Restoration of positive mood, in addition to reducing negative mood, is an important treatment goal in the management of depression. The need to restore positive mood states in depressed patients is not adequately addressed by available treatments for major depressive disorder (MDD), suggesting that this mood dimension could be a useful target for drug development. However, for positive mood restoration to become a valid target for antidepressant drug development certain questions should be answered: are symptoms of decreased positive mood phenomenologically distinct from other symptoms of MDD? Should they be considered a distinct aspect of MDD in the diagnostic nomenclature? Is there evidence for differential responsiveness to treatment? Is the underlying pathophysiology understood and different from that of other MDD symptoms? Is low positive mood specific to depression or does it contribute to psychopathology in other disorders? Beyond these basic questions, this review identifies a number of design issues that need to be considered when conducting studies that target improving positive mood. These design issues include (1) what population to study, (2) what line of treatment to target, (3) the appropriateness and validation of methods and measures to evaluate positive mood and its restoration, (4) the role of functional outcome measures in determining success of the treatment, and (5) optimal designs for add-on therapy versus monotherapy agents.
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th ed.Arlington, VA: American Psychiatric Publishing, pp.5–25.
2.
BodkinJALasserRAWinesJDJr. (1997) Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatr58: 137–145.
3.
BogdanRPizzagalliDA (2009) The heritability of hedonic capacity and perceived stress: A twin study evaluation of candidate depressive phenotypes. Psychol Med39: 211–218.
4.
BrownTAChorpitaBFBarlowDH (1998) Structural relationships among dimensions of the DSM-IV anxiety and mood disorders and dimensions of negative affect, positive affect, and autonomic arousal. J Abnorm Psychol107: 179–192.
5.
BuchananRWDavidMGoffG. (2005) A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull31: 1–15.
6.
DavidsonRJ (1998) Affective style and affective disorders: Perspectives from affective neuroscience. Cogn Emot12: 307–330.
7.
DichterGSKozinkRVMcClernonFJ. (2012) Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes. J Affect Disord136: 1126–1134.
8.
DienerEEmmonsRA (1985) The independence of positive and negative affect. J Pers Soc Psychol47: 1105–1117.
9.
DietzL. (2008) Mother–child interactions in depressed children and children at high risk and low risk for future depression. J Am Acad Child Adolesc Psychiatry7: 574–582.
10.
DunnBD (2012) Helping depressed clients reconnect to positive emotion experience: Current insights and future directions. Clin Psychol Psychother19: 326–340.
11.
Food and Drug Administration (2009) Guidance for industry on patient-reported outcome measures: Use in medical product development to support labeling claims. Fed Reg74: 65132–65133.
12.
ForbesEE (2009) Where’s the fun in that? Broadening the focus on reward function in depression. Biol Psychiatry66: 199–200.
13.
ForbesEEChristopher MayJSiegleGJ. (2006) Reward-related decision-making in pediatric major depressive disorder: An fMRI study. J Child Psychol Psychiatr47: 1031–1040.
14.
ForbesEEHaririARMartinSL. (2009) Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. Am J Psychiatr166: 64–73.
15.
ForbesEEOlinoTMRyanND. (2010) Reward-related brain function as a predictor of treatment response in adolescents with major depressive disorder. Cognit Affect Behav Neurosci10: 107–118.
16.
ForbesEEShawDSDahlRE (2007) Alterations in reward-related decision making in boys with recent and future depression. Biol Psychiatry61: 633–639.
17.
FredricksonBL (2004) The broaden-and-build theory of positive emotions. Philos Trans R Soc Lond B Biol Sci29: 1367–1378.
18.
GeschwindNNicolsonNAPeetersF. (2011a) Early improvement in positive rather than negative emotion predicts remission from depression after pharmacotherapy. Eur Neuropsychopharmacol21: 241–247.
19.
GeschwindNPeetersFDrukkerM. (2011b) Mindfulness training increases momentary positive emotions and reward experience in adults vulnerable to depression: A randomized controlled trial. J Consult Clin Psychol79: 618–628.
20.
GeschwindNPeetersFJacobsN. (2010) Meeting risk with resilience: High daily life reward experience preserves mental health. Acta Psychiatr Scand122: 129–138.
21.
GrayJA (1987) The Psychology of Fear and Stress. 2nd ed.Cambridge, UK: Cambridge University Press.
22.
HellerASJohnstoneTLightSN. (2013) Relationships between changes in sustained fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment. Am J Psychiatry170: 197–206.
23.
InselTCuthbertBGarveyM. (2010) Research Domain Criteria (RDoC): Toward a new classification framework for research on mental disorders. Am J Psychiatry167: 748–751.
24.
JamersonBDKrishnanKRRobertsJ. (2003) Effect of bupropion SR on specific symptom clusters of depression: Analysis of the 31-item Hamilton Rating Scale for depression. Psychopharmacol Bull37: 67–78.
25.
KaschKL. (2002) Behavioral activation and inhibition systems and the severity and course of depression. J Abnorm Psychol111: 589–597.
26.
KnutsonBWolkowitzOMColeSW. (1998) Selective alteration of personality and social behavior by serotonergic intervention. Am J Psychiatry155: 373–379.
27.
KozelFARaoULuH. (2011) Functional connectivity of brain structures correlates with treatment outcome in major depressive disorder. Front Psychiatry2: 1–7.
28.
LaughrenT (2001) A regulatory perspective on psychiatric syndromes in Alzheimer disease. Am J Geriat Psychiatry9: 340–345.
29.
LaughrenTLevinR (2005) Food and Drug Administration perspective on negative symptoms in schizophrenia as a target for a drug treatment claim. Schizophr Bulletin32: 220–222.
30.
LaughrenTLevinR (2011) Food and Drug Administration commentary on methodological issues in negative symptom trials. Schizophr Bull37: 255–256.
31.
LaughrenTP (2003) Comorbid mood disorders and medical illness: A Food and Drug Administration perspective. Biol Psychiatry53: 195–199.
32.
McCabeCCowenPJHarmerCJ (2009) Neural representation of reward in recovered depressed patients. Psychopharmacology (Berl)205: 667–677.
33.
McCabeCMishorZWowenPJ. (2010) Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment. Biol Psychiatry67: 439–445.
34.
McClintockSMHusainMMWisniewskiSR. (2011) Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J Clin Psychopharmacol31: 180–186.
35.
McMakinDLOlinoTMPortaG. (2012) Anhedonia predicts poorer recovery among youth with selective serotonin reuptake inhibitor treatment-resistant depression. J Am Acad Child Adolesc Psychiatry51: 404–411.
36.
MalhiGSParkerGBCrawfordJ. (2005) Treatment-resistant depression: Resistant to definition?Acta Psychiatr Scand112: 302–309.
37.
Menne-LothmannCJacobsNDeromC. (2012) Genetic and environmental causes of individual differences in daily life positive affect and reward experience and its overlap with stress-sensitivity. Behav Genet42: 778–786.
38.
MorrisSECuthbertBN (2012) Research Domain Criteria: Cognitive systems, neural circuits, and dimensions of behavior. Dialog Clin Neurosci14: 29–37.
39.
NierenbergAABentlyKHFarabaughAH. (2012) The absence of depressive symptoms is not the presence of wellness: Validation of the clinical positive affect scale. Aust NZ J Psychiatry. 46: 1165–72.
40.
NierenbergAAHusainMMTrivediMH. (2010) Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: A STAR*D report. Psychol Med40: 41–50.
41.
NuttDDemyttenaereKJankaZ. (2007) The other face of depression, reduced positive affect: The role of catecholamines in causation and cure. J Psychopharmacol21: 461–471.
42.
OlinoTMMcMakinDLDahlRE. (2011) “I won, but I’m not getting my hopes up”: Depression moderates the relationship of outcomes and reward anticipation. Psychiatr Res194: 393–395.
43.
OssewaardeLVerkesRJHermansEJ. (2011) Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits. Biol Psychiatry150: 568–574.
44.
OsuchEABluhmRLWilliamsonPC. (2009) Brain activation to favorite music in healthy controls and depressed patients. Neuroreport20: 1204–1208.
45.
PineDSCohenECohenP. (1999) Adolescent depressive symptoms as predictors of adult depression: moodiness or mood disorder?Am J Psychiatr156: 133–135.
46.
PizzagalliDAHolmesAJDillonDG. (2009) Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry166: 702–710.
47.
PriscoSEspositoE (1995) Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area. Br J Pharmacol116: 1923–1931.
48.
RobinsonOJCoolsRCarlisiCO. (2011) Ventral striatum response during reward and punishment reversal learning in unmedicated major depressive disorder. Am J Psychiatry169: 152–159.
49.
RottenbergJKaschKLGrossJJ. (2002) Sadness and amusement reactivity differentially predict concurrent and prospective functioning in Major Depressive Disorder. Emotion2: 135–146.
50.
RussoSJNestlerEJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci14; 609–625.
51.
RyffCDSingerBHDienberg LoveG (2004) Positive health: Connecting well-being with biology. Philos Trans R Soc Lond B Biol Sci29: 1383–1394.
52.
SchlaepferTECohenMXFrickC. (2008) Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology33: 368–377.
53.
ShelineYIBarchDMDonnellyJM. (2001) Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study. Biol Psychiatry50: 651–658.
54.
SheltonRCTomarkenAJ (2001) Can recovery from depression be achieved?Psychiatr Serv52: 1469–1478.
55.
SiegristJ (2008) Chronic psychosocial stress at work and risk of depression: Evidence from prospective studies. Eur Arch Psychiatry Clin Neurosci258: 115–119.
56.
SmoskiMJFelderJBizzellJ. (2009) fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder. J Affect Disord118: 69–78.
57.
SteeleJKumarPEbmeierK (2007) Blunted response to feedback information in depressive illness. Brain130: 2367.
58.
TangTZDeRubeisRJHollonSD. (2009) Personality change during depression treatment: A placebo-controlled trial. Arch Gen Psychiatry66: 1322–1330.
59.
TomarkenAJDichterGSFreidC. (2004) Assessing the effects of Bupropion SR on mood dimensions of depression. J Affect Disord78: 235–241.
60.
TreadwayMTZaldDH (2011) Reconsidering anhedonia in depression: Lessons from translational neuroscience. Neurosci Biobehav Rev35: 537–555.
61.
TreadwayMTBuckholtzJWSchwartzmanAN. (2009) Worth the ‘EEfRT’? The effort expenditure for rewards task as an objective measure of motivation and anhedonia. PLoS One4: e6598.
62.
TremblayLKNaranjoCAGrahamSJ. (2005) Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry62: 1228.
63.
UherRPerlisRHHenigsbergN. (2012a) Depression symptom dimensions as predictors of antidepressant treatment outcome: Replicable evidence for interest-activity symptoms. Psychol Med42: 967–980.
64.
UherRPerlisRHPlacentinoA. (2012b) Self-report and clinician-rated measures of depression severity: Can one replace the other?Depress Anxiety2: 1043–1049.
65.
WackerJDillonDGPizzagalliDA (2009) The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: Integration of resting EG, fMRI, and volumetric techniques. Neuroimage46: 327–337.
66.
WardenaarKJGiltayEJvan VeenT. (2012) Symptom dimensions as predictors of the two-year course of depressive and anxiety disorders. J Affect Disord136: 1198e.
67.
WatsonDClarkLA (1988) Positive and negative affectivity and their relation to anxiety and depressive disorders. J Abnorm Psychol97: 346–353.
68.
WatsonDClarkLATellegenA (1988) Development and validation of brief measures of positive and negative affect: The PANAS scales. J Pers Soc Psychol54: 1063–1070.
69.
WatsonDClarkLAWeberK. (1995a) Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J Abnorm Psychol104: 15–25.
70.
WatsonDWeberKAssenheimerJS. (1995b) Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J Abnorm Psychol104: 3–14.
71.
WichersMC. (2007) Evidence that moment-to-moment variation in positive emotions buffers genetic risk for depression: A momentary assessment twin study. Acta Psychiatr Scand115: 451–457.
72.
WichersMGeschwindNJacobsN. (2009) Transition from stress sensitivity to a depressive state: Longitudinal twin study. Br J Psychiatry195: 498–503.
73.
WichersMPeetersFGeschwindN. (2010) Unveiling patterns of affective responses in daily life may improve outcome prediction in depression: A momentary assessment study. J Affect Disord124: 191–195.
74.
WichersMMenne-LothmannCVercauterenP. (2012) Positive affect and recovery from depression. Eur Neuropsychopharmacol22: S140.
75.
WillnerP (2005) Chronic mild stress (CMS) revisited: Consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology52: 90–110.
76.
Winograd-GurvichCFitzgeraldPBGeorgiou-KaristianisN. (2006) Negative symptoms: A review of schizophrenia, melancholic depression and Parkinson’s disease. Brain Res Bull16: 312–321.
