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Pro-motivational agent

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See also: Disorders of diminished motivation § Treatment

A pro-motivational agent is a drug which increases motivation.[1][2] They can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD),[3][1] as well as in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, for instance due to stroke, traumatic brain injury, or neurodegenerative diseases.[4][5] They are also used non-medically by healthy people to increase motivation and productivity, for instance in educational contexts.[6][2][7][8]

There are limited clinical data on medications in treating motivational deficits and disorders.[9][10] In any case, drugs used for pro-motivational purposes are generally dopaminergic agents, for instance dopamine reuptake inhibitors (DRIs) like methylphenidate and modafinil, dopamine releasing agents (DRAs) like amphetamine, and other dopaminergic medications.[1][2][11] Adenosine receptor antagonists, like caffeine and istradefylline, can also produce pro-motivational effects.[11][12][13][14] Acetylcholinesterase inhibitors, like donepezil, have been used as well.[15][16][4][9]

Some drugs do not appear to have pro-motivational effects and can actually produce anti-motivational effects.[1][11][17] Examples of these drugs include selective serotonin reuptake inhibitors (SSRIs),[17][18][19] selective norepinephrine reuptake inhibitors (NRIs),[17] and antipsychotics (which are dopamine receptor antagonists or partial agonists).[20][21][22][23] Cannabinoids have also been associated with motivational deficits.[24][25][26][1][27]

List of pro-motivational agents

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Dopaminergic agents

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Dopaminergic agents that have been found to produce pro-motivational effects in animals and/or humans include the following:[1][11]

A limitation of bupropion as a dopaminergic agent is that it achieves very limited clinical occupancy of the dopamine transporter (DAT).[38][39][40][41]

Dopamine D2-like receptor agonists, including pramipexole, ropinirole, rotigotine, piribedil, bromocriptine, cabergoline, pergolide, and lisuride, have also been used to treat disorders of diminished motivation in humans.[16][4][5][10][42][43][44] The clinical data on these agents for this use is very limited, but therapeutic successes have been reported.[10][43] D2-like receptor agonists are known to have sedative-like and non-rewarding effects in humans.[45][46][47] In any case, dopamine D2-like receptor antagonists, like haloperidol and other antipsychotics, are known to produce anti-motivational effects in animals[1][11][10][2] and humans.[20][21][48][49][50][51] Bromocriptine has been reported to improve anergia and motivation in humans in very limited clinical reports.[42][52][53] On the other hand, pergolide failed to show pro-motivational effects in animals.[54]

Other dopaminergic drugs that have been used or suggested in the treatment of disorders of diminished motivation include rasagiline (a selective monoamine oxidase B (MAO-B) inhibitor; but see more below), tolcapone (a centrally-acting catechol-O-methyltransferase (COMT) inhibitor), and amantadine (an indirectly acting dopaminergic agent that acts via unknown mechanisms).[10][16][55][15][56] Amantadine is widely used to treat multiple sclerosis-related fatigue, among other fatigue- and motivation-related disorders, and is recommended by the United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for this use, although clinical data are limited.[56][57][58][59][60]

Adenosinergic agents

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Adenosine receptor antagonists, including caffeine, istradefylline (KW-6002), Lu AA47070, MSX-3, MSX-4, preladenant (SCH-420814), and theophylline, have shown pro-motivational effects in animals and humans.[11][12][13][61][14][62] Caffeine and theophylline act as non-selective antagonists of the adenosine receptors (including A1, A2A, A2B, and A3).[11][63][64][65] Conversely, agents like istradefylline and preladenant are selective adenosine A2A receptor antagonists.[11] Adenosine A2A receptor antagonists, including the non-selective antagonists like caffeine, show pro-motivational effects in animals, whereas selective adenosine A1 receptor antagonists, like DPCPX and CPX, do not.[11][66] Adenosine A2A receptor antagonists appear to exert their pro-motivational effects in the nucleus accumbens core and can reverse the anti-motivational effects of dopamine D2 receptor antagonists like haloperidol in animals.[11][12][13][67][68] Istradefylline is approved in the treatment of Parkinson's disease and has been found to improve symptoms of apathy, anhedonia, and depression in people with the condition.[14][62]

Cholinergic agents

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Acetylcholinesterase inhibitors, like donepezil, rivastigmine, and galantamine, have been used in the treatment of disorders of diminished motivation.[15][16][4][9] These drugs inhibit acetylcholinesterase, which metabolizes the neurotransmitter acetylcholine, thereby increasing acetylcholine levels in the brain.[69] They are approved and used in the treatment of Alzheimer's disease and provide modest cognitive improvements in people with the disease.[69][70][71] Although acetylcholinesterase inhibitors have been used to treat disorders of diminished motivation, the muscarinic acetylcholine receptor agonist pilocarpine has actually shown anti-motivational effects in animals that can be reversed by the muscarinic acetylcholine receptor antagonist scopolamine.[67] In addition, scopolamine has been found to reverse the anti-motivational effects of the dopamine D2 receptor antagonist haloperidol in animals.[67] In any case, in spite of the preceding findings, acetylcholinesterase inhibitors have been found to be clinically effective, albeit modestly, for apathy in dementia and Parkinson's disease.[72][73][74]

Other agents

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Agomelatine, a serotonin 5-HT2C receptor antagonist and melatonin MT1 and MT2 receptor agonist, has indirect dopaminergic actions and has been suggested as a possible treatment for disorders of diminished motivation like anhedonia and abulia.[75] It has been found to be effective in the treatment of apathy in people with dementia.[76][72][77][78] The drug was also reported to reverse escitalopram-associated apathy in a case report.[75][79]

The GPR139 agonist zelatriazin (TAK-041; NBI-1065846) has shown pro-motivational effects in animals.[80][81] On the basis of these findings, it has been speculated that the drug might be useful in the treatment of apathy in humans.[80][81] Zelatriazin was under development for the treatment of anhedonia in major depressive disorder and the negative symptoms of schizophrenia and reached phase 3 clinical trials.[82][83][84] However, its development was discontinued due to lack of clinical effectiveness.[82][85]

The tumor necrosis factor α (TNF-α) monoclonal antibody infliximab has been found to increase motivation in people with depression with high inflammation (as measured by high C-reactive protein levels).[86][87] The drug has also been found to reduce symptoms of depression and anhedonia, for instance in people with high inflammation.[88][89][86]

Ineffective agents

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Norepinephrine reuptake inhibitors (NRIs) like atomoxetine and selective serotonin reuptake inhibitors (SSRIs) like escitalopram have been used and recommended in the treatment of disorders of diminished motivation.[5][15][90] However, NRIs like desipramine and atomoxetine, SSRIs like fluoxetine and citalopram, and MAO-A-inhibiting monoamine oxidase inhibitors (MAOIs) like moclobemide and pargyline have all not shown pro-motivational effects in animals.[1][11][28][91][37] In fact, these drugs can produce further motivational deficits in animals.[17][91][92][37] Serotonergic antidepressants like SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs) have also been implicated in inducing apathy and emotional blunting in humans.[18][19][93]

In contrast to selegiline, selective MAO-B inhibitors without concomitant catecholaminergic activity enhancer (CAE) actions, like rasagiline, SU-11739, and lazabemide, are poorly effective in reversing behavioral deficits induced by the dopamine depleting agent tetrabenazine in animals.[94][95]

Antipsychotics, which classically act as dopamine receptor antagonists (mostly of the D2-like receptors), are well-known as having anti-motivational effects.[1][11][20][21][48][49][51] In fact, these effects may play a key role in their effectiveness against the positive and psychotic symptoms of schizophrenia by blunting the emotions underlying delusions.[20][21][48][49][51] A novel class of antipsychotics, sometimes referred to as third-generation antipsychotics, act as dopamine D2-like receptor partial agonists instead of as pure antagonists and hence have mixed agonistic and antagonistic effects.[96][97] These drugs include aripiprazole, brexpiprazole, and cariprazine.[97] Aripiprazole has been suggested, at low doses, as a possible treatment for disorders of diminished motivation.[55] However, aripiprazole and cariprazine showed anti-motivational effects in animals and failed to reverse the motivational deficits induced by the dopamine depleting agent tetrabenazine.[23][22] Accordingly, aripiprazole reduced activation of the mesolimbic motivational pathway in humans similarly to but less robustly than haloperidol.[98][99] On the other hand, another study found that aripiprazole reversed stress-induced motivational anhedonia in animals.[100][101] Different dopamine receptor partial agonists used in schizophrenia are known to vary in their intrinsic activities at the dopamine receptors and in their profiles of effects.[102]

Some atypical DRIs, like JJC8-091, in contrast to other DRIs, are not effective in producing pro-motivational effects in animals.[103]

References

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  62. ^ a b Turner V, Husain M (2022). "Anhedonia in Neurodegenerative Diseases". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 58: 255–277. doi:10.1007/7854_2022_352. ISBN 978-3-031-09682-2. PMID 35435648. Recently, PD patients have been treated with istradefylline, an adenosine A2A receptor antagonist used for treatment of motor symptoms. The drug was given to 14 PD patients for 12 weeks, measuring anhedonia, apathy and depression using the SHAPS, Apathy Scale and BDI. On istradefylline, SHAPS, Apathy Scale and BDI scores significantly reduced from baseline scores at 4-, 8- and 12-weeks, with mean SHAPS scores at week 12 about 50% reduced from baseline scores, indicating that istradefylline reduces anhedonia (Nagayama et al. 2019). As apathy and depression rates dropped as well as anhedonia, this trial also provided evidence for the overlapping relationship between the three symptoms. [...] Taken together, there is some evidence that dopamine agonists such as pramipexole and piribedil, or the adenosine A2A receptor antagonist istradefylline can improve anhedonia and apathy in PD.
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  77. ^ Theleritis C, Siarkos K, Politis A, Smyrnis N, Papageorgiou C, Politis AM (July 2023). "A Systematic Review of Pharmacological Interventions for Apathy in Aging Neurocognitive Disorders". Brain Sci. 13 (7): 1061. doi:10.3390/brainsci13071061. PMC 10377475. PMID 37508993.
  78. ^ Callegari I, Mattei C, Benassi F, Krueger F, Grafman J, Yaldizli Ö, Sassos D, Massucco D, Scialò C, Nobili F, Serrati C, Amore M, Cocito L, Emberti Gialloreti L, Pardini M (2016). "Agomelatine Improves Apathy in Frontotemporal Dementia". Neurodegener Dis. 16 (5–6): 352–356. doi:10.1159/000445873. PMID 27229348.
  79. ^ De Berardis D, Valchera A, Fornaro M, Serroni N, Marini S, Moschetta FS, Martinotti G, Di Giannantonio M (April 2013). "Agomelatine reversal of escitalopram-induced apathy: a case report". Psychiatry Clin Neurosci. 67 (3): 190–191. doi:10.1111/pcn.12032. PMID 23581873.
  80. ^ a b Zhang R, Chen J (December 2023). "Research progress on the role of orphan receptor GPR139 in neuropsychiatric behaviours". Eur J Pharmacol. 960: 176150. doi:10.1016/j.ejphar.2023.176150. PMID 38059447. In 2021, Reichard et al., (2021) developed the GPR139 agonist TAK041, also known as NBI-1065846. TAK-041 has good physical and chemical properties, can cross the blood–brain barrier, and shows potential in preclinical studies to treat schizophrenia symptoms. Several clinical trials indicate that TAK-041 is safe and metabolically stable (Kamel et al., 2021; Reichard et al., 2021; Yin et al., 2022). Apathy is a condition characterised by a lack of motivation, emotion, or interest and is a common symptom of many psychiatric and neurological disorders. Munster et al. (2022) provided preclinical evidence supporting GPR139 agonism (using TAK-041) as a molecular mechanism for treating apathy. The research and development of TAK-041 have effectively promoted the process of de-orphaning GPR139 and its clinical application value.
  81. ^ a b Münster A, Sommer S, Kúkeľová D, Sigrist H, Koros E, Deiana S, Klinder K, Baader-Pagler T, Mayer-Wrangowski S, Ferger B, Bretschneider T, Pryce CR, Hauber W, von Heimendahl M (August 2022). "Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions". Neuropharmacology. 213: 109078. doi:10.1016/j.neuropharm.2022.109078. PMID 35561791.
  82. ^ a b "TAK 041". AdisInsight. 26 September 2023. Retrieved 26 September 2024.
  83. ^ Lu Y, Hatzipantelis CJ, Langmead CJ, Stewart GD (July 2024). "Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia". Br J Pharmacol. 181 (14): 2095–2113. doi:10.1111/bph.16221. PMID 37605621.
  84. ^ Reichard HA, Schiffer HH, Monenschein H, Atienza JM, Corbett G, Skaggs AW, Collia DR, Ray WJ, Serrats J, Bliesath J, Kaushal N, Lam BP, Amador-Arjona A, Rahbaek L, McConn DJ, Mulligan VJ, Brice N, Gaskin PL, Cilia J, Hitchcock S (August 2021). "Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia". J Med Chem. 64 (15): 11527–11542. doi:10.1021/acs.jmedchem.1c00820. PMID 34260228.
  85. ^ "Neurocrine Biosciences Provides Development Pipeline Update". Neurocrine Biosciences. 9 November 2023. Retrieved 26 September 2024. The investigational NBI-1065846, as part of the collaboration with Takeda Pharmaceutical Company Limited (Takeda), did not meet its primary endpoint in the Phase 2 TERPSIS™ study evaluating its efficacy compared to placebo in patients with anhedonia in major depressive disorder. No further development with NBI-1065846 is planned at this time.
  86. ^ a b Lee Y, Subramaniapillai M, Brietzke E, Mansur RB, Ho RC, Yim SJ, McIntyre RS (December 2018). "Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression". Ther Adv Psychopharmacol. 8 (12): 337–348. doi:10.1177/2045125318791944. PMC 6278744. PMID 30524702.
  87. ^ Treadway MT, Etuk SM, Cooper JA, Hossein S, Hahn E, Betters SA, Liu S, Arulpragasam AR, DeVries BA, Irfan N, Nuutinen MR, Wommack EC, Woolwine BJ, Bekhbat M, Kragel PA, Felger JC, Haroon E, Miller AH (September 2024). "A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation". Mol Psychiatry. doi:10.1038/s41380-024-02751-x. PMID 39289477.
  88. ^ Rahmati-Dehkordi F, Birang N, Jalalian MN, Tamtaji Z, Dadgostar E, Aschner M, Shafiee Ardestani M, Jafarpour H, Mirzaei H, Nabavizadeh F, Tamtaji OR (September 2024). "Can infliximab serve as a new therapy for neuropsychiatric symptoms?". Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-024-03397-w. PMID 39225829.
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  90. ^ Tay J, Morris RG, Markus HS (July 2021). "Apathy after stroke: Diagnosis, mechanisms, consequences, and treatment". Int J Stroke. 16 (5): 510–518. doi:10.1177/1747493021990906. PMC 8267086. PMID 33527880.
  91. ^ a b Yohn SE, Collins SL, Contreras-Mora HM, Errante EL, Rowland MA, Correa M, Salamone JD (February 2016). "Not All Antidepressants Are Created Equal: Differential Effects of Monoamine Uptake Inhibitors on Effort-Related Choice Behavior". Neuropsychopharmacology. 41 (3): 686–694. doi:10.1038/npp.2015.188. PMC 4707815. PMID 26105139.
  92. ^ Yohn SE, Errante EE, Rosenbloom-Snow A, Somerville M, Rowland M, Tokarski K, Zafar N, Correa M, Salamone JD (October 2016). "Blockade of uptake for dopamine, but not norepinephrine or 5-HT, increases selection of high effort instrumental activity: Implications for treatment of effort-related motivational symptoms in psychopathology". Neuropharmacology. 109: 270–280. doi:10.1016/j.neuropharm.2016.06.018. PMID 27329556.
  93. ^ Camino S, Strejilevich SA, Godoy A, Smith J, Szmulewicz A (July 2023). "Are all antidepressants the same? The consumer has a point". Psychological Medicine. 53 (9): 4004–4011. doi:10.1017/S0033291722000678. PMID 35346413.
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  96. ^ Lieberman JA (2004). "Dopamine partial agonists: a new class of antipsychotic". CNS Drugs. 18 (4): 251–267. doi:10.2165/00023210-200418040-00005. PMID 15015905.
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  98. ^ de Bartolomeis A, Barone A, Begni V, Riva MA (February 2022). "Present and future antipsychotic drugs: A systematic review of the putative mechanisms of action for efficacy and a critical appraisal under a translational perspective". Pharmacol Res. 176: 106078. doi:10.1016/j.phrs.2022.106078. PMID 35026403. Aripiprazole, brexpiprazole, and cariprazine are representative of a new class of APs that act as "dopamine stabilizers", namely partial agonists at D2R/D3R [16]. Partial agonists may act as functional agonists or antagonists, depending on the surrounding levels of endogenous ligand. According to this view, D2R partial agonists may act as functional antagonists within the mesolimbic system, where a hyperdopaminergic state may contribute to positive symptoms; on the other hand, they act as functional agonists in the mesocortical pathway, where extracellular dopamine levels are low, thus mitigating, or at least not worsening, negative and cognitive symptoms [17], [18]. [...]
  99. ^ Bolstad I, Andreassen OA, Groote I, Server A, Sjaastad I, Kapur S, Jensen J (December 2015). "Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study". Eur Neuropsychopharmacol. 25 (12): 2252–2261. doi:10.1016/j.euroneuro.2015.09.016. hdl:10852/50193. PMID 26476705. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups.
  100. ^ Scheggi S, De Montis MG, Gambarana C (November 2018). "Making Sense of Rodent Models of Anhedonia". Int J Neuropsychopharmacol. 21 (11): 1049–1065. doi:10.1093/ijnp/pyy083. PMC 6209858. PMID 30239762. In self-administration protocols, the schedule used to assess the motivation to work for a natural (or a drug) reward is commonly the progressive ratio (PR) schedule (Hodos, 1961) where increasing effort is required to obtain the reward as the ratio requirement progressively increases, and the last ratio completed is the breaking point. The breaking point measures the effort the animal is willing to exert to obtain the reinforcing stimulus and is then considered an index of motivation, or of the perceived reinforcing value of the stimulus. Thus, a decrease in breaking point may be regarded as a core symptom in animal models of anhedonia, although this decrease is not reliably observed in all the models. Reductions in breakpoints for sucrose have been reported in a genetic animal model of depression, the congenital learned helpless rat (Vollmayr et al., 2004), in a chronic unavoidable stress protocol in rats (Marchese et al., 2013; Scheggi et al., 2016), and in rats and mice exposed to chronic social defeat (Bergamini et al., 2016; Spierling et al., 2017). This index of reduced motivation for a natural reward can be restored to control values by treatments endowed with antidepressant and/or promotivational activity, for example, lithium, clozapine, aripiprazole, and lamotrigine (Marchese et al., 2013; Scheggi et al., 2015, 2017b; Scheggi, Pelliccia, De Montis and Gambarana, unpublished data). Conversely, exposure to the CMS model does not usually affect sucrose breaking point.
  101. ^ Scheggi S, Pelliccia T, Gambarana C, De Montis MG (February 2018). "Aripiprazole relieves motivational anhedonia in rats". J Affect Disord. 227: 192–197. doi:10.1016/j.jad.2017.10.032. PMID 29100151.
  102. ^ Keks N, Hope J, Schwartz D, McLennan H, Copolov D, Meadows G (May 2020). "Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia". CNS Drugs. 34 (5): 473–507. doi:10.1007/s40263-020-00718-4. PMID 32246399.
  103. ^ Ecevitoglu A, Meka N, Rotolo RA, Edelstein GA, Srinath S, Beard KR, Carratala-Ros C, Presby RE, Cao J, Okorom A, Newman AH, Correa M, Salamone JD (July 2024). "Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors". Neuropsychopharmacology. 49 (8): 1309–1317. doi:10.1038/s41386-024-01826-1. PMC 11224370. PMID 38429498.
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