 65–73 (2009), with permission from Elsevier.

Incentive salience

The incentive salience hypothesis proposes that dopamine has greater effects on “wanting,” or incentive salience, than on “liking,” or hedonic processes. “Incentive” is defined as the amount of work an organism will do in relation to the reward value of the stimulus. “Salience” is defined as how attractive a given stimulus is to an organism.

This hypothesis was pioneered by the neuroscientists Kent Berridge and Terry Robinson, who were intrigued by the possibility of understanding the neural mechanisms of “wanting” and “liking.”Reference Berridge41 They began by characterizing phenotypic expressions of “liking” and “disliking” in rodent models, which could be elicited by contact with rewarding or aversive stimuli, such as sweet or bitter tastes (see Figure 2). They then stimulated specific reward-mediating pathways via microinjection of neurochemicals, such as dopamine and the μ opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), into the limbic forebrain, and measured amplification or abrogation of liking reactions. Contrary to the hedonia hypothesis, first articulated by Wise, as, “The dopamine junctions represent a synaptic way station … where sensory inputs are translated into the hedonic messages we experience as pleasure, euphoria or ‘yumminess,’”Reference Wise40 (p. 94) they found that activation of the mesolimbic DA system was neither necessary nor sufficient for altering the hedonic impact of a stimulus, ie, for mediating “liking.”Reference Berridge41

Figure 2

“Liking” reactions and brain hedonic hotspots. Far left: Positive hedonic “liking” reactions are elicited by sucrose taste from human infant and adult rat (eg, rhythmic tongue protrusion). By contrast, negative aversive “disliking” reactions are elicited by bitter quinine taste (center left; see online video). From Steiner etal., 2001. Right: Opioid hedonic hotspot in medial shell of nucleus accumbens where μ opioid agonist DAMGO causes increases in the number of “liking” reactions elicited by sucrose taste (red). Purple shows where opioid activation suppresses “liking” and “disliking” reactions elicited by quinine. Dopamine lacks any identified yellow hedonic hotspot and possesses only suppression regions (purple equivalents) as far as is known. Permission to reproduce this figure from Berridge KC. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl). 2007;191(3):391–431, was given with kind permission from Springer Science and Business Media.

Additionally, genetically engineered hyperdopaminergic mutant mice, lacking the gene transporter for dopamine reuptake, demonstrate significant amplification of “wanting” (measured by 3 different tests of incentive motivation) but not “liking” in response to sucrose rewards.Reference Berridge41, Reference Pecina, Cagniard, Berridge, Aldridge and Zhuang42 Elegant research performed by Salamone etal. Reference Salamone, Correa, Mingote and Weber43 has also demonstrated that antagonism of dopamine in the NAcc specifically impairs activational aspects of motivation affecting rodent feeding behaviors, which may parallel, phenomenologically, the depressive symptoms of anergia, psychomotor slowing, and behavioral isolation. Finally, in rodent models, neurochemical lesioning of ascending DA projections through the medial forebrain did not suppress the hedonic impact of rewards, even with the loss of approximately 99% of DA neurons in both the NAcc and neostriatum.Reference Berridge and Robinson44

The failure of pro-dopaminergic signaling to elicit increased liking reactions contrasts with the effects of other specific neurotransmitter systems, including opioids and cannabinoids, which do change the hedonic impact of various stimuli. For example, microinjection of these neurotransmitters or their agonists into circumscribed portions of limbic structures such as the medial shell of the nucleus accumbens or the posterior portion of the ventral pallidum can double or triple the number of “liking” reactions elicited by sucrose taste.Reference Pecina and Berridge45, Reference Smith and Berridge46 In dynamic models of neural connectivity, these “hedonic hotspots” form circuits connecting multiple brainstem and forebrain regions, described by Berridge etal. as “akin to multiple islands of an archipelago that trade together.”Reference Berridge, Robinson and Aldridge38

Relevance to human reward processing

These findings have now been extended to humans by examining the behavioral and neural correlates of dopamine neurotransmission in Parkinson's patients with dopamine dysregulation syndrome and in healthy volunteers. For example, Volkow etal. Reference Volkow, Wang and Fowler47 and colleagues found that individual variation in dopamine receptor occupancy in the striatum was associated with “nonhedonic” ratings of food desire (ie, greater receptor occupancy was linked to a greater incentive impact of food), leading to the conclusion that “the present data are consistent with the notion that dopamine increases the incentive salience of a conditioned cue (e.g., the sight, smell, and taste of food), causing the cue to increase the motivational state of ‘wanting’ for the reward without necessarily enhancing its hedonic properties” (p. 179). To map the neural processes of wanting and liking in humans, Brian Knutson at Stanford has developed a unique instrument, the monetary incentive delay (MID), which separates anticipatory reward processing (“wanting”) and consummatory reward processing (“liking”) through a blocked fMRI paradigm.Reference Knutson, Westdorp, Kaiser and Hommer48 Subjects are shown cues signifying reward, loss, or neutral conditions. This initial anticipatory phase is followed by a timed task requiring subjects to click on an electronic target flashed across their computer screens. In a third phase, subjects receive feedback for their performance as actual money gained, lost, or maintained. This work has shown that “wanting” and “liking” are linked with differential activation of distinct regions of the cortical-basal ganglia circuit. In healthy individuals, anticipatory reward appears to recruit the ventral striatum, including the NAcc, VTA, and orbital frontal cortex (OFC), while consummatory reward processing leads to activation of the OFC, medial prefrontal cortex (mPFC), and putamen.Reference Haber and Knutson49

Novel treatment strategies

Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or “liking,” it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it may provide a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD, as well as provide an explanatory model for why randomized, controlled trials of stimulants have failed to demonstrate separation from placebo.Reference Candy, Jones, Williams, Tookman and King32 In healthy individuals, “wanting” and “liking” appear to be tightly linked during every day social interactions and goal-directed activity. In contrast, many patients with MDD are socially withdrawn and disconnected from natural contact with rewards. If pro-dopaminergic agents have greater effects on “wanting” than “liking,” as hypothesized by the incentive salience model, when depressed individuals are given a stimulant in the absence of concurrent behavioral change, the expected therapeutic benefits would be minimal. Similar to an injured athlete, who is guided through rehabilitation by an athletic trainer, patients with MDD may need a cognitive behavioral therapist (CBT) to help recondition adaptive social and reward rhythms for stimulants to have true antidepressant effects.

There are several evidence-based psychotherapies for depression, including behavioral activation (BA) therapy, self-system therapy (SST), and well-being therapy (WBT), which help patients to increase contact with natural rewards and decrease reward-interfering cognitive distortions. BA is a component form of CBT; its premise is that behavioral change drives mood change and, ultimately, recovery from depression. The BA therapist initially works with the patient to identify context-dependent rewards, and then shapes behavioral change through an ideographically determined schedule of pleasant and rewarding activities.Reference Jacobson, Martell and Dimidjian50 SST fosters an understanding of depression as stemming from failures of goal-pursuit, and targets self-appraisal and regulatory mechanisms related to hedonic and motivational deficits.Reference Vieth, Strauman and Kolden51 WBT integrates hedonic and eudaimonic approaches to increase well-being and has been demonstrated to be effective for the treatment of the residual phase of affective disorders.Reference Fava, Rafanelli, Cazzaro, Conti and Grandi52 For a more comprehensive review of evidence-based psychotherapies targeting specific aspects of reward-processing and positive emotional regulation, please see Carl etal. Reference Carl, Soskin, Kerns and Barlow53

Based on the incentive salience hypothesis of dopamine function, we suggest that a combination of treatment with a stimulant and behaviorally activating psychotherapy could have a synergistic effect. The stimulant could facilitate the function of the mesocortical and mesostriatal pathways that are involved in motivated, approach-oriented behavior and the initiation of action (“wanting”), increasing the likelihood that the patient will engage in these approach-oriented psychotherapies and their recommended activities. This facilitated participation by the patient would then lead to exposure to potentially rewarding experiences. Dynamic interactions between the “wanting” and “liking” pathwaysReference Berridge, Robinson and Aldridge38 could also lead to the increased subjective experience of pleasure during these activities. Although additional work will be needed to test this model, the empirical evidence for the success of these types of psychotherapies, integrated with new insights into the organization of reward processing circuitry described above, provides a compelling rationale for this type of combined treatment, particularly in patients with prominent anergic features.

Conclusion

Based on the incentive salience hypothesis, we propose that stimulants may be rediscovered as effective antidepressants, if they are combined with psychotherapies that provide adaptive behavioral and environmental substrates for their neural effects. Proof-of-concept studies may help to test for specific and/or synergistic effects on incentive processing. The strongest initial design may be prospective identification, selecting for MDD patients with residual anhedonic deficits, and then randomizing to combined stimulant and psychotherapy treatment versus psychotherapy alone. Similar to augmentation studies with D-cycloserine,Reference Ressler, Rothbaum and Tannenbaum54 studies examining the therapeutic and neural mechanisms of combined interventions for MDD could support a new paradigm for treating the debilitating deficits in motivation and reward processing experienced by many patients with MDD.

Disclosures

David Soskin, MD, has received research support from Harvard Medical School, Kaplen Fellowship, and PharmoRx. He has received honoraria for speaking and/or consulting with MGH Psychiatry Academy/Primedia and ClearView Healthcare Partners. Daphne Holt, MD, PhD, and Garret Sacco, BA, have nothing to disclose. Maurizio Fava, MD, has the following lifetime disclosures: research support: Abbot Laboratories, Alkermes, Inc., Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells Inc., Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clintara, LLC, Covance, Covidien, Eli Lilly and Company, ElMindA, Ltd., EnVivo Pharmaceuticals, Inc., Euthymics Bioscience, Inc., Forest Pharmaceuticals, Inc., Ganeden Biotech, Inc., GlaxoSmithKline, Harvard Clinical Research Institute, Icon Clinical Research, i3 Innovus/Ingenix, Janssen R&D, LLC, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, MedAvante, National Alliance for Research on Schizophrenia & Depression (NARSAD), National Center for Complementary and Alternative Medicine (NCCAM), National Institute of Drug Abuse (NIDA), National Institute of Mental Health (NIMH), Neuralstem, Inc., Novartis AG, Organon Pharmaceuticals, PamLab, LLC, Pfizer Inc., Pharmaceutical Research Associates, Inc., Pharmavite® LLC, PharmoRx Therapeutics, Photothera, Roche Pharmaceuticals, RCT Logic, LLC (formerly Clinical Trials Solutions, LLC), Sanofi-Aventis US LLC, Shire, Solvay Pharmaceuticals, Inc., Synthelabo, Wyeth-Ayerst Laboratories; advisory/consulting: Abbott Laboratories, Affectis Pharmaceuticals AG, Alkermes, Inc., Amarin Pharma Inc., Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer AG, Best Practice Project Management, Inc., BioMarin Pharmaceuticals, Inc., Biovail Corporation, BrainCells Inc., Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Inc., CNS Response, Inc., Compellis Pharmaceuticals, Cypress Pharmaceutical, Inc., DiagnoSearch Life Sciences (P) Ltd., Dainippon Sumitomo Pharma Co. Inc., Dov Pharmaceuticals, Inc., Edgemont Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, EnVivo Pharmaceuticals, Inc., ePharmaSolutions, EPIX Pharmaceuticals, Inc., Euthymics Bioscience, Inc., Fabre-Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals, Inc., Genomind, LLC, GlaxoSmithKline, Grunenthal GmbH, i3 Innovus/Ingenis, Janssen Pharmaceutica, Jazz Pharmaceuticals, Inc., Johnson & Johnson Pharmaceutical Research & Development, LLC, Knoll Pharmaceuticals Corp., Labopharm Inc., Lorex Pharmaceuticals, Lundbeck Inc., MedAvante, Inc., Merck & Co., Inc., MSI Methylation Sciences, Inc., Naurex, Inc., Neuralstem, Inc., Neuronetics, Inc., NextWave Pharmaceuticals, Novartis AG, NuPathe, Nutrition 21, Orexigen Therapeutics, Inc., Organon Pharmaceuticals, Otsuka Pharmaceuticals, Pamlab, LLC, Pfizer Inc., PharmaStar, Pharmavite® LLC, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals, Inc., Puretech Ventures, PsychoGenics, Psylin Neurosciences, Inc., Rexahn Pharmaceuticals, Inc., Ridge Diagnostics, Inc., Roche, Sanofi-Aventis US LLC, Sepracor Inc., Servier Laboratories, Schering-Plough Corporation, Solvay Pharmaceuticals, Inc., Somaxon Pharmaceuticals, Inc., Somerset Pharmaceuticals, Inc., Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Inc., Synthelabo, Takeda Pharmaceutical Company Limited, Tal Medical, Inc., Tetragenex Pharmaceuticals, Inc., Teva, TransForm Pharmaceuticals, Inc., Transcept Pharmaceuticals, Inc., Vanda Pharmaceuticals, Inc.; speaking/publishing: Adamed Co., Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Cephalon, Inc., CME Institute/Physicians Postgraduate Press, Inc., Eli Lilly and Company, Forest Pharmaceuticals, Inc., GlaxoSmithKline, Imedex, LLC, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis AG, Organon Pharmaceuticals, Pfizer Inc., PharmaStar, United BioSource, Corp., Wyeth-Ayerst Laboratories; equity holdings: Compellis, PsyBrain, Inc.; royalty/patent, other income: patent for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to RCT Logic, LLC, and patent application for a combination of azapirones and bupropion in major depressive disorder (MDD); copyright: MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd.

References

1.Healy, D. The Antidepressant Era. Cambridge, MA: Harvard University Press; 1997: 317.Google Scholar
2. History of Twentieth Century Medicine Group, Wellcome Trust, Wellcome Trust. Medicine, Society, and History Division. Wellcome witnesses to twentieth century medicine, 1997. http://eprints.ucl.ac.uk/2078/1/wit2.pdfGoogle Scholar
3.Shorter, E, Tyrer, P. Separation of anxiety and depressive disorders: blind alley in psychopharmacology and classification of disease. BMJ. 2003; 327(7407): 158–160.CrossRefGoogle ScholarPubMed
4.Papakostas, GI, Fava, M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009; 19(1): 34–40.CrossRefGoogle ScholarPubMed
5.Gelenberg, AJ, Thase, ME, Meyer, RE, etal. The history and current state of antidepressant clinical trial design: a call to action for proof-of-concept studies. J Clin Psychiatry. 2008; 69(10): 1513–1528.CrossRefGoogle Scholar
6.Fava, M, Davidson, KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996; 19(2): 179–200.CrossRefGoogle ScholarPubMed
7.Ramana, R, Paykel, ES, Cooper, Z, etal. Remission and relapse in major depression: a two-year prospective follow-up study. Psychol Med. 1995; 25(6): 1161–1170.CrossRefGoogle ScholarPubMed
8.Rush, AJ, Trivedi, MH, Wisniewski, SR, etal. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163(11): 1905–1917.CrossRefGoogle ScholarPubMed
9.Thase, ME, Nierenberg, AA, Vrijland, P, etal. Remission with mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient data from 15 controlled trials of acute phase treatment of major depression. Int Clin Psychopharmacol. 2010; 25(4): 189–198.CrossRefGoogle ScholarPubMed
10.Rasmussen, N. America's first amphetamine epidemic 1929–1971: a quantitative and qualitative retrospective with implications for the present. Am J Public Health. 2008; 98(6): 974–985.CrossRefGoogle ScholarPubMed
11.Taneja, I, Haman, K, Shelton, RC, Robertson, D. A randomized, double-blind, crossover trial of modafinil on mood. J Clin Psychopharmacol. 2007; 27(1): 76–79.CrossRefGoogle ScholarPubMed
12.Depue, RA, Iacono, WG. Neurobehavioral aspects of affective disorders. Annu Rev Psychol. 1989; 40: 457–492.CrossRefGoogle ScholarPubMed
13.Depue, RA, Collins, PF. Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion. Behav Brain Sci. 1999; 22(3): 491–517; discussion 518–569.CrossRefGoogle ScholarPubMed
14.Blood, AJ, Zatorre, RJ. Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proc Natl Acad Sci U S A. 2001; 98(20): 11818–11823.CrossRefGoogle ScholarPubMed
15.Kunig, G, Leenders, KL, Martin-Solch, C, etal. Reduced reward processing in the brains of parkinsonian patients. Neuroreport. 2000; 11(17): 3681–3687.CrossRefGoogle ScholarPubMed
16.Martin-Solch, C, Magyar, S, Kunig, G, etal. Changes in brain activation associated with reward processing in smokers and nonsmokers: a positron emission tomography study. Exp Brain Res. 2001; 139(3): 278–286.CrossRefGoogle ScholarPubMed
17.Drevets, WC, Gautier, C, Price, JC, etal. Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry. 2001; 49(2): 81–96.CrossRefGoogle ScholarPubMed
18.Roy, A, Agren, H, Pickar, D, etal. Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression. Am J Psychiatry. 1986; 143(12): 1539–1545.Google ScholarPubMed
19.Lambert, G, Johansson, M, Agren, H, Friberg, P. Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders. Arch Gen Psychiatry. 2000; 57(8): 787–793.CrossRefGoogle ScholarPubMed
20.Agren, H, Reibring, L. PET studies of presynaptic monoamine metabolism in depressed patients and healthy volunteers. Pharmacopsychiatry. 1994; 27(1): 2–6.CrossRefGoogle ScholarPubMed
21.Klimek, V, Schenck, JE, Han, H, Stockmeier, CA, Ordway, GA. Dopaminergic abnormalities in amygdaloid nuclei in major depression: a postmortem study. Biol Psychiatry. 2002; 52(7): 740–748.CrossRefGoogle ScholarPubMed
22.Di Mascio, M, Di Giovanni, G, Di Matteo, V, Prisco, S, Esposito, E. Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area. Brain Res Bull. 1998; 46(6): 547–554.CrossRefGoogle ScholarPubMed
23.Meyer, JH, McNeely, HE, Sagrati, S, etal. Elevated putamen D(2) receptor binding potential in major depression with motor retardation: an [11C]raclopride positron emission tomography study. Am J Psychiatry. 2006; 163(9): 1594–1602.CrossRefGoogle ScholarPubMed
24.Parsey, RV, Oquendo, MA, Zea-Ponce, Y, etal. Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry. 2001; 50(5): 313–322.CrossRefGoogle ScholarPubMed
25.Hirvonen, J, Karlsson, H, Kajander, J, etal. Striatal dopamine D2 receptors in medication-naive patients with major depressive disorder as assessed with [11C]raclopride PET. Psychopharmacology (Berl). 2008; 197(4): 581–590.CrossRefGoogle ScholarPubMed
26.Krishnan, V, Nestler, EJ. The molecular neurobiology of depression. Nature. 2008; 455(7215): 894–902.CrossRefGoogle ScholarPubMed
27.Nestler, EJ, Carlezon, WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006; 59(12): 1151–1159.CrossRefGoogle ScholarPubMed
28.Roybal, K, Theobold, D, Graham, A, etal. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A. 2007; 104(15): 6406–6411.CrossRefGoogle ScholarPubMed
29.Nelson, JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000; 61(Suppl 2): 13–19.Google ScholarPubMed
30.Fava, M, Thase, ME, DeBattista, C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005; 66(1): 85–93.CrossRefGoogle ScholarPubMed
31.Ravindran, AV, Kennedy, SH, O'Donovan, MC, etal. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008; 69(1): 87–94.CrossRefGoogle ScholarPubMed
32.Candy, M, Jones, L, Williams, R, Tookman, A, King, M. Psychostimulants for depression. Cochrane Database Syst Rev. 2008; (2): CD006722.Google ScholarPubMed
33.Pecina, S, Smith, KS, Berridge, KC. Hedonic hot spots in the brain. Neuroscientist. 2006; 12(6): 500–511.CrossRefGoogle ScholarPubMed
34.Salamone, JD, Correa, M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012; 76(3): 470–485.CrossRefGoogle ScholarPubMed
35.McClure, SM, Daw, ND, Montague, PR. A computational substrate for incentive salience. Trends Neurosci. 2003; 26(8): 423–428.CrossRefGoogle ScholarPubMed
36.Kelley, AE, Delfs, JM. Dopamine and conditioned reinforcement: I. differential effects of amphetamine microinjections into striatal subregions. Psychopharmacology (Berl). 1991; 103(2): 187–196.CrossRefGoogle ScholarPubMed
37.Wyvell, CL, Berridge, KC. Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward “wanting” without enhanced “liking” or response reinforcement. J Neurosci. 2000; 20(21): 8122–8130.CrossRefGoogle ScholarPubMed
38.Berridge, KC, Robinson, TE, Aldridge, JW. Dissecting components of reward: ‘liking’, ‘wanting’, and learning. Curr Opin Pharmacol. 2009; 9(1): 65–73.CrossRefGoogle ScholarPubMed
39.Knutson, B, Bjork, JM, Fong, GW, etal. Amphetamine modulates human incentive processing. Neuron. 2004; 43(2): 261–269.CrossRefGoogle ScholarPubMed
40.Wise, R. The dopamine synapse and the notion of ‘pleasure centers’ in the brain. Trends Neurosci. 1980; 3: 91–95.CrossRefGoogle Scholar
41.Berridge, KC. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl). 2007; 191(3): 391–431.CrossRefGoogle ScholarPubMed
42.Pecina, S, Cagniard, B, Berridge, KC, Aldridge, JW, Zhuang, X. Hyperdopaminergic mutant mice have higher “wanting” but not “liking” for sweet rewards. J Neurosci. 2003; 23(28): 9395–9402.CrossRefGoogle Scholar
43.Salamone, JD, Correa, M, Mingote, SM, Weber, SM. Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine. Curr Opin Pharmacol. 2005; 5(1): 34–41.CrossRefGoogle ScholarPubMed
44.Berridge, KC, Robinson, TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev. 1998; 28(3): 309–369.CrossRefGoogle ScholarPubMed
45.Pecina, S, Berridge, KC. Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness? J Neurosci. 2005; 25(50): 11777–11786.CrossRefGoogle ScholarPubMed
46.Smith, KS, Berridge, KC. Opioid limbic circuit for reward: Interaction between hedonic hotspots of nucleus accumbens and ventral pallidum. J Neurosci. 2007; 27(7): 1594–1605.CrossRefGoogle ScholarPubMed
47.Volkow, ND, Wang, GJ, Fowler, JS, etal. “Nonhedonic” food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect. Synapse. 2002; 44(3): 175–180.CrossRefGoogle ScholarPubMed
48.Knutson, B, Westdorp, A, Kaiser, E, Hommer, D. FMRI visualization of brain activity during a monetary incentive delay task. Neuroimage. 2000; 12(1): 20–27.CrossRefGoogle ScholarPubMed
49.Haber, SN, Knutson, B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2010; 35(1): 4–26.CrossRefGoogle ScholarPubMed
50.Jacobson, N, Martell, CR, Dimidjian, S. Behavioral activation treatment for depression: returning to contextual roots. Clinical Psychology: Science and Practice. 2001; 8: 255–270.Google Scholar
51.Vieth, AZ, Strauman, TJ, Kolden, GG, etal. Self-system therapy (SST): a theory-based psychotherapy for depression. Clinical Psychology: Science and Practice. 2003; 10: 245–268.Google Scholar
52.Fava, GA, Rafanelli, C, Cazzaro, M, Conti, S, Grandi, S. Well-being therapy: a novel psychotherapeutic approach for residual symptoms of affective disorders. Psychol Med. 1998; 28(2): 475–480.CrossRefGoogle ScholarPubMed
53.Carl, JR, Soskin, DP, Kerns, C, Barlow, DH. Positive emotion regulation in emotional disorders: a theoretical review. Clin Psychol Rev. 2013; 33(3): 343–360.CrossRefGoogle ScholarPubMed
54.Ressler, KJ, Rothbaum, BO, Tannenbaum, L, etal. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004; 61(11): 1136–1144.CrossRefGoogle ScholarPubMed
Figure 0

Figure 1 NAc amphetamine amplification of cue-triggered “wanting.” Transient peaks of “wanting” for sucrose reward are triggered by 30-s appearances of a Pavlovian sucrose cue in a Pavlovian-Instrumental Transfer test (CS+; right). Amphetamine microinjection in nucleus accumbens magnifies “wanting” for sugar reward—only in the presence of the reward cue (CS+), indicating magnification of the cue's incentive salience. Only cue-triggered “wanting” was enhanced by this dopamine-related stimulation. By contrast, “liking” reactions to sucrose were not amplified by amphetamine microinjections in NAc (not shown). Drug-induced sensitization of NAc-related systems produces a similar pattern of effects that lasts much longer. Reprinted from Current Opinion in Pharmacology, Volume 9, Berridge, KC, Robinson, TE & Aldridge, JW. Dissecting components of reward: ‘liking’, ‘wanting’, and learning, 65–73 (2009), with permission from Elsevier.

Figure 1

Figure 2 “Liking” reactions and brain hedonic hotspots. Far left: Positive hedonic “liking” reactions are elicited by sucrose taste from human infant and adult rat (eg, rhythmic tongue protrusion). By contrast, negative aversive “disliking” reactions are elicited by bitter quinine taste (center left; see online video). From Steiner etal., 2001. Right: Opioid hedonic hotspot in medial shell of nucleus accumbens where μ opioid agonist DAMGO causes increases in the number of “liking” reactions elicited by sucrose taste (red). Purple shows where opioid activation suppresses “liking” and “disliking” reactions elicited by quinine. Dopamine lacks any identified yellow hedonic hotspot and possesses only suppression regions (purple equivalents) as far as is known. Permission to reproduce this figure from Berridge KC. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl). 2007;191(3):391–431, was given with kind permission from Springer Science and Business Media.