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Abstract

Apathy is a disabling syndrome associated with poor functional outcomes that is common across a broad range of neurological and psychiatric conditions. Currently, there are no established therapies specifically for the condition, and safe and effective treatments are urgently needed. Advances in the understanding of motivation and goal-directed behavior in humans and animals have shed light on the cognitive and neurobiological mechanisms contributing to apathy, providing an important foundation for the development of new treatments. Here, we review the cognitive components, neural circuitry, and pharmacology of apathy and motivation, highlighting converging evidence of shared transdiagnostic mechanisms. Though no pharmacological treatments have yet been licensed, we summarize trials of existing and novel compounds to date, identifying several promising candidates for clinical use and avenues of future drug development.

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2024-01-23
2024-05-01
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Literature Cited

  1. 1.
    Starkstein SE, Leentjens AFG. 2008. The nosological position of apathy in clinical practice. J. Neurol. Neurosurg. Psychiatry 79:101088–92
    [Google Scholar]
  2. 2.
    Robert P, Onyike CU, Leentjens AFG, Dujardin K, Aalten P et al. 2009. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur. Psychiatry 24:298–104
    [Google Scholar]
  3. 3.
    Dickson SS, Husain M. 2022. Are there distinct dimensions of apathy? The argument for reappraisal. Cortex 149:246–56
    [Google Scholar]
  4. 4.
    Marin RS, Biedrzycki RC, Firinciogullari S. 1991. Reliability and validity of the apathy evaluation scale. Psychiatry Res. 38:2143–62
    [Google Scholar]
  5. 5.
    Foussias G, Agid O, Fervaha G, Remington G 2014. Negative symptoms of schizophrenia: clinical features, relevance to real world functioning and specificity versus other CNS disorders. Eur. Neuropsychopharmacology 24:5693–709
    [Google Scholar]
  6. 6.
    Husain M, Roiser JP. 2018. Neuroscience of apathy and anhedonia: a transdiagnostic approach. Nat. Rev. Neurosci. 19:8470–84
    [Google Scholar]
  7. 7.
    Lanctôt KL, Agüera-Ortiz L, Brodaty H, Francis PT, Geda YE et al. 2017. Apathy associated with neurocognitive disorders: recent progress and future directions. Alzheimer's Dementia 13:184–100
    [Google Scholar]
  8. 8.
    Zhao Q-F, Tan L, Wang H-F, Jiang T, Tan M-S et al. 2016. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: systematic review and meta-analysis. J. Affect. Disord. 190:264–71
    [Google Scholar]
  9. 9.
    Chow TW, Binns MA, Cummings JL, Lam I, Black SE et al. 2009. Apathy symptom profile and behavioral associations in frontotemporal dementia vs. Alzheimer's disease. Arch. Neurol. 66:7888–93
    [Google Scholar]
  10. 10.
    den Brok MGHE, van Dalen JW, van Gool WA, Moll van Charante EP, de Bie RMA, Richard E 2015. Apathy in Parkinson's disease: a systematic review and meta-analysis. Mov. Disord. 30:6759–69
    [Google Scholar]
  11. 11.
    Caeiro L, Ferro JM, Costa J. 2013. Apathy secondary to stroke: a systematic review and meta-analysis. Cerebrovasc. Dis. 35:123–39
    [Google Scholar]
  12. 12.
    Yazbek H, Norton J, Capdevielle D, Larue A, Boulenger J-P et al. 2014. The Lille Apathy Rating Scale (LARS): exploring its psychometric properties in schizophrenia. Schizophr. Res. 157:1278–84
    [Google Scholar]
  13. 13.
    Barone P, Antonini A, Colosimo C, Marconi R, Morgante L et al. 2009. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. Mov. Disord. 24:111641–49
    [Google Scholar]
  14. 14.
    Dujardin K, Sockeel P, Delliaux M, Destée A, Defebvre L. 2009. Apathy may herald cognitive decline and dementia in Parkinson's disease. Mov. Disord. 24:162391–97
    [Google Scholar]
  15. 15.
    Schiehser DM, Liu L, Lessig SL, Song DD, Obtera KM et al. 2013. Predictors of discrepancies in Parkinson's disease patient and caregiver ratings of apathy, disinhibition, and executive dysfunction before and after diagnosis. J. Int. Neuropsychol. Soc. 19:3295–304
    [Google Scholar]
  16. 16.
    Lansdall CJ, Coyle-Gilchrist ITS, Vázquez Rodríguez P, Wilcox A, Wehmann E et al. 2019. Prognostic importance of apathy in syndromes associated with frontotemporal lobar degeneration. Neurology 92:14e1547–57
    [Google Scholar]
  17. 17.
    Turner V, Husain M. 2022. Anhedonia in neurodegenerative diseases. Curr. Top. Behav. Neurosci. 58:255–77
    [Google Scholar]
  18. 18.
    Tagariello P, Girardi P, Amore M. 2009. Depression and apathy in dementia: same syndrome or different constructs? A critical review. Arch. Gerontol. Geriatr. 49:2246–49
    [Google Scholar]
  19. 19.
    Connors MH, Teixeira-Pinto A, Ames D, Woodward M, Brodaty H. 2023. Distinguishing apathy and depression in dementia: a longitudinal study. Aust. N. Z. J. Psychiatry 57:6884–94
    [Google Scholar]
  20. 20.
    Richard E, Schmand B, Eikelenboom P, Yang SC, Ligthart SA et al. 2012. Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer's disease in non-depressed subjects. Dement. Geriatr. Cogn. Disord. 33:2–3204–9
    [Google Scholar]
  21. 21.
    Le Heron C, Apps MAJ, Husain M 2018. The anatomy of apathy: a neurocognitive framework for amotivated behaviour. Neuropsychologia 118:54–67
    [Google Scholar]
  22. 22.
    Hartmann MN, Kluge A, Kalis A, Mojzisch A, Tobler PN, Kaiser S. 2015. Apathy in schizophrenia as a deficit in the generation of options for action. J. Abnorm. Psychol. 124:2309–18
    [Google Scholar]
  23. 23.
    Ang Y-S, Manohar S, Plant O, Kienast A, Le Heron C et al. 2018. Dopamine modulates option generation for behavior. Curr. Biol. 28:101561–69.e3
    [Google Scholar]
  24. 24.
    Kuzis G, Sabe L, Tiberti C, Dorrego F, Starkstein SE. 1999. Neuropsychological correlates of apathy and depression in patients with dementia. Neurology 52:71403–7
    [Google Scholar]
  25. 25.
    Faerden A, Vaskinn A, Finset A, Agartz I, Barrett EA et al. 2009. Apathy is associated with executive functioning in first episode psychosis. BMC Psychiatry 9:11
    [Google Scholar]
  26. 26.
    Montoya-Murillo G, Ibarretxe-Bilbao N, Peña J, Ojeda N. 2019. The impact of apathy on cognitive performance in the elderly. Int. J. Geriatr. Psychiatry 34:5657–65
    [Google Scholar]
  27. 27.
    de Souza LC, Volle E, Bertoux M, Czernecki V, Funkiewiez A et al. 2010. Poor creativity in frontotemporal dementia: a window into the neural bases of the creative mind. Neuropsychologia 48:133733–42
    [Google Scholar]
  28. 28.
    Salamone JD, Correa M. 2018. Neurobiology and pharmacology of activational and effort-related aspects of motivation: rodent studies. Curr. Opin. Behav. Sci. 22:114–20
    [Google Scholar]
  29. 29.
    Le Bouc R, Borderies N, Carle G, Robriquet C, Vinckier F et al. 2023. Effort avoidance as a core mechanism of apathy in frontotemporal dementia. Brain 146:2712–26
    [Google Scholar]
  30. 30.
    Le Heron C, Plant O, Manohar S, Ang Y-S, Jackson M et al. 2018. Distinct effects of apathy and dopamine on effort-based decision-making in Parkinson's disease. Brain 141:51455–69
    [Google Scholar]
  31. 31.
    McGuigan S, Zhou S-H, Brosnan MB, Thyagarajan D, Bellgrove MA, Chong TT-J. 2019. Dopamine restores cognitive motivation in Parkinson's disease. Brain 142:3719–32
    [Google Scholar]
  32. 32.
    Schmidt L, Lebreton M, Cléry-Melin M-L, Daunizeau J, Pessiglione M. 2012. Neural mechanisms underlying motivation of mental versus physical effort. PLOS Biol. 10:2e1001266
    [Google Scholar]
  33. 33.
    Le Heron C, Manohar S, Plant O, Muhammed K, Griffanti L et al. 2018. Dysfunctional effort-based decision-making underlies apathy in genetic cerebral small vessel disease. Brain 141:113193–3210
    [Google Scholar]
  34. 34.
    Saleh Y, Le Heron C, Petitet P, Veldsman M, Drew D et al. 2021. Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making. Brain 144:41247–62
    [Google Scholar]
  35. 35.
    Fervaha G, Graff-Guerrero A, Zakzanis KK, Foussias G, Agid O, Remington G 2013. Incentive motivation deficits in schizophrenia reflect effort computation impairments during cost-benefit decision-making. J. Psychiatr. Res. 47:111590–96
    [Google Scholar]
  36. 36.
    Hartmann MN, Hager OM, Reimann AV, Chumbley JR, Kirschner M et al. 2015. Apathy but not diminished expression in schizophrenia is associated with discounting of monetary rewards by physical effort. Schizophr. Bull. 41:2503–12
    [Google Scholar]
  37. 37.
    Culbreth AJ, Moran EK, Barch DM. 2018. Effort-based decision-making in schizophrenia. Curr. Opin. Behav. Sci. 22:1–6
    [Google Scholar]
  38. 38.
    Muhammed K, Manohar S, Ben Yehuda M, Chong TT-J, Tofaris G et al. 2016. Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson's disease. Brain 139:102706–21
    [Google Scholar]
  39. 39.
    Dondaine T, Philippot P, Batail J-M, Jeune FL, Sauleau P et al. 2019. Apathy alters emotional arousal in chronic schizophrenia. J. Psychiatry Neurosci. 44:154–61
    [Google Scholar]
  40. 40.
    Brehm JW, Self EA. 1989. The intensity of motivation. Annu. Rev. Psychol. 40:109–31
    [Google Scholar]
  41. 41.
    Bonaz B, Lane RD, Oshinsky ML, Kenny PJ, Sinha R et al. 2021. Diseases, disorders, and comorbidities of interoception. Trends Neurosci. 44:139–51
    [Google Scholar]
  42. 42.
    Ricciardi L, Ferrazzano G, Demartini B, Morgante F, Erro R et al. 2016. Know thyself: exploring interoceptive sensitivity in Parkinson's disease. J. Neurol. Sci. 364:110–15
    [Google Scholar]
  43. 43.
    Moretta P, Spisto M, Ausiello FP, Iodice R, De Lucia N et al. 2022. Alteration of interoceptive sensitivity: expanding the spectrum of behavioural disorders in amyotrophic lateral sclerosis. Neurol. Sci. 43:95403–10
    [Google Scholar]
  44. 44.
    Santangelo G, Vitale C, Baiano C, D'Iorio A, Longo K et al. 2018. Interoceptive processing deficit: a behavioral marker for subtyping Parkinson's disease. Parkinsonism Relat. Disord. 53:64–69
    [Google Scholar]
  45. 45.
    Bouc RL, Rigoux L, Schmidt L, Degos B, Welter M-L et al. 2016. Computational dissection of dopamine motor and motivational functions in humans. J. Neurosci. 36:256623–33
    [Google Scholar]
  46. 46.
    Renfroe JB, Bradley MM, Okun MS, Bowers D. 2016. Motivational engagement in Parkinson's disease: preparation for motivated action. Int. J. Psychophysiol. 99:24–32
    [Google Scholar]
  47. 47.
    Kirschner M, Hager OM, Bischof M, Hartmann MN, Kluge A et al. 2016. Ventral striatal hypoactivation is associated with apathy but not diminished expression in patients with schizophrenia. J. Psychiatry Neurosci. 41:3152–61
    [Google Scholar]
  48. 48.
    Halahakoon DC, Kieslich K, O'Driscoll C, Nair A, Lewis G, Roiser JP 2020. Reward-processing behavior in depressed participants relative to healthy volunteers: a systematic review and meta-analysis. JAMA Psychiatry 77:121286–95
    [Google Scholar]
  49. 49.
    Willner P. 2017. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol. Stress 6:78–93
    [Google Scholar]
  50. 50.
    Berridge KC, Robinson TE. 2003. Parsing reward. Trends Neurosci. 26:9507–13
    [Google Scholar]
  51. 51.
    Barch DM, Pagliaccio D, Luking K. 2016. Mechanisms underlying motivational deficits in psychopathology: similarities and differences in depression and schizophrenia. Behavioral Neuroscience of Motivation EH Simpson, PD Balsam 411–49. Cham, Switz: Springer
    [Google Scholar]
  52. 52.
    Jordan LL, Zahodne LB, Okun MS, Bowers D. 2013. Hedonic and behavioral deficits associated with apathy in Parkinson's disease: potential treatment implications. Mov. Disord. 28:91301–4
    [Google Scholar]
  53. 53.
    Dayan P, Niv Y. 2008. Reinforcement learning: the good, the bad and the ugly. Curr. Opin. Neurobiol. 18:2185–96
    [Google Scholar]
  54. 54.
    Jeong H, Taylor A, Floeder JR, Lohmann M, Mihalas S et al. 2022. Mesolimbic dopamine release conveys causal associations. Science 378:6626eabq6740
    [Google Scholar]
  55. 55.
    Buelow MT, Frakey LL, Grace J, Friedman JH. 2014. The contribution of apathy and increased learning trials to risky decision-making in Parkinson's disease. Arch. Clin. Neuropsychol. 29:1100–9
    [Google Scholar]
  56. 56.
    Martínez-Horta S, Pagonabarraga J, de Bobadilla RF, García-Sanchez C, Kulisevsky J. 2013. Apathy in Parkinson's disease: more than just executive dysfunction. J. Int. Neuropsychol. Soc. 19:5571–82
    [Google Scholar]
  57. 57.
    Costello H, Berry AJ, Reeves S, Weil RS, Joyce EM et al. 2022. Disrupted reward processing in Parkinson's disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry 93:5555–62
    [Google Scholar]
  58. 58.
    Strauss GP, Waltz JA, Gold JM. 2014. A review of reward processing and motivational impairment in schizophrenia. Schizophr. Bull. 40:Suppl. 2S107–16
    [Google Scholar]
  59. 59.
    Hartmann-Riemer MN, Aschenbrenner S, Bossert M, Westermann C, Seifritz E et al. 2017. Deficits in reinforcement learning but no link to apathy in patients with schizophrenia. Sci. Rep. 7:140352
    [Google Scholar]
  60. 60.
    Dowd EC, Frank MJ, Collins A, Gold JM, Barch DM. 2016. Probabilistic reinforcement learning in patients with schizophrenia: relationships to anhedonia and avolition. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 1:5460–73
    [Google Scholar]
  61. 61.
    Jarvis H, Stevenson I, Huynh AQ, Babbage E, Coxon J, Chong TT-J. 2022. Effort reinforces learning. J. Neurosci. 42:407648–58
    [Google Scholar]
  62. 62.
    Salamone JD, Koychev I, Correa M, McGuire P. 2015. Neurobiological basis of motivational deficits in psychopathology. Eur. Neuropsychopharmacol. 25:81225–38
    [Google Scholar]
  63. 63.
    Starkstein SE, Brockman S. 2018. The neuroimaging basis of apathy: empirical findings and conceptual challenges. Neuropsychologia 118:48–53
    [Google Scholar]
  64. 64.
    Adam R, Leff A, Sinha N, Turner C, Bays P et al. 2013. Dopamine reverses reward insensitivity in apathy following globus pallidus lesions. Cortex 49:51292–303
    [Google Scholar]
  65. 65.
    Bhatia KP, Marsden CD. 1994. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 117:4859–76
    [Google Scholar]
  66. 66.
    van Dalen JW, Moll van Charante EP, Nederkoorn PJ, van Gool WA, Richard E 2013. Poststroke apathy. Stroke 44:3851–60
    [Google Scholar]
  67. 67.
    Apostolova LG, Akopyan GG, Partiali N, Steiner CA, Dutton RA et al. 2007. Structural correlates of apathy in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 24:291–97
    [Google Scholar]
  68. 68.
    Tunnard C, Whitehead D, Hurt C, Wahlund LO, Mecocci P et al. 2011. Apathy and cortical atrophy in Alzheimer's disease. Int. J. Geriatr. Psychiatry 26:7741–48
    [Google Scholar]
  69. 69.
    Bruen PD, McGeown WJ, Shanks MF, Venneri A. 2008. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease. Brain 131:92455–63
    [Google Scholar]
  70. 70.
    Moon Y, Moon W-J, Kim H, Han S-H. 2014. Regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in Alzheimer's disease patients. Eur. Neurol. 71:5–6223–29
    [Google Scholar]
  71. 71.
    Gonçalves SdAB, Caramelli P, Mariano LI, Guimarães HC, Gambogi LB et al. 2020. Apathy in frontotemporal dementia is related to medial prefrontal atrophy and is independent of executive dysfunction. Brain Res. 1737:146799
    [Google Scholar]
  72. 72.
    Chua SE, Wright IC, Poline J-B, Liddle PF, Murray RM et al. 1997. Grey matter correlates of syndromes in schizophrenia: a semi-automated analysis of structural magnetic resonance images. Br. J. Psychiatry 170:5406–10
    [Google Scholar]
  73. 73.
    Mørch-Johnsen L, Nesvåg R, Faerden A, Haukvik UK, Jørgensen KN et al. 2015. Brain structure abnormalities in first-episode psychosis patients with persistent apathy. Schizophr. Res. 164:159–64
    [Google Scholar]
  74. 74.
    Galderisi S, Quarantelli M, Volpe U, Mucci A, Cassano GB et al. 2008. Patterns of structural MRI abnormalities in deficit and nondeficit schizophrenia. Schizophr. Bull. 34:2393–401
    [Google Scholar]
  75. 75.
    Ehrlich S, Yendiki A, Greve DN, Manoach DS, Ho B-C et al. 2012. Striatal function in relation to negative symptoms in schizophrenia. Psychol. Med. 42:2267–82
    [Google Scholar]
  76. 76.
    Parvizi J, Rangarajan V, Shirer WR, Desai N, Greicius MD. 2013. The will to persevere induced by electrical stimulation of the human cingulate gyrus. Neuron 80:61359–67
    [Google Scholar]
  77. 77.
    Zoon TJC, van Rooijen G, Balm GMFC, Bergfeld IO, Daams JG et al. 2021. Apathy induced by subthalamic nucleus deep brain stimulation in Parkinson's disease: a meta-analysis. Mov. Disord. 36:2317–26
    [Google Scholar]
  78. 78.
    Hauber W, Sommer S. 2009. Prefrontostriatal circuitry regulates effort-related decision making. Cereb. Cortex 19:102240–47
    [Google Scholar]
  79. 79.
    Ferenczi EA, Zalocusky KA, Liston C, Grosenick L, Warden MR et al. 2016. Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science 351:6268aac9698
    [Google Scholar]
  80. 80.
    Rudebeck PH, Walton ME, Smyth AN, Bannerman DM, Rushworth MFS. 2006. Separate neural pathways process different decision costs. Nat. Neurosci. 9:91161–68
    [Google Scholar]
  81. 81.
    Wagner S, Sebastian A, Lieb K, Tüscher O, Tadić A. 2014. A coordinate-based ALE functional MRI meta-analysis of brain activation during verbal fluency tasks in healthy control subjects. BMC Neurosci. 15:119
    [Google Scholar]
  82. 82.
    Benedek M, Jauk E, Fink A, Koschutnig K, Reishofer G et al. 2014. To create or to recall? Neural mechanisms underlying the generation of creative new ideas. NeuroImage 88:125–33
    [Google Scholar]
  83. 83.
    Pessiglione M, Vinckier F, Bouret S, Daunizeau J, Le Bouc R 2018. Why not try harder? Computational approach to motivation deficits in neuro-psychiatric diseases. Brain 141:3629–50
    [Google Scholar]
  84. 84.
    Suzuki S, Lawlor VM, Cooper JA, Arulpragasam AR, Treadway MT. 2021. Distinct regions of the striatum underlying effort, movement initiation, and effort discounting. Nat. Hum. Behav. 5:3378–88
    [Google Scholar]
  85. 85.
    Heron CL, Holroyd CB, Salamone J, Husain M. 2019. Brain mechanisms underlying apathy. J. Neurol. Neurosurg. Psychiatry 90:3302–12
    [Google Scholar]
  86. 86.
    Sun H-H, Pan P-L, Hu J-B, Chen J, Wang X-Y, Liu C-F 2020. Alterations of regional homogeneity in Parkinson's disease with “pure” apathy: a resting-state fMRI study. J. Affect. Disord. 274:792–98
    [Google Scholar]
  87. 87.
    Bortolon C, Macgregor A, Capdevielle D, Raffard S. 2018. Apathy in schizophrenia: a review of neuropsychological and neuroanatomical studies. Neuropsychologia 118:22–33
    [Google Scholar]
  88. 88.
    Jauhar S, Fortea L, Solanes A, Albajes-Eizagirre A, McKenna PJ, Radua J. 2021. Brain activations associated with anticipation and delivery of monetary reward: a systematic review and meta-analysis of fMRI studies. PLOS ONE 16:8e0255292
    [Google Scholar]
  89. 89.
    Yan C, Su L, Wang Y, Xu T, Yin D et al. 2016. Multivariate neural representations of value during reward anticipation and consummation in the human orbitofrontal cortex. Sci. Rep. 6:129079
    [Google Scholar]
  90. 90.
    Simon JJ, Biller A, Walther S, Roesch-Ely D, Stippich C et al. 2010. Neural correlates of reward processing in schizophrenia—relationship to apathy and depression. Schizophr. Res. 118:1154–61
    [Google Scholar]
  91. 91.
    Schultz W, Dayan P, Montague PR. 1997. A neural substrate of prediction and reward. Science 275:53061593–99
    [Google Scholar]
  92. 92.
    Hauser TU, Eldar E, Dolan RJ. 2017. Separate mesocortical and mesolimbic pathways encode effort and reward learning signals. PNAS 114:35E7395–404
    [Google Scholar]
  93. 93.
    Nunes EJ, Randall PA, Hart EE, Freeland C, Yohn SE et al. 2013. Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: implications for animal models of the motivational symptoms of depression. J. Neurosci. 33:4919120–30
    [Google Scholar]
  94. 94.
    Mingote S, Weber SM, Ishiwari K, Correa M, Salamone JD. 2005. Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions. Eur. J. Neurosci. 21:61749–57
    [Google Scholar]
  95. 95.
    Yohn SE, Thompson C, Randall PA, Lee CA, Müller CE et al. 2015. The VMAT-2 inhibitor tetrabenazine alters effort-related decision making as measured by the T-maze barrier choice task: reversal with the adenosine A2A antagonist MSX-3 and the catecholamine uptake blocker bupropion. Psychopharmacology 232:71313–23
    [Google Scholar]
  96. 96.
    Blundo C, Gerace C. 2015. Dopamine agonists can improve pure apathy associated with lesions of the prefrontal-basal ganglia functional system. Neurol. Sci. 36:71197–201
    [Google Scholar]
  97. 97.
    Thobois S, Lhommée E, Klinger H, Ardouin C, Schmitt E et al. 2013. Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain 136:51568–77
    [Google Scholar]
  98. 98.
    Costello H, Yamamori Y, Reeves S, Schrag A, Howard R, Roiser JP. 2023. Longitudinal decline in striatal dopamine transporter binding in Parkinson's disease: associations with apathy and anhedonia. J. Neurol. 94:10863–70
    [Google Scholar]
  99. 99.
    Pogarell O, Koch W, Karch S, Dehning S, Müller N et al. 2012. Dopaminergic neurotransmission in patients with schizophrenia in relation to positive and negative symptoms. Pharmacopsychiatry 45:Suppl. 1S36–41
    [Google Scholar]
  100. 100.
    Udo N, Hashimoto N, Toyonaga T, Isoyama T, Oyanagi Y et al. 2020. Apathy in Alzheimer's disease correlates with the dopamine transporter level in the caudate nuclei. Dement. Geriatr. Cogn. Disord. Extra 10:286–93
    [Google Scholar]
  101. 101.
    Caroff SN, Aggarwal S, Yonan C. 2018. Treatment of tardive dyskinesia with tetrabenazine or valbenazine: a systematic review. J. Comp. Eff. Res. 7:2135–48
    [Google Scholar]
  102. 102.
    Chong TT-J, Bonnelle V, Manohar S, Veromann K-R, Muhammed K et al. 2015. Dopamine enhances willingness to exert effort for reward in Parkinson's disease. Cortex 69:40–46
    [Google Scholar]
  103. 103.
    Roiser JP, Howes OD, Chaddock CA, Joyce EM, McGuire P. 2013. Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis. Schizophr. Bull. 39:61328–36
    [Google Scholar]
  104. 104.
    Korb S, Götzendorfer SJ, Massaccesi C, Sezen P, Graf I et al. 2020. Dopaminergic and opioidergic regulation during anticipation and consumption of social and nonsocial rewards. eLife 9:e55797
    [Google Scholar]
  105. 105.
    Buchel C, Miedl S, Sprenger C. 2018. Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system. eLife 7:e39648
    [Google Scholar]
  106. 106.
    Costa KM, Schoenbaum G. 2022. Dopamine. Curr. Biol. 32:15R817–24
    [Google Scholar]
  107. 107.
    Hamid AA, Pettibone JR, Mabrouk OS, Hetrick VL, Schmidt R et al. 2016. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19:1117–26
    [Google Scholar]
  108. 108.
    Hamid AA, Frank MJ, Moore CI. 2021. Wave-like dopamine dynamics as a mechanism for spatiotemporal credit assignment. Cell 184:102733–49.e16
    [Google Scholar]
  109. 109.
    Chong TT-J. 2018. Updating the role of dopamine in human motivation and apathy. Curr. Opin. Behav. Sci. 22:35–41
    [Google Scholar]
  110. 110.
    Klein MO, Battagello DS, Cardoso AR, Hauser DN, Bittencourt JC, Correa RG. 2019. Dopamine: functions, signaling, and association with neurological diseases. Cell. Mol. Neurobiol. 39:131–59
    [Google Scholar]
  111. 111.
    Swift JL, Godin AG, Doré K, Freland L, Bouchard N et al. 2011. Quantification of receptor tyrosine kinase transactivation through direct dimerization and surface density measurements in single cells. PNAS 108:177016–21
    [Google Scholar]
  112. 112.
    Espinoza S, Salahpour A, Masri B, Sotnikova TD, Messa M et al. 2011. Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor. Mol. Pharmacol. 80:3416–25
    [Google Scholar]
  113. 113.
    Chong TT-J, Husain M. 2016. The role of dopamine in the pathophysiology and treatment of apathy. Progress in Brain Research B Studer, S Knecht 389–426. Amsterdam: Elsevier
    [Google Scholar]
  114. 114.
    Beaulieu J-M, Gainetdinov RR. 2011. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 63:1182–217
    [Google Scholar]
  115. 115.
    Yohn SE, Santerre JL, Nunes EJ, Kozak R, Podurgiel SJ et al. 2015. The role of dopamine D1 receptor transmission in effort-related choice behavior: effects of D1 agonists. Pharmacol. Biochem. Behav. 135:217–26
    [Google Scholar]
  116. 116.
    Soutschek A, Kozak R, de Martinis N, Howe W, Burke CJ et al. 2020. Activation of D1 receptors affects human reactivity and flexibility to valued cues. Neuropsychopharmacology 45:5780–85
    [Google Scholar]
  117. 117.
    Trifilieff P, Feng B, Urizar E, Winiger V, Ward RD et al. 2013. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol. Psychiatry 18:91025–33
    [Google Scholar]
  118. 118.
    Eisenstein SA, Bogdan R, Chen L, Moerlein SM, Black KJ et al. 2017. Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia. J. Psychiatr. Res. 86:9–17
    [Google Scholar]
  119. 119.
    Farrar AM, Segovia KN, Randall PA, Nunes EJ, Collins LE et al. 2010. Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors. Neuroscience 166:41056–67
    [Google Scholar]
  120. 120.
    Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M. 2010. Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study. Mov. Disord. 25:101437–43
    [Google Scholar]
  121. 121.
    López-Cruz L, Salamone JD, Correa M. 2018. Caffeine and selective adenosine receptor antagonists as new therapeutic tools for the motivational symptoms of depression. Front. Pharmacol. 9:526
    [Google Scholar]
  122. 122.
    Sun X, Liu M, Xu X, Shi C, Zhang L et al. 2023. Accumbal adenosine A2A receptor inactivation biases for large and costly rewards in the effort- but not delay-based decision making. Neuropharmacology 222:109273
    [Google Scholar]
  123. 123.
    Salamone JD, Farrar AM, Font L, Patel V, Schlar DE et al. 2009. Differential actions of adenosine A1 and A2A antagonists on the effort-related effects of dopamine D2 antagonism. Behav. Brain Res. 201:1216–22
    [Google Scholar]
  124. 124.
    Favier M, Carcenac C, Savasta M, Carnicella S. 2023. Dopamine D3 receptors: a potential target to treat motivational deficits in Parkinson's disease. Curr. Top. Behav. Neurosci. 60:109–32
    [Google Scholar]
  125. 125.
    Carnicella S, Drui G, Boulet S, Carcenac C, Favier M et al. 2014. Implication of dopamine D3 receptor activation in the reversion of Parkinson's disease-related motivational deficits. Transl. Psychiatry 4:6e401
    [Google Scholar]
  126. 126.
    Purves-Tyson TD, Owens SJ, Rothmond DA, Halliday GM, Double KL et al. 2017. Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain. Transl. Psychiatry 7:1e1003
    [Google Scholar]
  127. 127.
    Sulzer D, Cragg SJ, Rice ME. 2016. Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6:3123–48
    [Google Scholar]
  128. 128.
    Karoum F, Chrapusta SJ, Egan MF. 1994. 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J. Neurochem. 63:3972–79
    [Google Scholar]
  129. 129.
    Tunbridge EM, Harrison PJ, Weinberger DR. 2006. Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol. Psychiatry 60:2141–51
    [Google Scholar]
  130. 130.
    Korn C, Akam T, Jensen KHR, Vagnoni C, Huber A et al. 2021. Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility. Mol. Psychiatry 26:127188–99
    [Google Scholar]
  131. 131.
    Richter A, de Boer L, Guitart-Masip M, Behnisch G, Seidenbecher CI, Schott BH. 2021. Motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function. J. Neural Transm. 128:111705–20
    [Google Scholar]
  132. 132.
    Mitaki S, Isomura M, Maniwa K, Yamasaki M, Nagai A et al. 2013. Apathy is associated with a single-nucleotide polymorphism in a dopamine-related gene. Neurosci. Lett. 549:87–91
    [Google Scholar]
  133. 133.
    Cools R. 2019. Chemistry of the adaptive mind: lessons from dopamine. Neuron 104:1113–31
    [Google Scholar]
  134. 134.
    Faulkner P, Deakin JFW. 2014. The role of serotonin in reward, punishment and behavioural inhibition in humans: insights from studies with acute tryptophan depletion. Neurosci. Biobehav. Rev. 46:3365–78
    [Google Scholar]
  135. 135.
    Zhou F-M, Liang Y, Salas R, Zhang L, De Biasi M, Dani JA. 2005. Corelease of dopamine and serotonin from striatal dopamine terminals. Neuron 46:165–74
    [Google Scholar]
  136. 136.
    Kapur S, Remington G 1996. Serotonin-dopamine interaction and its relevance to schizophrenia. Am. J. Psychiatry 153:4466–76
    [Google Scholar]
  137. 137.
    Bailey MR, Williamson C, Mezias C, Winiger V, Silver R et al. 2016. The effects of pharmacological modulation of the serotonin 2C receptor on goal-directed behavior in mice. Psychopharmacology 233:4615–24
    [Google Scholar]
  138. 138.
    Cools R, Nakamura K, Daw ND. 2011. Serotonin and dopamine: unifying affective, activational, and decision functions. Neuropsychopharmacology 36:198–113
    [Google Scholar]
  139. 139.
    Nakamura K, Matsumoto M, Hikosaka O. 2008. Reward-dependent modulation of neuronal activity in the primate dorsal raphe nucleus. J. Neurosci. 28:205331–43
    [Google Scholar]
  140. 140.
    Fonseca MS, Murakami M, Mainen ZF. 2015. Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing. Curr. Biol. 25:3306–15
    [Google Scholar]
  141. 141.
    Nakayama K, Sakurai T, Katsu H. 2004. Mirtazapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation. Brain Res. Bull. 63:3237–41
    [Google Scholar]
  142. 142.
    Seymour B, Daw ND, Roiser JP, Dayan P, Dolan R. 2012. Serotonin selectively modulates reward value in human decision-making. J. Neurosci. 32:175833–42
    [Google Scholar]
  143. 143.
    Roiser JP, Blackwell AD, Cools R, Clark L, Rubinsztein DC et al. 2006. Serotonin transporter polymorphism mediates vulnerability to loss of incentive motivation following acute tryptophan depletion. Neuropsychopharmacology 31:102264–72
    [Google Scholar]
  144. 144.
    Meyniel F, Goodwin GM, Deakin JW, Klinge C, MacFadyen C et al. 2016. A specific role for serotonin in overcoming effort cost. eLife 5:e17282
    [Google Scholar]
  145. 145.
    Zahodne LB, Bernal-Pacheco O, Bowers D, Ward H, Oyama G et al. 2012. Are selective serotonin reuptake inhibitors associated with greater apathy in Parkinson's disease?. J. Neuropsychiatry Clin. Neurosci. 24:3326–30
    [Google Scholar]
  146. 146.
    Poe GR, Foote S, Eschenko O, Johansen JP, Bouret S et al. 2020. Locus coeruleus: a new look at the blue spot. Nat. Rev. Neurosci. 21:11644–59
    [Google Scholar]
  147. 147.
    Mintzer J, Lanctôt KL, Scherer RW, Rosenberg PB, Herrmann N et al. 2021. Effect of methylphenidate on apathy in patients with Alzheimer disease: the ADMET 2 randomized clinical trial. JAMA Neurol. 78:111324–32
    [Google Scholar]
  148. 148.
    David MCB, Giovane MD, Liu KY, Gostick B, Rowe JB et al. 2022. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer's disease: systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry 93:101080–90
    [Google Scholar]
  149. 149.
    Varazzani C, San-Galli A, Gilardeau S, Bouret S. 2015. Noradrenaline and dopamine neurons in the reward/effort trade-off: a direct electrophysiological comparison in behaving monkeys. J. Neurosci. 35:207866–77
    [Google Scholar]
  150. 150.
    Borderies N, Bornert P, Gilardeau S, Bouret S. 2020. Pharmacological evidence for the implication of noradrenaline in effort. PLOS Biol. 18:10e3000793
    [Google Scholar]
  151. 151.
    Betts MJ, Kirilina E, Otaduy MCG, Ivanov D, Acosta-Cabronero J et al. 2019. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain 142:92558–71
    [Google Scholar]
  152. 152.
    Ye R, O'Callaghan C, Rua C, Hezemans FH, Holland N et al. 2022. Locus coeruleus integrity from 7 T MRI relates to apathy and cognition in parkinsonian disorders. Mov. Disord. 37:81663–72
    [Google Scholar]
  153. 153.
    Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. 2002. β-Blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 288:3351–57
    [Google Scholar]
  154. 154.
    Dubois M, Habicht J, Michely J, Moran R, Dolan RJ, Hauser TU. 2021. Human complex exploration strategies are enriched by noradrenaline-modulated heuristics. eLife 10:e59907
    [Google Scholar]
  155. 155.
    Cremer A, Kalbe F, Müller JC, Wiedemann K, Schwabe L. 2023. Disentangling the roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human decision-making. Neuropsychopharmacology 48:1078–86
    [Google Scholar]
  156. 156.
    Nobis L, Husain M 2021. Pharmacology of apathy. Apathy: Clinical and Neuroscientific Perspectives from Neurology and Psychiatry K Lanctot, A Aleman Oxford, UK: Oxford Univ. Press https://doi.org/10.1093/med/9780198841807.003.0013
    [Crossref] [Google Scholar]
  157. 157.
    Husain M. 2023. Noradrenergic therapies for apathy in Alzheimer's disease?. J. Neurol. Neurosurg. Psychiatry 94:93
    [Google Scholar]
  158. 158.
    Hezemans FH, Wolpe N, O'Callaghan C, Ye R, Rua C et al. 2022. Noradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes. PLOS Comput. Biol. 18:5e1010079
    [Google Scholar]
  159. 159.
    Threlfell S, Clements MA, Khodai T, Pienaar IS, Exley R et al. 2010. Striatal muscarinic receptors promote activity dependence of dopamine transmission via distinct receptor subtypes on cholinergic interneurons in ventral versus dorsal striatum. J. Neurosci. 30:93398–408
    [Google Scholar]
  160. 160.
    Thiele A. 2013. Muscarinic signaling in the brain. Annu. Rev. Neurosci. 36:271–94
    [Google Scholar]
  161. 161.
    Collins AL, Aitken TJ, Greenfield VY, Ostlund SB, Wassum KM. 2016. Nucleus accumbens acetylcholine receptors modulate dopamine and motivation. Neuropsychopharmacology 41:122830–38
    [Google Scholar]
  162. 162.
    Hailwood JM, Heath CJ, Phillips BU, Robbins TW, Saksida LM, Bussey TJ. 2019. Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation. Neuropsychopharmacology 44:61068–75
    [Google Scholar]
  163. 163.
    Krystal JH, Kane JM, Correll CU, Walling DP, Leoni M et al. 2022. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial. Lancet 400:103692210–20
    [Google Scholar]
  164. 164.
    Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. 2021. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N. Engl. J. Med. 384:8717–26
    [Google Scholar]
  165. 165.
    Azhar L, Kusumo RW, Marotta G, Lanctot KL, Herrman N. 2022. Pharmacological management of apathy in dementia. CNS Drugs 36:2143–65
    [Google Scholar]
  166. 166.
    Kita H, Kitai ST. 1988. Glutamate decarboxylase immunoreactive neurons in rat neostriatum: their morphological types and populations. Brain Res. 447:2346–52
    [Google Scholar]
  167. 167.
    Kumar J, Liddle EB, Fernandes CC, Palaniyappan L, Hall EL et al. 2020. Glutathione and glutamate in schizophrenia: a 7T MRS study. Mol. Psychiatry 25:4873–82
    [Google Scholar]
  168. 168.
    Strasser A, Luksys G, Xin L, Pessiglione M, Gruetter R, Sandi C. 2020. Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans. Neuropsychopharmacology 45:122048–57
    [Google Scholar]
  169. 169.
    Wiehler A, Branzoli F, Adanyeguh I, Mochel F, Pessiglione M. 2022. A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions. Curr. Biol. 32:163564–75.e5
    [Google Scholar]
  170. 170.
    Cochrane GD, Rizvi S, Abrantes AM, Crabtree B, Cahill J, Friedman JH. 2015. The association between fatigue and apathy in patients with either Parkinson's disease or multiple sclerosis. Parkinsonism Relat. Disord. 21:91093–95
    [Google Scholar]
  171. 171.
    Root DH, Barker DJ, Estrin DJ, Miranda-Barrientos JA, Liu B et al. 2020. Distinct signaling by ventral tegmental area glutamate, GABA, and combinatorial glutamate-GABA neurons in motivated behavior. Cell Rep. 32:9108094
    [Google Scholar]
  172. 172.
    Farrell MR, Esteban JSD, Faget L, Floresco SB, Hnasko TS, Mahler SV. 2021. Ventral pallidum GABA neurons mediate motivation underlying risky choice. J. Neurosci. 41:204500–4513
    [Google Scholar]
  173. 173.
    Farrar AM, Font L, Pereira M, Mingote S, Bunce JG et al. 2008. Forebrain circuitry involved in effort-related choice: Injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior. Neuroscience 152:2321–30
    [Google Scholar]
  174. 174.
    Ketter TA, Post RM, Theodore WH. 1999. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology 53:5 Suppl. 2S53–67
    [Google Scholar]
  175. 175.
    Lanctôt KL, Herrmann N, Rothenburg L, Eryavec G. 2007. Behavioral correlates of GABAergic disruption in Alzheimer's disease. Int. Psychogeriatr. 19:1151–58
    [Google Scholar]
  176. 176.
    Curran HV, Freeman TP, Mokrysz C, Lewis DA, Morgan CJA, Parsons LH. 2016. Keep off the grass? Cannabis, cognition and addiction. Nat. Rev. Neurosci. 17:5293–306
    [Google Scholar]
  177. 177.
    Fatahi Z, Reisi Z, Rainer G, Haghparast A, Khani A. 2018. Cannabinoids induce apathetic and impulsive patterns of choice through CB1 receptors and TRPV1 channels. Neuropharmacology 133:75–84
    [Google Scholar]
  178. 178.
    Mateo Y, Johnson KA, Covey DP, Atwood BK, Wang H-L et al. 2017. Endocannabinoid actions on cortical terminals orchestrate local modulation of dopamine release in the nucleus accumbens. Neuron 96:51112–26.e5
    [Google Scholar]
  179. 179.
    Lawn W, Freeman TP, Pope RA, Joye A, Harvey L et al. 2016. Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: an evaluation of the cannabis ‘amotivational’ hypotheses. Psychopharmacology 233:193537–52
    [Google Scholar]
  180. 180.
    Fabbri M, Ferreira JJ, Rascol O. 2022. COMT inhibitors in the management of Parkinson's disease. CNS Drugs 36:3261–82
    [Google Scholar]
  181. 181.
    Finberg JPM. 2014. Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: Focus on modulation of CNS monoamine neurotransmitter release. Pharmacol. Ther. 143:2133–52
    [Google Scholar]
  182. 182.
    Pomponi M, Loria G, Salvati S, Di Biase A, Conte G et al. 2014. DHA effects in Parkinson disease depression. Basal Ganglia 4:261–66
    [Google Scholar]
  183. 183.
    Rascol O, Fabbri M, Poewe W. 2021. Amantadine in the treatment of Parkinson's disease and other movement disorders. Lancet Neurol. 20:121048–56
    [Google Scholar]
  184. 184.
    Johannessen CU, Johannessen SI. 2003. Valproate: past, present, and future. CNS Drug Rev. 9:2199–216
    [Google Scholar]
  185. 185.
    Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O et al. 2010. Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br. J. Pharmacol. 160:2283–91
    [Google Scholar]
  186. 186.
    Sumiyoshi T, Park S, Jayathilake K, Roy A, Ertugrul A, Meltzer HY. 2007. Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr. Res. 95:1158–68
    [Google Scholar]
  187. 187.
    Fagiolini A, Comandini A, Dell'Osso MC, Kasper S. 2012. Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs 26:121033–49
    [Google Scholar]
  188. 188.
    Anttila SAK, Leinonen EVJ. 2001. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 7:3249–64
    [Google Scholar]
  189. 189.
    Walker FR. 2013. A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: Do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression?. Neuropharmacology 67:304–17
    [Google Scholar]
  190. 190.
    Johnson JW, Kotermanski SE. 2006. Mechanism of action of memantine. Curr. Opin. Pharmacol. 6:161–67
    [Google Scholar]
  191. 191.
    Trzepacz PT, Cummings J, Konechnik T, Forrester TD, Chang C et al. 2013. Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease. Int. Psychogeriatr. 25:5707–19
    [Google Scholar]
  192. 192.
    Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M et al. 2008. Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 33:92187–99
    [Google Scholar]
  193. 193.
    Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE et al. 2011. A multicenter, inpatient, Phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J. Clin. Psychopharmacol. 31:3349–55
    [Google Scholar]
  194. 194.
    Tsai GE, Yang P, Chang Y-C, Chong M-Y. 2006. D-Alanine added to antipsychotics for the treatment of schizophrenia. Biol. Psychiatry 59:3230–34
    [Google Scholar]
  195. 195.
    Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P et al. 2005. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol. Psychiatry 57:6577–85
    [Google Scholar]
  196. 196.
    Minzenberg MJ, Carter CS. 2008. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33:71477–502
    [Google Scholar]
  197. 197.
    Jenner P, Mori A, Aradi SD, Hauser RA. 2021. Istradefylline—a first generation adenosine A2A antagonist for the treatment of Parkinson's disease. Expert Rev. Neurother. 21:3317–33
    [Google Scholar]
  198. 198.
    Kaufer D. 1998. Beyond the cholinergic hypothesis: the effect of metrifonate and other cholinesterase inhibitors on neuropsychiatric symptoms in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 9:Suppl. 28–14
    [Google Scholar]
  199. 199.
    Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A et al. 2012. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N. Engl. J. Med. 366:10893–903
    [Google Scholar]
  200. 200.
    Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA. 2015. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J. Psychopharmacol. 29:5596–607
    [Google Scholar]
  201. 201.
    Nogo D, Jasrai AK, Kim H, Nasri F, Ceban F et al. 2022. The effect of ketamine on anhedonia: improvements in dimensions of anticipatory, consummatory, and motivation-related reward deficits. Psychopharmacology 239:72011–39
    [Google Scholar]
  202. 202.
    Mkrtchian A, Evans JW, Kraus C, Yuan P, Kadriu B et al. 2021. Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals. Mol. Psychiatry 26:73292–301
    [Google Scholar]
  203. 203.
    Manera V, Abrahams S, Agüera-Ortiz L, Bremond F, David R et al. 2020. Recommendations for the nonpharmacological treatment of apathy in brain disorders. Am. J. Geriatr. Psychiatry 28:4410–20
    [Google Scholar]
  204. 204.
    Bagattini C, Brignani D, Bonnì S, Quattrini G, Gasparotti R, Pievani M. 2021. Functional imaging to guide network-based TMS treatments: toward a tailored medicine approach in Alzheimer's disease. Front. Neurosci 15:687493
    [Google Scholar]
  205. 205.
    Dandekar MP, Fenoy AJ, Carvalho AF, Soares JC, Quevedo J. 2018. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol. Psychiatry 23:51094–112
    [Google Scholar]
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