Disorders of diminished motivation

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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]

Contents

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. [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]

Related Research Articles

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Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Stimulant</span> Drug that increases activity of central nervous system

Stimulants are a class of drugs that increase the activity of the brain. They are used for various purposes, such as enhancing alertness, attention, motivation, cognition, mood, and physical performance. Some of the most common stimulants are caffeine, nicotine, amphetamines, cocaine, methylphenidate, and modafinil.

<span class="mw-page-title-main">Methylphenidate</span> Central nervous system stimulant

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<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

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<span class="mw-page-title-main">Atomoxetine</span> Medication used to treat ADHD

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<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

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<span class="mw-page-title-main">Dopaminergic pathways</span> Projection neurons in the brain that synthesize and release dopamine

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<span class="mw-page-title-main">Mesocortical pathway</span>

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<span class="mw-page-title-main">Dopamine receptor</span> Class of G protein-coupled receptors

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<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

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<span class="mw-page-title-main">Tolcapone</span> Chemical compound

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<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.

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<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

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<span class="mw-page-title-main">Motivation-enhancing drug</span> Drug increasing motivation in humans

A motivation-enhancing drug, also known as a pro-motivational drug, is a drug which increases motivation. Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). They can also be used in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, disorders that can be caused by conditions like stroke, traumatic brain injury (TBI), and neurodegenerative diseases. Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts.

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