Dopamine dysregulation syndrome

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Dopamine dysregulation syndrome
Dopamine.svg
Two-dimensional skeletal formula of the dopamine molecule. Dopamine receptor agonists mediate the development of DDS.
Specialty Neurology, Psychiatry
Symptoms Disinhibition, impulsivity, hypersexuality, repetitive and obsessive behavior, addiction to offending medication
Complications Psychosis, addiction, marital problems, financial problems
CausesDopaminergic drugs (e.g., dopamine agonists, levodopa)
TreatmentReduce intake of dopaminergic drug
Medication Antipsychotics, valproate

Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It is characterized by severely disinhibited patterns of behavior, [1] leading to problems such as addiction to the offending medication, gambling addiction, or compulsive sexual behavior, [2] along with a general orientation towards immediate gratification. It typically occurs in people with Parkinson's disease (PD) or restless legs syndrome (RLS) who have taken dopamine agonist medications for an extended period of time. [2]

Contents

Signs and symptoms

Punding, a possible symptom of DDS, is the repetition of complex motor behaviors such as collecting or arranging objects. Punding.jpg
Punding, a possible symptom of DDS, is the repetition of complex motor behaviors such as collecting or arranging objects.
A slot machine, commonly used for gambling. Slot machine.jpg
A slot machine, commonly used for gambling.

The most common symptom is craving for the dopaminergic medication. However, other behavioral symptoms can appear independently of cravings or co-occur with it. [3] Cravings are an intense impulse of the subject to obtain medication even in the absence of symptoms that indicate its intake. [3] To fulfill this need, the person will self-administer extra doses. When self-administration is not possible, aggressive outbursts or the use of strategies such as symptom simulation or bribery to access additional medication can also appear. [3]

Hypomania, manifesting with feelings of euphoria, omnipotence, or grandiosity are prone to appear in those moments when medication effects are at it’s maximum; dysphoria, characterized by sadness, psychomotor slowing, fatigue or apathy are typical with dopamine replacement therapy (DRT) withdrawal. [3] Different impulse-control disorders have been described including compulsive gambling, compulsive shopping, eating disorders, and hypersexuality. [3] Behavioral disturbances, most commonly aggressive tendencies, are the norm. Psychosis is also common. [3]

Causes

Parkinson's disease is a common neurodegenerative disease characterized by a degeneration of dopamine neurons in the substantia nigra and a loss of dopamine in the putamen. It is described as a motor disease, but it also produces cognitive and behavioral symptoms. The most common treatment is dopamine replacement therapy, which consists in the administration of levodopa (L-DOPA) or dopamine agonists (e.g., pramipexole or ropinirole) to patients. Dopamine replacement therapy is well known to improve motor symptoms but its effects in cognitive and behavioral symptoms are more complex. [4] Dopamine has been related to the normal learning of stimuli with behavioral and motivational significance, attention, and most importantly the reward system. [5] In accordance with the role of dopamine in reward processing, addictive drugs stimulate dopamine release. [5] Although the exact mechanism has yet to be elucidated, the role of dopamine in the reward system and addiction has been proposed as the origin of DDS. [5] Models of addiction have been used to explain how dopamine replacement therapy produces DDS. [3] One of these models of addiction proposes that over the usage course of a drug there is a habituation to the rewarding effects that it produces at the initial stages. This habituation is thought to be dopamine mediated. With long-term administration of levodopa, the reward system gets used to it and needs higher quantities. As the user increases drug intake there is a loss of dopaminergic receptors in the striatum which acts in addition to an impairment in goal-direction mental functions to produce an enhancement of sensitization to dopamine therapy. The behavioral and mood symptoms of the syndrome are produced by the dopamine overdose. [5]

Diagnosis

Diagnosis of the syndrome is clinical since there are no laboratory tests to confirm it. For diagnosis a person with documented responsiveness to medication has to increase medication intake beyond dosage needed to relieve their parkinsonian symptoms in a pathological addiction-like pattern. A current mood disorder (e.g., depression, anxiety, or hypomania), behavioral disorder (e.g., excessive gambling, shopping, or sexual tendency, aggression, or social isolation) or an altered perception about the effect of medication also have to be present. [6] A questionnaire on the typical symptoms of DDS has also been developed and can help in the diagnosis process. [7]

Prevention

The main prevention measure proposed is the prescription of the lowest possible dose of dopamine replacement therapy to individuals at risk. [5] The minimization of the use of dopamine agonists, and of short duration formulations of L-DOPA can also decrease risk of the syndrome. [5]

Management

First choice management measure consists in the enforcement of a dopaminergic drug dosage reduction. If this decrease is maintained, dysregulation syndrome features soon decrease. [5] Cessation of dopamine agonists therapy may also be of use. [8] Some behavioral characteristics may respond to psychotherapy; and social support is important to control risk factors. In some cases antipsychotic drugs may also be of use in the presence of psychosis, aggression, gambling, or hypersexuality. [5]

Based upon five case reports, [9] [10] valproate may have efficacy in controlling the symptoms of levodopa-induced DDS that arise from the use of levodopa for the treatment of Parkinson's disease. [11] [12] [13]

Epidemiology

DDS is not common among PD patients. Prevalence may be around 4%. [2] [6] Its prevalence is higher among males with an early onset of the disease. [3] Previous substance abuse such as heavy drinking or drug intake seems to be the main risk factor along with a history of affective disorder. [3]

History

PD was first formally described in 1817; [14] however, L-dopa did not enter clinical practice until almost 1970. [15] [16] In these initial works there were already reports of neuropsychiatric complications. [16] During the following decades cases featuring DDS symptoms in relation to dopamine therapy such as hypersexuality, gambling or punding, appeared. [17] [18] [19] DDS was first described as a syndrome in the year 2000. [20] Three years later the first review articles on the syndrome were written, showing an increasing awareness of the DDS importance. [2] [5] [3] Diagnostic criteria were proposed in 2005. [6]

Related Research Articles

<span class="mw-page-title-main">Substantia nigra</span> Structure in the basal ganglia of the brain

The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.

<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.

Hypersexuality is a medical condition that causes unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment. It is controversial whether it should be included as a clinical diagnosis used by mental healthcare professionals. Nymphomaniac and sex maniac were terms previously used for the condition in women and men, respectively.

<span class="mw-page-title-main">Restless legs syndrome</span> Neurological disorder that causes a strong urge to move ones legs

Restless legs syndrome (RLS), (also known as Willis–Ekbom disease(WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporarily by moving them. This feeling is often described as aching, tingling, or crawling in nature. Occasionally, arms may also be affected. The feelings generally happen when at rest and therefore can make it hard to sleep. Sleep disruption may leave people with RLS sleepy during the day, with low energy, and irritable or depressed. Additionally, many have limb twitching during sleep, a condition known as periodic limb movement disorder. RLS is not the same as habitual foot-tapping or leg-rocking.

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

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of the hands to an uncontrollable movement of the upper body or lower extremities. Discoordination can also occur internally especially with the respiratory muscles and it often goes unrecognized. Dyskinesia is a symptom of several medical disorders that are distinguished by their underlying causes.

Impulse-control disorder (ICD) is a class of psychiatric disorders characterized by impulsivity – failure to resist a temptation, an urge, or an impulse; or having the inability to not speak on a thought. Many psychiatric disorders feature impulsivity, including substance-related disorders, behavioral addictions, attention deficit hyperactivity disorder, autism spectrum disorder, fetal alcohol spectrum disorders, antisocial personality disorder, borderline personality disorder, conduct disorder and some mood disorders.

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

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Ropinirole</span> Dopamine agonist medication

Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). It is taken by mouth.

<span class="mw-page-title-main">Punding</span> Compulsive performance of repetitive, mechanical tasks

Punding is compulsive performance of repetitive, mechanical tasks, such as assembling and disassembling, collecting, or sorting objects. It can also apply to digital objects, such as computer files and data. The term was originally coined to describe complex, prolonged, purposeless, and stereotyped behaviour in phenmetrazine and chronic amphetamine users, by Swedish forensic psychiatrist G. Rylander, in 1968. It was later described in Parkinson's disease, but mainly in cases of patients being treated with dopaminergic drugs. It has also been described in methamphetamine and cocaine users, as well as in some patients with gambling addictions, and hypersexuality.

<span class="mw-page-title-main">Pramipexole</span> Dopamine agonist medication

Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

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

Dihydroergocryptine (DHEC), sold under the brand names Almirid and Cripar among others, is a dopamine agonist of the ergoline group that is used as an antiparkinson agent in the treatment of Parkinson's disease. It is taken by mouth.

<span class="mw-page-title-main">Levodopa</span> Dopaminergic medication

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.

<span class="mw-page-title-main">Signs and symptoms of Parkinson's disease</span> Signs and symptoms

Signs and symptoms of Parkinson's disease are varied. Parkinson's disease affects movement, producing motor symptoms. Non-motor symptoms, which include dysautonomia, cognitive and neurobehavioral problems, and sensory and sleep difficulties, are also common. When other diseases mimic Parkinson's disease, they are categorized as parkinsonism.

Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.

<span class="mw-page-title-main">Kufor–Rakeb syndrome</span> Medical condition

Kufor–Rakeb syndrome (KRS) is an autosomal recessive disorder of juvenile onset also known as Parkinson disease-9 (PARK9). It is named after Kufr Rakeb in Irbid, Jordan. Kufor–Rakeb syndrome was first identified in this region in Jordan with a Jordanian couple's 5 children who had rigidity, mask-like face, and bradykinesia. The disease was first described in 1994 by Najim Al-Din et al. The OMIM number is 606693.

Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.

Dopamine therapy is the regulation of levels of the neurotransmitter dopamine through the use of either agonists, or antagonists; and has been used in the treatment of disorders characterized by a dopamine imbalance. Dopamine replacement therapy (DRT) is an effective treatment for patients with decreased levels of dopamine. Often dopamine antagonists, compounds that activate dopamine receptors in the absence of that receptor's physiological ligand, the neurotransmitter dopamine, are used in this therapy. DRT has been shown to reduce symptoms and increase lifespan for patients with Parkinson's disease. Dopamine regulation plays a critical role in human mental and physical health. The neurons that contain the neurotransmitter are clustered in the midbrain region in an area called the substantia nigra. In Parkinson's patients, the death of dopamine-transmitting neurons in this area leads to abnormal nerve-firing patterns that cause motor problems. Research in patients with schizophrenia indicates abnormalities in dopamine receptor structure and function.

References

  1. ↑ Grall-Bronnec, Marie (August 31, 2017). "Dopamine Agonists and Impulse Control Disorders: A Complex Association". Drug Safety. 41 (1): 19–75. doi:10.1007/s40264-017-0590-6. PMC   5762774 . PMID   28861870.
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  3. 1 2 3 4 5 6 7 8 9 10 Lawrence AD, Evans AH, Lees AJ (October 2003). "Compulsive use of dopamine replacement therapy in Parkinson's disease: reward systems gone awry?". Lancet Neurol. 2 (10): 595–604. doi:10.1016/S1474-4422(03)00529-5. PMID   14505581. S2CID   13529178.
  4. ↑ Cools R (2006). "Dopaminergic modulation of cognitive function-implications for L-DOPA treatment in Parkinson's disease". Neurosci Biobehav Rev. 30 (1): 1–23. doi:10.1016/j.neubiorev.2005.03.024. PMID   15935475. S2CID   329869.
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  8. ↑ Kimber TE, Thompson PD, Kiley MA (February 2008). "Resolution of dopamine dysregulation syndrome following cessation of dopamine agonist therapy in Parkinson's disease". J Clin Neurosci . 15 (2): 205–8. doi:10.1016/j.jocn.2006.04.019. PMID   18068992. S2CID   29101333.
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  10. ↑ Epstein J, Madiedo CJ, Lai L, Hayes MT (2014). "Successful treatment of dopamine dysregulation syndrome with valproic acid". The Journal of Neuropsychiatry and Clinical Neurosciences. 26 (3): E3. doi:10.1176/appi.neuropsych.13060126. PMID   25093777.
  11. ↑ Pirritano D, Plastino M, Bosco D, Gallelli L, Siniscalchi A, De Sarro G (2014). "Gambling disorder during dopamine replacement treatment in Parkinson's disease: a comprehensive review". Biomed Res Int. 2014: 1–9. doi: 10.1155/2014/728038 . PMC   4119624 . PMID   25114917.
  12. ↑ Connolly B, Fox SH (2014). "Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease". Neurotherapeutics. 11 (1): 78–91. doi:10.1007/s13311-013-0238-x. PMC   3899484 . PMID   24288035.
  13. ↑ Averbeck BB, O'Sullivan SS, Djamshidian A (2014). "Impulsive and compulsive behaviors in Parkinson's disease". Annu Rev Clin Psychol. 10: 553–80. doi:10.1146/annurev-clinpsy-032813-153705. PMC   4197852 . PMID   24313567.
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  18. ↑ Vogel HP, Schiffter R (July 1983). "Hypersexuality--a complication of dopaminergic therapy in Parkinson's disease". Pharmacopsychiatria. 16 (4): 107–10. doi:10.1055/s-2007-1017459. PMID   6685318. S2CID   1107353.
  19. ↑ Seedat S, Kesler S, Niehaus DJ, Stein DJ (2000). "Pathological gambling behaviour: emergence secondary to treatment of Parkinson's disease with dopaminergic agents". Depress Anxiety. 11 (4): 185–6. doi: 10.1002/1520-6394(2000)11:4<185::AID-DA8>3.0.CO;2-H . PMID   10945141. S2CID   35486805.
  20. ↑ Giovannoni G, O'Sullivan JD, Turner K, Manson AJ, Lees AJ (April 2000). "Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies". J. Neurol. Neurosurg. Psychiatry. 68 (4): 423–8. doi:10.1136/jnnp.68.4.423. PMC   1736875 . PMID   10727476.
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