Philosophy:Disorders of diminished motivation

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Short description: Group of psychiatric and neurological conditions

Disorders of diminished motivation (DDM) are a group of disorders involving diminished motivation and associated emotions.[1][2][3][4] Many different terms have been used to refer to diminished motivation.[4][1][2][3][5][6][7] Often however, a spectrum is defined encompassing apathy, abulia, and akinetic mutism, with apathy the least severe and akinetic mutism the most extreme.[1][2][3]

DDM can be caused by psychiatric disorders like depression and schizophrenia, brain injuries, strokes, and neurodegenerative diseases.[4][3][1][5] Damage to the anterior cingulate cortex and to the striatum, which includes the nucleus accumbens and caudate nucleus and is part of the mesolimbic dopamine reward pathway, have been especially associated with DDM.[3][8][4] Diminished motivation can also be induced by certain drugs, including antidopaminergic agents like antipsychotics,[9][10][4][11] selective serotonin reuptake inhibitors (SSRIs),[12][13] and cannabis, among others.[14][15][16]

DDM can be treated with dopaminergic and other activating medications, such as dopamine reuptake inhibitors, dopamine releasing agents, and dopamine receptor agonists, among others.[1][2][3][11] These kinds of drugs have also been used by healthy people to improve motivation.[17][11] A limitation of some medications used to increase motivation is development of tolerance to their effects.[18][19]

Definition

Disorders of diminished motivation (DDM) is an umbrella term referring to a group of psychiatric and neurological disorders involving diminished capacity for motivation, will, and affect.[1][2][3][4]

A multitude of terms have been used to refer to DDM of varying severities and varieties, including apathy, abulia, akinetic mutism, athymhormia, avolition, amotivation, anhedonia, psychomotor retardation, affective flattening, akrasia, and psychic akinesia (auto-activation deficit or loss of psychic self-activation), among others.[4][1][2][3][5][6][20][7] Other constructs, like fatigue, lethargy, and anergia, also overlap with the concept of DDM.[6][2][21][4][7] Alogia (poverty of speech) and asociality (lack of social interest) are associated with DDM as well.[20][7]

Often however, a spectrum of DDM is defined encompassing apathy, abulia, and akinetic mutism, with apathy being the mildest form and akinetic mutism being the most severe or extreme form.[1][2][3] Akinetic mutism involves alertness but absence of movement and speech due to profound lack of will.[1][2][3][7] People with the condition are indifferent even to biologically relevant stimuli such as pain, hunger, and thirst.[7]

Causes

Less extreme forms of DDM, for instance apathy or anhedonia, can be a symptom of psychiatric disorders and related conditions, like depression, schizophrenia, or drug withdrawal.[4][3][1][5] More extreme forms of DDM, for instance severe apathy, abulia, or akinetic mutism, can be a result of traumatic brain injury (TBI), stroke, or neurodegenerative diseases like dementia or Parkinson's disease.[4][1][2][3][5]

Reduction in motivation and affect can also be induced by certain drugs, such as dopamine receptor antagonists including D2 receptor receptor antagonists like antipsychotics (e.g., haloperidol) and metoclopramide[10][22][23][24][25][26] and D1 receptor antagonists like ecopipam,[9][27][4][11] dopamine-depleting agents like tetrabenazine and reserpine,[9][27][11] dopaminergic neurotoxins like 6-hydroxydopamine (6-OHDA) and methamphetamine,[9][27][4][28][29] serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs)[12][13][30][9] and MAO-A-inhibiting monoamine oxidase inhibitors (MAOIs),[31] and cannabis or cannabinoids (CB1 receptor agonists).[14][15][16][9][32]

Damage to a variety of brain areas have been implicated in DDM.[3] However, damage to or reduced functioning of the anterior cingulate cortex (ACC) and striatum have been especially implicated in DDM.[3][8][4] The striatum is part of the dopaminergic mesolimbic pathway, which connects the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc) of the ventral striatum and basal ganglia.[33][3][8][4] Strokes affecting other striatal and basal ganglia structures, like the caudate nucleus of the dorsal striatum, have also been associated with DDM.[34][3][35]

Treatment

DDM, like abulia and akinetic mutism, can be treated with dopaminergic and other activating medications.[1][2][3][11] These include psychostimulants and releasers or reuptake inhibitors of dopamine and/or norepinephrine like amphetamine, methylphenidate, bupropion, modafinil, and atomoxetine; D2-like dopamine receptor agonists like pramipexole, ropinirole, rotigotine, piribedil, bromocriptine, cabergoline, and pergolide; the dopamine precursor levodopa; and MAO-B-selective monoamine oxidase inhibitors (MAOIs) like selegiline and rasagiline, among others.[1][2][3][11][4] Selegiline is also a catecholaminergic activity enhancer (CAE), and this may additionally or alternatively be involved in its pro-motivational effects.[36][37][31]

The dopamine D1 receptor appears to have an important role in motivation and reward.[38] Centrally acting dopamine D1-like receptor agonists like tavapadon and razpipadon and D1 receptor positive modulators like mevidalen and glovadalen are under development for medical use, including treatment of Parkinson's disease and notably of dementia-related apathy.[39][40][41] Centrally active catechol-O-methyltransferase inhibitors (COMTIs) like tolcapone, which are likewise dopaminergic agents, have been studied in the treatment of psychiatric disorders but not in the treatment of DDM.[42][43] Genetic variants in catechol-O-methyltransferase (COMT) have been associated with motivation and apathy susceptibility,[42][44][45][46][47] as well as with reward, mood, and other neuropsychological variables.[48][49][50]

Besides in people with DDM, psychostimulants and related agents have been used non-medically to enhance motivation in healthy people, for instance in academic contexts.[17][11][51][52] This has provoked discussions on the ethics of such uses.[17][11][52]

A limitation of certain medications used to improve motivation, like psychostimulants, is development of tolerance to their effects.[18][19] Rapid acute tolerance to amphetamines is believed to be responsible for the dissociation between their relatively short durations of action (~4 hours for main desired effects) and their much longer elimination half-lives (~10 hours) and durations in the body (~2 days).[19][53][54][55][56][57][58] It appears that continually increasing or ascending concentration–time curves are beneficial for prolonging effects, which has resulted in administration multiple times per day and development of delayed- and extended-release formulations.[19][54][55] Medication holidays and breaks can be helpful in resetting tolerance.[18]

Another possible limitation of amphetamine specifically is dopaminergic neurotoxicity, which might occur even at therapeutic doses.[59][60][61][62][63][64]

Besides medications, various psychological and physiological processes, including arousal,[65] mood,[66][67][68][69][70] expectancy effects (e.g., placebo),[71][72] novelty,[73][74] psychological stress or urgency,[75][76][65] rewarding and aversive stimuli,[65] availability of rewards,[77] addiction,[78] and sleep amount,[79] among others, can also context- and/or stimulus-dependently modulate or enhance brain dopamine signaling and motivation to varying degrees. Relatedly, the psychostimulant effects of amphetamine are greatly potentiated by environmental novelty in animals.[80][81]

Attention deficit hyperactivity disorder (ADHD) often involves motivational deficits,[82][83] and the ADHD academic Russell Barkley has referred to the condition as a "motivational deficit disorder" in various publications and presentations.[84][85][86][87] However, ADHD has perhaps more accurately been conceptualized as a disorder of executive function and of directing or allocating attention and motivation rather than a global deficiency in these processes.[82][88][89] People with ADHD are often highly motivated towards stimuli that interest them, not uncommonly experiencing a flow-like state called hyperfocus while engaging such stimuli.[90][82] In any case, as with management of DDM, psychostimulants and other catecholaminergic agents are used in people with ADHD to treat their symptoms, including difficulties with attention, executive control, and motivation, and are clinically effective for such purposes.[91][92][93][94][95] Amphetamines in the treatment of ADHD appear to have among the largest effect sizes in terms of effectiveness of any interventions (medications or forms of psychotherapy) used in the management of psychiatric disorders generally.[96]

DDM (and ADHD) should not be confused with "motivational deficiency disorder" ("MoDeD"; "extreme laziness"), a fake or spoof disease created for humorous purposes in 2006 to raise awareness about disease mongering, overdiagnosis, and medicalization.[97][98]

See also

  • Motivation-enhancing drug

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "Disorders of diminished motivation". The Journal of Head Trauma Rehabilitation 20 (4): 377–388. 2005. doi:10.1097/00001199-200507000-00009. PMID 16030444. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "Disorders of diminished motivation: What they are, and how to treat them". Current Psychiatry 17 (1): 10–18, 20. January 2018. https://cdn.mdedge.com/files/s3fs-public/Document/December-2017/CP01701010.PDF. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 "On the pathophysiology and treatment of akinetic mutism". Neuroscience and Biobehavioral Reviews 112: 270–278. May 2020. doi:10.1016/j.neubiorev.2020.02.006. PMID 32044373. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 "The role of dopamine in the pathophysiology and treatment of apathy". Motivation: Theory, Neurobiology and Applications. Progress in Brain Research. 229. 2016. pp. 389–426. doi:10.1016/bs.pbr.2016.05.007. ISBN 978-0-444-63701-7. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Updating Apathy: Using Research Domain Criteria to Inform Clinical Assessment and Diagnosis of Disorders of Motivation". The Journal of Nervous and Mental Disease 207 (9): 707–714. September 2019. doi:10.1097/NMD.0000000000000860. PMID 30256334. 
  6. ↑ 6.0 6.1 6.2 "Apathy and depression: Which clinical specificities?". Personalized Medicine in Psychiatry 7-8: 21–26. March 2018. doi:10.1016/j.pmip.2017.12.001. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Neurobiological basis of motivational deficits in psychopathology". Eur Neuropsychopharmacol 25 (8): 1225–1238. August 2015. doi:10.1016/j.euroneuro.2014.08.014. PMID 25435083. 
  8. ↑ 8.0 8.1 8.2 "Apathy: A Conceptual Review". Current Psychiatry Research and Reviews 15 (2): 88–104. 13 September 2019. doi:10.2174/1573400515666190306150306. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine". Annu Rev Psychol 75: 1–32. January 2024. doi:10.1146/annurev-psych-020223-012208. PMID 37788571. 
  10. ↑ 10.0 10.1 "Experiences of taking neuroleptic medication and impacts on symptoms, sense of self and agency: a systematic review and thematic synthesis of qualitative data". Soc Psychiatry Psychiatr Epidemiol 55 (2): 151–164. February 2020. doi:10.1007/s00127-019-01819-2. PMID 31875238. 
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  13. ↑ 13.0 13.1 "Apathy associated with antidepressant drugs: a systematic review". Acta Neuropsychiatrica 35 (4): 189–204. August 2023. doi:10.1017/neu.2023.6. PMID 36644883. https://eprints.soton.ac.uk/474930/1/Manuscript_ACN_22_2004_hide_DSB_071222.docx. 
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  17. ↑ 17.0 17.1 17.2 "Enhancing Motivation by Use of Prescription Stimulants: The Ethics of Motivation Enhancement". AJOB Neuroscience 6 (1): 4–10. 2 January 2015. doi:10.1080/21507740.2014.990543. ISSN 2150-7740. 
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  19. ↑ 19.0 19.1 19.2 19.3 "Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy". Clinical Drug Investigation 36 (5): 341–356. May 2016. doi:10.1007/s40261-015-0354-y. PMID 27021968. 
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  21. ↑ "Mental fatigue: costs and benefits". Brain Research Reviews 59 (1): 125–139. November 2008. doi:10.1016/j.brainresrev.2008.07.001. PMID 18652844. https://pure.rug.nl/ws/files/31814601/Summary.pdf. 
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  23. ↑ Moncrieff, Joanna (2007). "What Do Neuroleptics Really Do? A Drug-Centred Account". The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment. Palgrave Macmillan London. pp. 100–117. doi:10.1007/978-0-230-58944-5_7. ISBN 978-0-230-57431-1. 
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  31. ↑ 31.0 31.1 "Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions". Pharmacol Biochem Behav 166: 13–20. March 2018. doi:10.1016/j.pbb.2018.01.001. PMID 29309800. 
  32. ↑ "Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats". J Psychiatry Neurosci 42 (2): 131–138. March 2017. doi:10.1503/jpn.150363. PMID 28245177. 
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  36. ↑ "Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP, a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain"]. CNS Drug Reviews 7 (3): 317–345. 2001. doi:10.1111/j.1527-3458.2001.tb00202.x. PMID 11607046. 
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  38. ↑ Witt K (November 2023). Unravelling the Role of the Dopamine D1 Receptor in Anhedonia, Asociality, and Avolition (Thesis). Victoria University of Wellington Library. doi:10.26686/wgtn.24646128.
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  42. ↑ 42.0 42.1 "Apathy and Motivation: Biological Basis and Drug Treatment". Annu Rev Pharmacol Toxicol 64: 313–338. January 2024. doi:10.1146/annurev-pharmtox-022423-014645. PMID 37585659. "Synaptic clearance mechanisms also mediate dopamine's function and vary across corticostriatal regions (127). For example, in the [ventral striatum (VS)], rapid recycling via [dopamine transporter (DAT)] predominates (127). In contrast, in the [prefrontal cortex (PFC)], DAT recycling is minimal and enzymatic degradation by catecholO-methyltransferase (COMT) is the primary mechanism for clearance, modulating evoked dopamine release measured over minutes (128–130). Reinforcement learning and apathy have both been associated with functional polymorphisms in COMT (131, 132). [...] COMT inhibitors: COMT is a catecholamine-degrading enzyme. Enzymatic degradation by COMT is the primary mechanism for synaptic dopamine clearance in the prefrontal cortex. COMT inhibitors increase cortical dopamine by inhibiting this key catabolic pathway either directly within the brain (tolcapone) or peripherally (180).". 
  43. ↑ "A systematic review of the cognitive effects of the COMT inhibitor, tolcapone, in adult humans". CNS Spectrums 29 (3): 166–175. June 2024. doi:10.1017/S1092852924000130. PMID 38487834. 
  44. ↑ Paholpak, Pongsatorn; Mendez, Mario F. (2016). "Apathy". Genomics, Circuits, and Pathways in Clinical Neuropsychiatry. Elsevier. pp. 327–344. doi:10.1016/b978-0-12-800105-9.00021-4. ISBN 978-0-12-800105-9. "There are limited numbers of studies on the genetics of apathy. Although dopaminergic neurons have been the center of attention in studies on the motivation system for many years, a correlation between dopamine-related genes and severity of apathy is not established. The only positive genetic association came from a study of 963 healthy participants, 213 of whom had apathy, which showed an association between the single nucleotide polymorphism (SNP) in the catechol-Omethyltransferase (COMT) gene (rs4680) and a lower risk of apathy (Mitaki et al., 2013). The authors concluded that the SNP in the COMT gene leads to a reduction in COMT activity and increased dopamine in the PFC. Those with apathy also had more severe depression, so it was possible that this gene affected not only motivation but also the mood state (Mitaki et al., 2013) (Table 21.1)." 
  45. ↑ "Apathy associated with neurocognitive disorders: Recent progress and future directions". Alzheimers Dement 13 (1): 84–100. January 2017. doi:10.1016/j.jalz.2016.05.008. PMID 27362291. "Studies relating to other hypothesized genetic correlates of apathy, such as the catechol-O-methyl transferase (COMT) gene, a dopamine-related gene, have been similarly inconclusive. Although a number of authors have reported no association in AD patients [116,119], a recent casecontrol study in neurologically normal subjects found that a single-nucleotide polymorphism in the COMT gene (rs4680) was associated with a lower risk for apathy [120].". 
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  50. ↑ "Manic symptom severity correlates with COMT activity in the striatum: A post-mortem study". World J Biol Psychiatry 18 (3): 247–254. April 2017. doi:10.1080/15622975.2016.1208844. PMID 27458023. 
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  52. ↑ 52.0 52.1 "Neuroethical issues in cognitive enhancement: Modafinil as the example of a workplace drug?". Brain Neurosci Adv 3. 2019. doi:10.1177/2398212818816018. PMID 32166175. 
  53. ↑ "A review of the clinical pharmacology of methamphetamine". Addiction 104 (7): 1085–1099. July 2009. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289. "Metabolism does not appear to be altered by chronic exposure, thus dose escalation appears to arise from pharmacodynamic rather than pharmacokinetic tolerance [24]. [...] The terminal plasma half-life of methamphetamine of approximately 10 hours is similar across administration routes, but with substantial inter-individual variability. Acute effects persist for up to 8 hours following a single moderate dose of 30 mg [30]. [...] peak plasma methamphetamine concentration occurs after 4 hours [35]. Nevertheless, peak cardiovascular and subjective effects occur rapidly (within 5–15 minutes). The dissociation between peak plasma concentration and clinical effects indicates acute tolerance, which may reflect rapid molecular processes such as redistribution of vesicular monoamines and internalization of monoamine receptors and transporters [6,36]. Acute subjective effects diminish over 4 hours, while cardiovascular effects tend to remain elevated. This is important, as the marked acute tachyphylaxis to subjective effects may drive repeated use within intervals of 4 hours, while cardiovascular risks may increase [11,35].". 
  54. ↑ 54.0 54.1 "A review of amphetamine extended release once-daily options for the management of attention-deficit hyperactivity disorder". Expert Review of Neurotherapeutics 24 (4): 421–432. April 2024. doi:10.1080/14737175.2024.2321921. PMID 38391788. "For several decades, clinical benefits of amphetamines have been limited by the pharmacologic half-life of around 4 hours. Although higher doses can produce higher maximum concentrations, they do not affect the half-life of the dose. Therefore, to achieve longer durations of effect, stimulants had to be dosed at least twice daily. Further, these immediate-release doses were found to have their greatest effect shortly after administration, with a rapid decline in effect after reaching peak blood concentrations. The clinical correlation of this was found in comparing math problems attempted and solved between a mixed amphetamine salts preparation (MAS) 10 mg once at 8 am vs 8 am followed by 12 pm [14]. The study also demonstrated the phenomenon of acute tolerance, where even if blood concentrations were maintained over the course of the day, clinical efficacy in the form of math problems attempted and solved would diminish over the course of the day. These findings eventually led to the development of a once daily preparation (MAS XR) [15], which is a composition of 50% immediate-release beads and 50% delayed release beads intended to mimic this twice-daily dosing with only a single administration.". 
  55. ↑ 55.0 55.1 "Psychopharmacology: concepts and opinions about the use of stimulant medications". Journal of Child Psychology and Psychiatry, and Allied Disciplines 50 (1–2): 180–193. January 2009. doi:10.1111/j.1469-7610.2008.02062.x. PMID 19220601. 
  56. ↑ "Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects". Frontiers in Pharmacology 8: 617. 2017. doi:10.3389/fphar.2017.00617. PMID 28936175. 
  57. ↑ "Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response". Journal of Neuroscience Methods 317: 71–81. April 2019. doi:10.1016/j.jneumeth.2019.02.005. PMID 30768951. 
  58. ↑ "Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine". The Journal of Pharmacology and Experimental Therapeutics 369 (1): 107–120. April 2019. doi:10.1124/jpet.118.254508. PMID 30733244. 
  59. ↑ "Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease?". Harvard Review of Psychiatry 29 (2): 142–158. 2021. doi:10.1097/HRP.0000000000000283. PMID 33560690. "It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 [...] An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine.". 
  60. ↑ "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". Journal of Attention Disorders 11 (1): 8–16. July 2007. doi:10.1177/1087054706295605. PMID 17606768. "Recently, however, new data from Ricaurte et al. (2005) indicate that primates may be much more susceptible than rats to AMPH-induced neurotoxicity. They examined the effect of the drug in adult baboons and squirrel monkeys, as clinically used to treat ADHD. In the first two studies, baboons were trained to orally selfadminister a mixture of AMPH salts (a 3:1 ratio of dextro [S(+)] and levo [R(-)] AMPH, which simulated a common formulation for ADHD treatment). AMPH was administered twice daily for approximately 4 weeks at escalating doses of 2.5 to 20 mg (0.67 to 1.00 mg/kg). During the second study, plasma AMPH concentrations were determined at the end of each week. In the third study, AMPH was administered by orogastric gavage to squirrel monkeys and doses were adjusted (to 0.58-0.68 mg/kg) so that for approximately the last 3 weeks plasma drug concentrations were comparable to those reported in clinical populations of children receiving chronic AMPH treatment—100 to 150 ng/ml (McGough et al., 2003). Measurements in all three investigations were taken 2 to 4 weeks after drug treatment. Results from the first two studies showed significant reductions in striatal dopamine concentration, dopamine transporter density, and vesicular monoamine transporter sites. Plasma AMPH concentration at the end of the 4 week treatment period was 168 ± 25 ng/ml. In squirrel monkeys, brain dopamine concentrations and vesicular transporter sites were also significantly reduced although dopamine transporter decreases were not statistically significant. These results raise obvious concerns about clinical drug treatment of ADHD, although extrapolation to human populations may be premature until possible species differences in mechanism of action, developmental variables, or metabolism are determined.". 
  61. ↑ "Psychostimulants and movement disorders". Frontiers in Neurology 6: 75. 2015. doi:10.3389/fneur.2015.00075. PMID 25941511. "Amphetamine treatment similar to that used for ADHD has been demonstrated to produce brain dopaminergic neurotoxicity in primates, causing the damage of dopaminergic nerve endings in the striatum that may also occur in other disorders with long-term amphetamine treatment (57).". 
  62. ↑ "Clinical neuroscience of amphetamine-type stimulants". Clinical neuroscience of amphetamine-type stimulants: From basic science to treatment development. Progress in Brain Research. 223. 2016. pp. 295–310. doi:10.1016/bs.pbr.2015.07.010. ISBN 978-0-444-63545-7. "Repeated exposure to moderate to high levels of methamphetamine has been related to neurotoxic effects on the dopaminergic and serotonergic systems, leading to potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and Melega, 2002). Preclinical evidence suggests that d-amphetamine, even when administered at commonly prescribed therapeutic doses, also results in toxicity to brain dopaminergic axon terminals (Ricaurte et al., 2005)." 
  63. ↑ "Potential adverse effects of amphetamine treatment on brain and behavior: a review". Molecular Psychiatry 14 (2): 123–142. February 2009. doi:10.1038/mp.2008.90. PMID 18698321. "Though the paradigm used by Ricaurte et al. 53 arguably still incorporates amphetamine exposure at a level above much clinical use,14,55 it raises important unanswered questions. Is there a threshold of amphetamine exposure above which persistent changes in the dopamine system are induced? [...]". 
  64. ↑ "Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates". The Journal of Pharmacology and Experimental Therapeutics 315 (1): 91–98. October 2005. doi:10.1124/jpet.105.087916. PMID 16014752. 
  65. ↑ 65.0 65.1 65.2 "Theories of motivation: A comprehensive analysis of human behavior drivers". Acta Psychologica 244. April 2024. doi:10.1016/j.actpsy.2024.104177. PMID 38354564. 
  66. ↑ "Darwinian models of depression: a review of evolutionary accounts of mood and mood disorders". Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (5): 815–826. July 2006. doi:10.1016/j.pnpbp.2006.01.007. PMID 16647176. 
  67. ↑ "The evolutionary origins of mood and its disorders". Current Biology 22 (17): R712–R721. September 2012. doi:10.1016/j.cub.2012.06.020. PMID 22975002. Bibcode: 2012CBio...22.R712N. 
  68. ↑ "Origins and consequences of mood flexibility: a computational perspective". Neuroscience and Biobehavioral Reviews 147. April 2023. doi:10.1016/j.neubiorev.2023.105084. PMID 36764635. 
  69. ↑ "The behavioral activation system and mania". Annual Review of Clinical Psychology 8: 243–267. 2012. doi:10.1146/annurev-clinpsy-032511-143148. PMID 22077912. 
  70. ↑ "Mania and dysregulation in goal pursuit: a review". Clinical Psychology Review 25 (2): 241–262. February 2005. doi:10.1016/j.cpr.2004.11.002. PMID 15642648. 
  71. ↑ "Placebo effects: clinical aspects and neurobiology". Brain 131 (Pt 11): 2812–2823. November 2008. doi:10.1093/brain/awn116. PMID 18567924. 
  72. ↑ "Motivation and placebos: do different mechanisms occur in different contexts?". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 366 (1572): 1828–1837. June 2011. doi:10.1098/rstb.2010.0391. PMID 21576140. 
  73. ↑ "NOvelty-related motivation of anticipation and exploration by dopamine (NOMAD): implications for healthy aging". Neuroscience and Biobehavioral Reviews 34 (5): 660–669. April 2010. doi:10.1016/j.neubiorev.2009.08.006. PMID 19715723. 
  74. ↑ "Neurotransmitters and Novelty: A Systematic Review". Journal of Psychopharmacology 30 (1): 3–12. January 2016. doi:10.1177/0269881115612238. PMID 26601905. 
  75. ↑ "Stress effects on the neural substrates of motivated behavior". Nature Neuroscience 18 (10): 1405–1412. October 2015. doi:10.1038/nn.4114. PMID 26404715. 
  76. ↑ "Stress and the dopaminergic reward system". Experimental & Molecular Medicine 52 (12): 1879–1890. December 2020. doi:10.1038/s12276-020-00532-4. PMID 33257725. 
  77. ↑ "Too much, too little. Understanding the mechanisms underlying disorders of excessive and diminished motivation." (in it). ITA. 28 October 2019. https://iris.sissa.it/handle/20.500.11767/103954. 
  78. ↑ "The neural basis of addiction: a pathology of motivation and choice". The American Journal of Psychiatry 162 (8): 1403–1413. August 2005. doi:10.1176/appi.ajp.162.8.1403. PMID 16055761. 
  79. ↑ "Cognitive methods for assessing mental energy". Nutritional Neuroscience 10 (5–6): 229–242. 2007. doi:10.1080/10284150701722273. PMID 18284031. 
  80. ↑ "Drug-induced neurobehavioral plasticity: the role of environmental context". Behavioural Pharmacology 15 (5–6): 327–339. September 2004. doi:10.1097/00008877-200409000-00004. PMID 15343056. 
  81. ↑ "Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression: modulation by environmental novelty". The Journal of Neuroscience 18 (24): 10579–10593. December 1998. doi:10.1523/JNEUROSCI.18-24-10579.1998. PMID 9852594. 
  82. ↑ 82.0 82.1 82.2 "The experience of effort in ADHD: a scoping review". Frontiers in Psychology 15. 2024. doi:10.3389/fpsyg.2024.1349440. PMID 38895497. 
  83. ↑ "Review of the Evidence for Motivation Deficits in Youth with ADHD and Their Association with Functional Outcomes". Clin Child Fam Psychol Rev 21 (4): 500–526. December 2018. doi:10.1007/s10567-018-0268-3. PMID 30141121. 
  84. ↑ Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment (Third ed.). Guilford Publications. 2005. p. 445. ISBN 978-1-60623-750-2. https://books.google.com/books?id=4Fvt6X3Xd-UC&pg=PT445. Retrieved 3 August 2024. 
  85. ↑ Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment (Fourth ed.). Guilford Publications. 2014. p. 1. ISBN 978-1-4625-1772-5. https://books.google.com/books?id=0J0gBQAAQBAJ&pg=PP1. Retrieved 3 August 2024. 
  86. ↑ Treating ADHD in Children and Adolescents. Guilford Publications. 2022. p. 1. ISBN 978-1-4625-4514-8. https://books.google.com/books?id=fLCFEAAAQBAJ&pg=PP1. Retrieved 3 August 2024. 
  87. ↑ "ADHD as Motivation Deficit Disorder". 12 June 2023. https://www.youtube.com/watch?v=bR3RJU6838c. 
  88. ↑ "The misnomer of attention-deficit hyperactivity disorder". Applied Neuropsychology. Child 4 (2): 116–122. 2015. doi:10.1080/21622965.2015.1005487. PMID 25751517. 
  89. ↑ "Attention Deficit Hyperactivity Disorder (ADHD): Controversy, Developmental Mechanisms, and Multiple Levels of Analysis". Annual Review of Clinical Psychology 14: 291–316. May 2018. doi:10.1146/annurev-clinpsy-050817-084917. PMID 29220204. 
  90. ↑ "Hyperfocus: the forgotten frontier of attention". Psychological Research 85 (1): 1–19. February 2021. doi:10.1007/s00426-019-01245-8. PMID 31541305. 
  91. ↑ "Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review". Neurology and Therapy 11 (4): 1489–1517. December 2022. doi:10.1007/s40120-022-00392-2. PMID 35951288. 
  92. ↑ "Current nonstimulant medications for adults with attention-deficit/hyperactivity disorder". Expert Review of Neurotherapeutics 24 (8): 743–759. August 2024. doi:10.1080/14737175.2024.2370346. PMID 38915262. 
  93. ↑ "The Benefits and Limitations of Stimulants in Treating ADHD". New Discoveries in the Behavioral Neuroscience of Attention-Deficit Hyperactivity Disorder. Current Topics in Behavioral Neurosciences. 57. 2022. pp. 51–77. doi:10.1007/7854_2022_331. ISBN 978-3-031-11801-2. 
  94. ↑ "Amphetamines Improve the Motivation to Invest Effort in Attention-Deficit/Hyperactivity Disorder". J Neurosci 43 (41): 6898–6908. October 2023. doi:10.1523/JNEUROSCI.0982-23.2023. PMID 37666665. 
  95. ↑ "Stimulant medications affect arousal and reward, not attention networks". Cell 188 (26): 7529–7546.e20. December 2025. doi:10.1016/j.cell.2025.11.039. PMID 41448140. 
  96. ↑ "The efficacy of psychotherapies and pharmacotherapies for mental disorders in adults: an umbrella review and meta-analytic evaluation of recent meta-analyses". World Psychiatry 21 (1): 133–145. February 2022. doi:10.1002/wps.20941. PMID 35015359. "Large SMDs were found for amphetamines98, 100, 102, small to medium SMDs for methylphenidate100, 101.". 
  97. ↑ "Disease mongering, overdiagnosis, and media practices: a critical discourse analysis of sluggish cognitive tempo (SCT) and the motivational deficiency disorder (MoDeD) spoof". Text & Talk 45 (2): 207–226. 13 February 2024. doi:10.1515/text-2022-0197. ISSN 1860-7330. 
  98. ↑ "Scientists find new disease: Motivational deficiency disorder". BMJ 332 (7544): 745. 2006. doi:10.1136/bmj.332.7544.745-a. 



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