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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

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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

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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

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  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.
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  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.
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  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).
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