Wikipedia

Draft:Disorders of diminished motivation

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, and psychic akinesia (auto-activation deficit or loss of psychic self-activation), among others.[4][1][2][3][5][6] Other constructs, like fatigue, lethargy, and anergia, also overlap with the concept of DDM.[6][2][7][4]

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 complete inability to move or speak due to absence of will.[1][2][3]

Causes

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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 like antipsychotics (e.g., haloperidol) and ecopipam,[4][8] dopamine-depleting agents like tetrabenazine,[8] dopaminergic neurotoxins like oxidopamine (6-hydroxydopamine; 6-OHDA),[4] serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs),[9][10][11] and cannabis or cannabinoids.[12][13][14]

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][15][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.[3][15][4] Strokes affecting other striatal and basal ganglia structures, like the caudate nucleus of the dorsal striatum, have also been associated with DDM.[16][3][17]

Treatment

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DDM, like abulia and akinetic mutism, can be treated with dopaminergic and other activating medications.[1][2][3][8] 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 monoamine oxidase inhibitors (MAOIs) like selegiline and rasagiline, among others.[1][2][3][8][4] Selegiline is also a catecholaminergic activity enhancer (CAE), and this may additionally or alternatively be involved in its possible pro-motivational effects.[18][19]

Centrally acting D1-like dopamine receptor agonists and positive modulators, like mevidalen (LY-3154207), tavapadon (CVL-751, PF-06649751), and razpipadon (CVL-871), are also under development for medical use, including treatment of dementia-related apathy.[20][21][22] Centrally active catechol-O-methyltransferase inhibitors (COMTIs) like tolcapone have been studied in the treatment of psychiatric disorders but not in the treatment of DDM.[23]

Besides DDM, psychostimulants and related agents have been used non-medically to enhance motivation in healthy people, for instance in academic contexts.[24][8] This has provoked discussions on the ethics of such uses.[24][8]

Preclinical and clinical data on the effectiveness of drugs in enhancing motivation and treating DDM has been reviewed.[8][4]

A limitation of medications used to improve motivation, like psychostimulants, is development of tolerance to their effects.[25][26] Rapid acute tolerance to amphetamines is believed to be responsible for the dissociation between their relatively short durations of action (~4 hours for main effects) and their much longer elimination half-lives (~10 hours) and durations in the body (~2 days).[26][27][28][29][30][31][32] 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.[26][28][29] Medication holidays and breaks can be helpful in resetting tolerance.[25]

Besides medications, various psychological and physiological processes, including arousal,[33] mood,[34][35][36][37][38] expectancy effects (e.g., placebo),[39][40] novelty,[41][42] psychological stress or urgency,[43][44][33] rewarding and aversive stimuli,[33] addiction,[45] and sleep amount,[46] among others, can also context- and/or stimulus-dependently modulate or enhance brain dopamine signaling and motivation to varying degrees.

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DDM 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.[47][48]

On the other hand, attention deficit hyperactivity disorder (ADHD) often involves motivational deficits, and the ADHD academic Russell Barkley has referred to the condition as a "motivational deficit disorder" in various publications and presentations.[49][50][51][52][53] 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.[49][54][55] 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.[56][49] 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.[57][58][59] 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.[60]

References

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