Wikipedia

Disorders of diminished motivation

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

edit

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

edit
See also: Tetrabenazine § Animal model of motivational dysfunction

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

edit
See also: Motivation-enhancing drug

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]

edit

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.[91][92][93] 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.[94]

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.[95][96]

References

edit
  1. ^ a b c d e f g h i j k l m Marin RS, Wilkosz PA (2005). "Disorders of diminished motivation". The Journal of Head Trauma Rehabilitation. 20 (4): 377–388. doi:10.1097/00001199-200507000-00009. PMID 16030444.
  2. ^ a b c d e f g h i j k l Spiegel DR, Warren A, Takakura W, Servidio L, Leu N (January 2018). "Disorders of diminished motivation: What they are, and how to treat them" (PDF). Current Psychiatry. 17 (1): 10–18, 20.
  3. ^ a b c d e f g h i j k l m n o p q r Arnts H, van Erp WS, Lavrijsen JC, van Gaal S, Groenewegen HJ, van den Munckhof P (May 2020). "On the pathophysiology and treatment of akinetic mutism". Neuroscience and Biobehavioral Reviews. 112: 270–278. doi:10.1016/j.neubiorev.2020.02.006. hdl:2066/225901. PMID 32044373.
  4. ^ a b c d e f g h i j k l m n o Chong TT, Husain M (2016). "The role of dopamine in the pathophysiology and treatment of apathy". Motivation: Theory, Neurobiology and Applications. Progress in Brain Research. Vol. 229. pp. 389–426. doi:10.1016/bs.pbr.2016.05.007. ISBN 978-0-444-63701-7. PMID 27926449.
  5. ^ a b c d e Thant T, Yager J (September 2019). "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. doi:10.1097/NMD.0000000000000860. PMID 30256334.
  6. ^ a b c Batail JM, Palaric J, Guillery M, Gadoullet J, Sauleau P, Le Jeune F, et al. (March 2018). "Apathy and depression: Which clinical specificities?". Personalized Medicine in Psychiatry. 7–8: 21–26. doi:10.1016/j.pmip.2017.12.001.
  7. ^ a b c d e f Salamone JD, Koychev I, Correa M, McGuire P (August 2015). "Neurobiological basis of motivational deficits in psychopathology". Eur Neuropsychopharmacol. 25 (8): 1225–1238. doi:10.1016/j.euroneuro.2014.08.014. PMID 25435083.
  8. ^ a b c Lázaro-Perlado F (13 September 2019). "Apathy: A Conceptual Review". Current Psychiatry Research and Reviews. 15 (2): 88–104. doi:10.2174/1573400515666190306150306.
  9. ^ a b c d e f Salamone JD, Correa M (January 2024). "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. doi:10.1146/annurev-psych-020223-012208. PMID 37788571.
  10. ^ a b Thompson J, Stansfeld JL, Cooper RE, Morant N, Crellin NE, Moncrieff J (February 2020). "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. doi:10.1007/s00127-019-01819-2. PMID 31875238.
  11. ^ a b c d e f g h i Hailwood JM (27 September 2018). Novel Approaches Towards Pharmacological Enhancement of Motivation (Thesis). University of Cambridge. doi:10.17863/CAM.40216.
  12. ^ a b Jawad MY, Fatima M, Hassan U, Zaheer Z, Ayyan M, Ehsan M, et al. (July 2023). "Can antidepressant use be associated with emotional blunting in a subset of patients with depression? A scoping review of available literature". Human Psychopharmacology. 38 (4): e2871. doi:10.1002/hup.2871. PMID 37184083.
  13. ^ a b Masdrakis VG, Markianos M, Baldwin DS (August 2023). "Apathy associated with antidepressant drugs: a systematic review". Acta Neuropsychiatrica. 35 (4): 189–204. doi:10.1017/neu.2023.6. PMID 36644883.
  14. ^ a b Skumlien M, Langley C, Lawn W, Voon V, Curran HV, Roiser JP, et al. (November 2021). "The acute and non-acute effects of cannabis on reward processing: A systematic review". Neuroscience and Biobehavioral Reviews. 130: 512–528. doi:10.1016/j.neubiorev.2021.09.008. PMID 34509513.
  15. ^ a b Pacheco-Colón I, Limia JM, Gonzalez R (August 2018). "Nonacute effects of cannabis use on motivation and reward sensitivity in humans: A systematic review". Psychology of Addictive Behaviors. 32 (5): 497–507. doi:10.1037/adb0000380. PMC 6062456. PMID 29963875.
  16. ^ a b Skumlien M, Langley C, Sahakian BJ (19 December 2023). "Is Cannabis Use Associated with Motivation? A Review of Recent Acute and Non-Acute Studies". Current Behavioral Neuroscience Reports. 11: 33–43. doi:10.1007/s40473-023-00268-1. ISSN 2196-2979.
  17. ^ a b c Kjærsgaard T (2 January 2015). "Enhancing Motivation by Use of Prescription Stimulants: The Ethics of Motivation Enhancement". AJOB Neuroscience. 6 (1): 4–10. doi:10.1080/21507740.2014.990543. ISSN 2150-7740.
  18. ^ a b c Handelman K, Sumiya F (July 2022). "Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report". Brain Sciences. 12 (8): 959. doi:10.3390/brainsci12080959. PMC 9332474. PMID 35892400.
  19. ^ a b c d Ermer JC, Pennick M, Frick G (May 2016). "Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy". Clinical Drug Investigation. 36 (5): 341–356. doi:10.1007/s40261-015-0354-y. PMC 4823324. PMID 27021968.
  20. ^ a b Stanton BR, Carson A (February 2016). "Apathy: a practical guide for neurologists". Practical Neurology. 16 (1): 42–47. doi:10.1136/practneurol-2015-001232. PMID 26502729.
  21. ^ Boksem MA, Tops M (November 2008). "Mental fatigue: costs and benefits" (PDF). Brain Research Reviews. 59 (1): 125–139. doi:10.1016/j.brainresrev.2008.07.001. PMID 18652844.
  22. ^ Belmaker RH, Lichtenberg P (2023). "Antipsychotic Drugs: Do They Define Schizophrenia or Do They Blunt All Emotions?". Psychopharmacology Reconsidered: A Concise Guide Exploring the Limits of Diagnosis and Treatment. Cham: Springer International Publishing. pp. 63–84. doi:10.1007/978-3-031-40371-2_6. ISBN 978-3-031-40370-5.
  23. ^ Moncrieff J (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 (inactive 2024-09-17). ISBN 978-0-230-57431-1.{{cite book}}: CS1 maint: DOI inactive as of September 2024 (link)
  24. ^ Moncrieff J (2013). "The Patient's Dilemma: Other Evidence on the Effects of Antipsychotics". The Bitterest Pills. London: Palgrave Macmillan UK. pp. 113–131. doi:10.1057/9781137277442_7. ISBN 978-1-137-27743-5.
  25. ^ Moncrieff J, Cohen D, Mason JP (August 2009). "The subjective experience of taking antipsychotic medication: a content analysis of Internet data". Acta Psychiatr Scand. 120 (2): 102–111. doi:10.1111/j.1600-0447.2009.01356.x. PMID 19222405.
  26. ^ Healy D (October 1989). "Neuroleptics and psychic indifference: a review". J R Soc Med. 82 (10): 615–619. doi:10.1177/014107688908201018. PMC 1292340. PMID 2572700.
  27. ^ a b c Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE (October 2018). "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev. 70 (4): 747–762. doi:10.1124/pr.117.015107. PMC 6169368. PMID 30209181.
  28. ^ Shin EJ, Jeong JH, Hwang Y, Sharma N, Dang DK, Nguyen BT, et al. (July 2021). "Methamphetamine-induced dopaminergic neurotoxicity as a model of Parkinson's disease". Archives of Pharmacal Research. 44 (7): 668–688. doi:10.1007/s12272-021-01341-7. PMID 34286473.
  29. ^ Rashidi SK, Khodagholi F, Rafie S, Kashipazha D, Safarian H, Khoshnam SE, et al. (4 June 2024). "Methamphetamine and the brain: Emerging molecular targets and signaling pathways involved in neurotoxicity". Toxin Reviews: 1–19. doi:10.1080/15569543.2024.2360425. ISSN 1556-9543.
  30. ^ 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.
  31. ^ a b Contreras-Mora H, Rowland MA, Yohn SE, Correa M, Salamone JD (March 2018). "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. doi:10.1016/j.pbb.2018.01.001. PMID 29309800.
  32. ^ Silveira MM, Adams WK, Morena M, Hill MN, Winstanley CA (March 2017). "Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats". J Psychiatry Neurosci. 42 (2): 131–138. doi:10.1503/jpn.150363. PMC 5373702. PMID 28245177.
  33. ^ Salamone JD, Pardo M, Yohn SE, López-Cruz L, SanMiguel N, Correa M (2016). "Mesolimbic Dopamine and the Regulation of Motivated Behavior". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 27: 231–257. doi:10.1007/7854_2015_383. ISBN 978-3-319-26933-7. PMID 26323245.
  34. ^ Bhatia KP, Marsden CD (August 1994). "The behavioural and motor consequences of focal lesions of the basal ganglia in man". Brain. 117 (4): 859–876. doi:10.1093/brain/117.4.859. PMID 7922471.
  35. ^ Chung CS, Caplan LR (2012-07-12). "Caudate nucleus infarcts and hemorrhages". In Caplan LR, Gijn J (eds.). Stroke syndromes (3rd ed.). Cambridge: Cambridge University Press. pp. 397–404. doi:10.1017/cbo9781139093286.034. ISBN 978-1-139-09328-6.
  36. ^ Knoll J (2001). "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. doi:10.1111/j.1527-3458.2001.tb00202.x. PMC 6494119. PMID 11607046.
  37. ^ Knoll J (August 2003). "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochemical Research. 28 (8): 1275–1297. doi:10.1023/a:1024224311289. PMID 12834268.
  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.
  39. ^ Jones-Tabah J, Mohammad H, Paulus EG, Clarke PB, Hébert TE (2021). "The Signaling and Pharmacology of the Dopamine D1 Receptor". Frontiers in Cellular Neuroscience. 15: 806618. doi:10.3389/fncel.2021.806618. PMC 8801442. PMID 35110997.
  40. ^ Wang HJ, Chinna-Meyyappan A, Feldman OJ, Lanctôt KL (June 2024). "Emerging therapies for treatment of agitation, psychosis, or apathy in Alzheimer's disease". Expert Opinion on Emerging Drugs: 1–15. doi:10.1080/14728214.2024.2363215. PMID 38822731.
  41. ^ Dolphin H, Dyer AH, McHale C, O'Dowd S, Kennelly SP (July 2023). "An Update on Apathy in Alzheimer's Disease". Geriatrics. 8 (4): 75. doi:10.3390/geriatrics8040075. PMC 10366907. PMID 37489323.
  42. ^ a b Costello H, Husain M, Roiser JP (January 2024). "Apathy and Motivation: Biological Basis and Drug Treatment". Annu Rev Pharmacol Toxicol. 64: 313–338. 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. ^ Kings E, Ioannidis K, Grant JE, Chamberlain SR (June 2024). "A systematic review of the cognitive effects of the COMT inhibitor, tolcapone, in adult humans". CNS Spectrums. 29 (3): 166–175. doi:10.1017/S1092852924000130. PMID 38487834.
  44. ^ Paholpak P, Mendez MF (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. ^ Lanctôt KL, Agüera-Ortiz L, Brodaty H, Francis PT, Geda YE, Ismail Z, et al. (January 2017). "Apathy associated with neurocognitive disorders: Recent progress and future directions". Alzheimers Dement. 13 (1): 84–100. 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].
  46. ^ Mitaki S, Isomura M, Maniwa K, Yamasaki M, Nagai A, Nabika T, et al. (August 2013). "Apathy is associated with a single-nucleotide polymorphism in a dopamine-related gene". Neurosci Lett. 549: 87–91. doi:10.1016/j.neulet.2013.05.075. PMID 23769684.
  47. ^ Åberg E, Fandiño-Losada A, Sjöholm LK, Forsell Y, Lavebratt C (March 2011). "The functional Val158Met polymorphism in catechol-O-methyltransferase (COMT) is associated with depression and motivation in men from a Swedish population-based study". J Affect Disord. 129 (1–3): 158–166. doi:10.1016/j.jad.2010.08.009. PMID 20828831.
  48. ^ Srivastava K, Ochuba O, Sandhu JK, Alkayyali T, Ruo SW, Waqar A, et al. (September 2021). "Effect of Catechol-O-Methyltransferase Genotype Polymorphism on Neurological and Psychiatric Disorders: Progressing Towards Personalized Medicine". Cureus. 13 (9): e18311. doi:10.7759/cureus.18311. PMC 8553290. PMID 34725583.
  49. ^ Corral-Frías NS, Pizzagalli DA, Carré JM, Michalski LJ, Nikolova YS, Perlis RH, et al. (June 2016). "COMT Val(158) Met genotype is associated with reward learning: a replication study and meta-analysis". Genes Brain Behav. 15 (5): 503–513. doi:10.1111/gbb.12296. PMC 4891272. PMID 27138112.
  50. ^ Bortolato M, Walss-Bass C, Thompson PM, Moskovitz J (April 2017). "Manic symptom severity correlates with COMT activity in the striatum: A post-mortem study". World J Biol Psychiatry. 18 (3): 247–254. doi:10.1080/15622975.2016.1208844. PMC 5468118. PMID 27458023.
  51. ^ Sharif S, Guirguis A, Fergus S, Schifano F (March 2021). "The Use and Impact of Cognitive Enhancers among University Students: A Systematic Review". Brain Sci. 11 (3): 355. doi:10.3390/brainsci11030355. PMC 8000838. PMID 33802176.
  52. ^ a b Brühl AB, d'Angelo C, Sahakian BJ (2019). "Neuroethical issues in cognitive enhancement: Modafinil as the example of a workplace drug?". Brain Neurosci Adv. 3: 2398212818816018. doi:10.1177/2398212818816018. PMC 7058249. PMID 32166175.
  53. ^ Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction. 104 (7): 1085–1099. 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. ^ a b Abbas K, Barnhardt EW, Nash PL, Streng M, Coury DL (April 2024). "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. 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. ^ a b Swanson JM, Volkow ND (January 2009). "Psychopharmacology: concepts and opinions about the use of stimulant medications". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 50 (1–2): 180–193. doi:10.1111/j.1469-7610.2008.02062.x. PMC 2681087. PMID 19220601.
  56. ^ Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME (2017). "Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects". Frontiers in Pharmacology. 8: 617. doi:10.3389/fphar.2017.00617. PMC 5594082. PMID 28936175.
  57. ^ Folgering JH, Choi M, Schlumbohm C, van Gaalen MM, Stratford RE (April 2019). "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. doi:10.1016/j.jneumeth.2019.02.005. PMID 30768951.
  58. ^ van Gaalen MM, Schlumbohm C, Folgering JH, Adhikari S, Bhattacharya C, Steinbach D, et al. (April 2019). "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. doi:10.1124/jpet.118.254508. PMID 30733244.
  59. ^ Baumeister AA (2021). "Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease?". Harvard Review of Psychiatry. 29 (2): 142–158. 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. ^ Advokat C (July 2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". Journal of Attention Disorders. 11 (1): 8–16. 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. ^ Asser A, Taba P (2015). "Psychostimulants and movement disorders". Frontiers in Neurology. 6: 75. doi:10.3389/fneur.2015.00075. PMC 4403511. 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. ^ Courtney KE, Ray LA (2016). "Clinical neuroscience of amphetamine-type stimulants". Clinical neuroscience of amphetamine-type stimulants: From basic science to treatment development. Progress in Brain Research. Vol. 223. pp. 295–310. doi:10.1016/bs.pbr.2015.07.010. ISBN 978-0-444-63545-7. PMID 26806782. 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. ^ Berman SM, Kuczenski R, McCracken JT, London ED (February 2009). "Potential adverse effects of amphetamine treatment on brain and behavior: a review". Molecular Psychiatry. 14 (2): 123–142. doi:10.1038/mp.2008.90. PMC 2670101. 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. ^ Ricaurte GA, Mechan AO, Yuan J, Hatzidimitriou G, Xie T, Mayne AH, et al. (October 2005). "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. doi:10.1124/jpet.105.087916. PMID 16014752.
  65. ^ a b c Bandhu D, Mohan MM, Nittala NA, Jadhav P, Bhadauria A, Saxena KK (April 2024). "Theories of motivation: A comprehensive analysis of human behavior drivers". Acta Psychologica. 244: 104177. doi:10.1016/j.actpsy.2024.104177. PMID 38354564.
  66. ^ Allen NB, Badcock PB (July 2006). "Darwinian models of depression: a review of evolutionary accounts of mood and mood disorders". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 30 (5): 815–826. doi:10.1016/j.pnpbp.2006.01.007. PMID 16647176.
  67. ^ Nettle D, Bateson M (September 2012). "The evolutionary origins of mood and its disorders". Current Biology. 22 (17): R712–R721. Bibcode:2012CBio...22.R712N. doi:10.1016/j.cub.2012.06.020. PMID 22975002.
  68. ^ Pessiglione M, Heerema R, Daunizeau J, Vinckier F (April 2023). "Origins and consequences of mood flexibility: a computational perspective". Neuroscience and Biobehavioral Reviews. 147: 105084. doi:10.1016/j.neubiorev.2023.105084. PMID 36764635.
  69. ^ Johnson SL, Edge MD, Holmes MK, Carver CS (2012). "The behavioral activation system and mania". Annual Review of Clinical Psychology. 8: 243–267. doi:10.1146/annurev-clinpsy-032511-143148. PMC 3409638. PMID 22077912.
  70. ^ Johnson SL (February 2005). "Mania and dysregulation in goal pursuit: a review". Clinical Psychology Review. 25 (2): 241–262. doi:10.1016/j.cpr.2004.11.002. PMC 2847498. PMID 15642648.
  71. ^ Oken BS (November 2008). "Placebo effects: clinical aspects and neurobiology". Brain. 131 (Pt 11): 2812–2823. doi:10.1093/brain/awn116. PMC 2725026. PMID 18567924.
  72. ^ Hyland ME (June 2011). "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. doi:10.1098/rstb.2010.0391. PMC 3130400. PMID 21576140.
  73. ^ Düzel E, Bunzeck N, Guitart-Masip M, Düzel S (April 2010). "NOvelty-related motivation of anticipation and exploration by dopamine (NOMAD): implications for healthy aging". Neuroscience and Biobehavioral Reviews. 34 (5): 660–669. doi:10.1016/j.neubiorev.2009.08.006. PMID 19715723.
  74. ^ Rangel-Gomez M, Meeter M (January 2016). "Neurotransmitters and Novelty: A Systematic Review". Journal of Psychopharmacology. 30 (1): 3–12. doi:10.1177/0269881115612238. PMID 26601905.
  75. ^ Hollon NG, Burgeno LM, Phillips PE (October 2015). "Stress effects on the neural substrates of motivated behavior". Nature Neuroscience. 18 (10): 1405–1412. doi:10.1038/nn.4114. PMC 4721524. PMID 26404715.
  76. ^ Baik JH (December 2020). "Stress and the dopaminergic reward system". Experimental & Molecular Medicine. 52 (12): 1879–1890. doi:10.1038/s12276-020-00532-4. PMC 8080624. PMID 33257725.
  77. ^ Terenzi D (28 October 2019). "Too much, too little. Understanding the mechanisms underlying disorders of excessive and diminished motivation" (in Italian). ITA. Retrieved 3 September 2024.
  78. ^ Kalivas PW, Volkow ND (August 2005). "The neural basis of addiction: a pathology of motivation and choice". The American Journal of Psychiatry. 162 (8): 1403–1413. doi:10.1176/appi.ajp.162.8.1403. PMID 16055761.
  79. ^ Lieberman HR (2007). "Cognitive methods for assessing mental energy". Nutritional Neuroscience. 10 (5–6): 229–242. doi:10.1080/10284150701722273. PMID 18284031.
  80. ^ Badiani A, Robinson TE (September 2004). "Drug-induced neurobehavioral plasticity: the role of environmental context". Behavioural Pharmacology. 15 (5–6): 327–339. doi:10.1097/00008877-200409000-00004. PMID 15343056.
  81. ^ Badiani A, Oates MM, Day HE, Watson SJ, Akil H, Robinson TE (December 1998). "Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression: modulation by environmental novelty". The Journal of Neuroscience. 18 (24): 10579–10593. doi:10.1523/JNEUROSCI.18-24-10579.1998. PMC 6793358. PMID 9852594.
  82. ^ a b c Wagner D, Mason SG, Eastwood JD (2024). "The experience of effort in ADHD: a scoping review". Frontiers in Psychology. 15: 1349440. doi:10.3389/fpsyg.2024.1349440. PMC 11184226. PMID 38895497.
  83. ^ Smith ZR, Langberg JM (December 2018). "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. doi:10.1007/s10567-018-0268-3. PMID 30141121.
  84. ^ Barkley RA (2005). Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment (Third ed.). Guilford Publications. p. 445. ISBN 978-1-60623-750-2. Retrieved 3 August 2024.
  85. ^ Barkley RA (2014). Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment (Fourth ed.). Guilford Publications. p. 1. ISBN 978-1-4625-1772-5. Retrieved 3 August 2024.
  86. ^ Barkley RA (2022). Treating ADHD in Children and Adolescents. Guilford Publications. p. 1. ISBN 978-1-4625-4514-8. Retrieved 3 August 2024.
  87. ^ Barkley R (12 June 2023). "ADHD as Motivation Deficit Disorder". YouTube. Retrieved 3 August 2024.
  88. ^ Wasserman T, Wasserman LD (2015). "The misnomer of attention-deficit hyperactivity disorder". Applied Neuropsychology. Child. 4 (2): 116–122. doi:10.1080/21622965.2015.1005487. PMID 25751517.
  89. ^ Hinshaw SP (May 2018). "Attention Deficit Hyperactivity Disorder (ADHD): Controversy, Developmental Mechanisms, and Multiple Levels of Analysis". Annual Review of Clinical Psychology. 14: 291–316. doi:10.1146/annurev-clinpsy-050817-084917. PMID 29220204.
  90. ^ Ashinoff BK, Abu-Akel A (February 2021). "Hyperfocus: the forgotten frontier of attention". Psychological Research. 85 (1): 1–19. doi:10.1007/s00426-019-01245-8. PMC 7851038. PMID 31541305.
  91. ^ Quintero J, Gutiérrez-Casares JR, Álamo C (December 2022). "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. doi:10.1007/s40120-022-00392-2. PMC 9588136. PMID 35951288.
  92. ^ Brancati GE, Magnesa A, Acierno D, Carli M, De Rosa U, Froli A, et al. (August 2024). "Current nonstimulant medications for adults with attention-deficit/hyperactivity disorder". Expert Review of Neurotherapeutics. 24 (8): 743–759. doi:10.1080/14737175.2024.2370346. PMID 38915262.
  93. ^ Coghill D (2022). "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. Vol. 57. pp. 51–77. doi:10.1007/7854_2022_331. ISBN 978-3-031-11801-2. PMID 35503597.
  94. ^ Leichsenring F, Steinert C, Rabung S, Ioannidis JP (February 2022). "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. doi:10.1002/wps.20941. PMC 8751557. PMID 35015359. Large SMDs were found for amphetamines98, 100, 102, small to medium SMDs for methylphenidate100, 101.
  95. ^ Heaney D, Riboni G (13 February 2024). "Disease mongering, overdiagnosis, and media practices: a critical discourse analysis of sluggish cognitive tempo (SCT) and the motivational deficiency disorder (MoDeD) spoof". Text & Talk. doi:10.1515/text-2022-0197. ISSN 1860-7330.
  96. ^ Moynihan R (2006). "Scientists find new disease: Motivational deficiency disorder". BMJ. 332 (7544): 745. doi:10.1136/bmj.332.7544.745-a. PMC 1420696.
Retrieved from "https://en.wiki.x.io/w/index.php?title=Disorders_of_diminished_motivation&oldid=1252078422"