Dopamine Dysregulation Syndrome Research Articles

Rewarding properties of L-Dopa in experimental parkinsonism are mediated by sensitized dopamine D1 receptors in the dorsal striatum.

Treatment of Parkinson's disease (PD) is based on the use of dopaminergic drugs, such as L-Dopa and dopamine receptor agonists. These substances counteract motor symptoms, but their administration is accompanied by motor and non-motor complications. Among these latter conditions a neurobehavioral disorder similar to drug abuse, known as dopamine dysregulation syndrome (DDS), is attracting increasing interest because of its profound negative impact on the patients' quality of life. Here we replicate DDS in a PD mouse model based on a bilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. Administration of L-Dopa induced locomotor sensitization and conditioned place preference in 6-OHDA lesion, but not in control mice, indicative of the acquisition of addictive-like properties following nigrostriatal dopamine depletion. These behavioral effects were accompanied by abnormal dopamine D1 receptor (D1R) signaling in the medium spiny neurons of the dorsal striatum, leading to hyperactivation of multiple signaling cascades and increased expression of ΔFosB, a stable transcription factor involved in addictive behavior. Systemic administration of the D1R antagonist, SCH23390, abolished these effects and the development of place preference, thereby counteracting the psychostimulant-like effect of L-Dopa. The rewarding properties of L-Dopa were also prevented by chemogenetic inactivation of D1R-expressing neurons in the dorsal striatum. Our results indicate the association between abnormal D1R-mediated transmission and DDS in PD and identify potential approaches for the treatment of this disorder.

The Incentive-Sensitization Theory of Addiction 30 Years On.

The incentive-sensitization theory (IST) of addiction was first published in 1993, proposing that (a) brain mesolimbic dopamine systems mediate incentive motivation ("wanting") for addictive drugs and other rewards, but not their hedonic impact (liking) when consumed; and (b) some individuals are vulnerable to drug-induced long-lasting sensitization of mesolimbic systems, which selectively amplifies their "wanting" for drugs without increasing their liking of the same drugs. Here we describe the origins of IST and evaluate its status 30 years on. We compare IST to other theories of addiction, including opponent-process theories, habit theories of addiction, and prefrontal cortical dysfunction theories of impaired impulse control. We also address critiques of IST that have been raised over the years, such as whether craving is important in addiction and whether addiction can ever be characterized as compulsive. Finally, we discuss several contemporary phenomena, including the potential role of incentive sensitization in behavioral addictions, the emergence of addiction-like dopamine dysregulation syndrome in medicated Parkinson's patients, the role of attentional capture and approach tendencies, and the role of uncertainty in incentive motivation.

Nonmotor Symptoms and Impulse Control Disorders in Parkinson's Disease Patients in India: A Cross-sectional Study.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with significant nonmotor symptom (NMS) burden, including impulse control disorders. This study aimed to comprehensively evaluate NMS and impulse control disorders in PD patients under primary care. A descriptive cross-sectional study was conducted on 32 PD patients and evaluated using standardized assessment tools. Demographics, comorbidities, and symptom burdens were recorded. Evaluation tools included the Hoehn and Yahr Scale, REM Sleep Behavior Disorder assessment, Geriatric Depression Scale, Montreal Cognitive Assessment scale for cognitive impairment, NMS scale, and identification of impulse control disorders. In PD, comorbidities were prevalent (84%), and most were at Hoehn and Yahr Stages 2 and 3. REM Sleep Behavior Disorder was present in 28.12%, with 5 receiving clonazepam treatment. Depression affected 28.12%, with 5 receiving pharmacological treatment. Cognitive impairment was notable in 9 patients. NMS burden was high, with varying severity. Impulse control disorders were limited, whereas one case of dopamine dysregulation syndrome was identified. This primary care-based study in India assessed NMS and impulse control disorders in PD patients, highlighting comorbidities and management opportunities. The study's strength lies in evaluating an unselected primary care population, whereas limitations include small sample size. This study emphasizes the importance of primary care physicians in monitoring and managing NMS in PD patients. Impulse control disorders and cognitive impairment are critical aspects that need attention. The findings support an integrated approach involving health-care professionals across various disciplines to provide holistic care for PD patients.

Dopamine Dysregulation Syndrome Presenting as Overuse of Mucuna pruriens Levodopa Supplement.

Dopamine Dysregulation Syndrome Presenting as Overuse of Mucuna pruriens Levodopa Supplement.

Management of Impulse Control and Related Disorders in Parkinson's Disease: An Expert Consensus.

Impulse-control and related behavioral disorders (ICBDs) significantly impact the lives of Parkinson's disease (PD) patients and caregivers, with lasting consequences if undiagnosed and untreated. While ICBD pathophysiology and risk factors are well-studied, a standardized severity definition and treatment evidence remain elusive. This work aimed to establish international expert consensus on ICBD treatment strategies. To comprehensively address diverse treatment availabilities, experts from various continents were included. From 2021 to 2023, global movement disorders specialists engaged in a Delphi process. A core expert group initiated surveys, involving a larger panel in three iterations, leading to refined severity definitions and treatment pathways. Experts achieved consensus on defining ICBD severity, emphasizing regular PD patient screenings for early detection. General treatment recommendations focused on continuous monitoring, collaboration with significant others, and seeking specialist advice for legal or financial challenges. For mild to severe ICBDs, gradual reduction in dopamine agonists was endorsed, followed by reductions in other PD medications. Second-line treatment strategies included diverse approaches like reversing the last medication change, cognitive behavior therapy, subthalamic nucleus deep brain stimulation, and specific medications like quetiapine, clozapine, and antidepressants. The panel reached consensus on distinct treatment pathways for punding and dopamine dysregulation syndrome, formulating therapy recommendations. Comprehensive discussions addressed management strategies for the exacerbation of either motor or non-motor symptoms following the proposed treatments. The consensus offers in-depth insights into ICBD management, presenting clear severity criteria and expert consensus treatment recommendations. The study highlights the critical need for further research to enhance ICBD management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Othello syndrome and dopamine dysregulation syndrome

Othello syndrome is a paranoid delusional jealousy characterised by false absolute certainty of the infidelity of a partner, leading to preoccupation with a partner's sexual unfaithfulness based on unfounded evidence. Here, we present a case of Othello syndrome comorbid to dopamine dsyregulation syndrome in a patient suffering from juvenile Parkinson's disease. The case investigates the relationship between compulsive levodopa use and delusional jealousy, the serious consequences of these conditions and the difficulty in patient management.

Early onset Parkinson’s disease in the cycle of 3,4-methylenedioxymethamphetamine and substance use: a case report

BackgroundCurrent evidence linking the development of Parkinson’s disease after the use of 3,4-methylenedioxymethamphetamine is mixed and limited, with only a few positive case reports demonstrating this.Case presentationWe examine this interesting case of a 49-year-old Chinese gentleman who used 3,4-methylenedioxymethamphetamine and subsequently developed early onset Parkinson’s disease at age 38 years. He had a family history of Parkinson’s disease, though the onset of his symptoms was significantly earlier than those of his family members. MDMA was a likely precipitating factor for the early onset of his symptoms. He then conversely used methamphetamines to augment his treatment of Parkinson’s symptoms. In the treatment of his Parkinson’s disease, dopamine replacement therapy and deep brain stimulation could perpetuate addictive behaviors such as dopamine dysregulation syndrome, and similarly perpetuate substance use in vulnerable individuals. He had also been diagnosed with a human immunodeficiency virus infection at age 43, and his antiretroviral therapy contributed to depressive symptoms, which then complicated the management of his substance use.We examined the importance of managing his subsequent psychiatric and medical comorbidities to prevent their debilitating psychosocial impacts.ConclusionsThis case implies that 3,4-methylenedioxymethamphetamine use may precipitate the early development of Parkinson’s disease in patients with genetic vulnerability. This highlights the risk in patients potentially paradoxically using substances to alleviate symptoms of Parkinson’s, which can in turn perpetuate the disease process.

Impulse control disorders in Parkinson's disease: a retrospective analysis of 1824 patients in a 12-year period.

This study aims to clinically evaluate the impulse control disorders (ICDs) encountered in treating Parkinson's disease. This is a retrospective analysis between 2010 and 2022. We retrieved the medical records of all patients diagnosed with idiopathic Parkinson's disease. The demographic and clinical findings were recorded. ICDs constituted a specific item in the examination, and each one (compulsive shopping, compulsive eating, pathological gambling, hypersexuality, punding, dopamine dysregulation syndrome, and hobbyism) was noted separately. In the study period, we identified 1824 patients (56.2% men, n = 1025). The mean age was 70.5 ± 11.9 years. In the cohort, 128 (7%) patients with Parkinson's disease had one or more ICDs. The ICDs were compulsive shopping, punding/hobbyism, compulsive eating, hypersexuality, pathological gambling, and dopamine dysregulation syndrome. When we compared patients with and without ICDs, patients with ICDs were younger (p ≤ 0.001), and the men/women ratio was higher in this group with ICDs. Although the mean daily pramipexole dose was higher in patients with ICDs, meandaily long-acting pramipexole dosewas only1.4 ± 0.92 mg/day. The significant findings in this study were (i) the lower frequency of ICDs (7%); (ii) the common occurrence of compulsive shopping, punding/hobbyism, and compulsive eating; and (iii) the development of ICDs under relatively lower doses of pramipexole. We suggest that ICDs in Parkinson's disease should be associated with a personal trait with dopamine agonists, and potential electrophysiological or genetic markers of this trait warrant further analysis to avoid treatment in these patients.

Predictors of dopamine dysregulation syndrome in patients with early Parkinson’s disease

BackgroundDopamine dysregulation syndrome (DDS) is a complication of Parkinson’s disease (PD) that seriously affects the quality of life of PD patients. Currently, the risk factors for DDS are poorly known, and it is critical to identify them in the early stages of PD.ObjectiveTo explore the incidence of and risk factors for DDS in patients with early PD.MethodsA retrospective cohort study was conducted on the general data, clinical features, and imaging data of patients with early PD in the PPMI database. Multivariate Cox regression analysis was performed to analyze the risk factors for the development of DDS in patients with early PD, and Kaplan‒Meier curves examined the frequency and predictors of incident DDS symptoms.ResultsAt baseline, 2.2% (n = 6) of patients with early PD developed DDS, and the cumulative incidence rates of DDS during the 5-year follow-up period were 2.8%, 6.4%, 10.8%, 15.5%, and 18.7%, respectively. In the multivariate Cox regression model controlling for age, sex, and drug use, hypersexuality (HR = 3.088; 95% CI: 1.416~6.732; P = 0.005), compulsive eating (HR = 3.299; 95% CI: 1.665~6.534; P = 0.001), compulsive shopping (HR = 3.899; 95% CI: 1.769~8.593; P = 0.001), anxiety (HR = 4.018; 95% CI: 2.136~7.599; P < 0.01), and lower Hoehn-Yahr (H-Y) stage (HR = 0.278; 95% CI: 0.152~0.509; P < 0.01) were independent risk factors for DDS in patients with early PD. PD patients with DDS had lower DAT uptake values than those patients without DDS.ConclusionEarly PD patients with hypersexuality, compulsive eating, compulsive shopping, anxiety, and lower H-Y stage were at increased risk for DDS. The occurrence of DDS may be related to the decrease in the average DAT uptake of the caudate and putamen.

Neural correlates of impulsive compulsive behaviors in Parkinson’s disease: A Japanese retrospective study

BackgroundImpulsive compulsive behaviors (ICBs) often disturb patients with Parkinson’s Disease (PD), of which impulse control disorder (ICD) and dopamine dysregulation syndrome (DDS) are two major subsets. The nucleus accumbens (NAcc) is involved in ICB; however, it remains unclear how the NAcc affects cortical function and defines the different behavioral characteristics of ICD and DDS. ObjectivesTo identify the cortico-striatal network primarily involved in ICB and the differences in these networks between patients with ICD and DDS using structural and resting-state functional magnetic resonance imaging. MethodsPatients with PD were recruited using data from a previous cohort study and divided into those with ICB (ICB group) and without ICB (non-ICB group) using the Japanese version of the Questionnaire for Impulsive Compulsive Disorders in Parkinson’s Disease (J-QUIP). From these two groups, we extracted 37 pairs matched for age, sex, disease duration, and levodopa equivalent daily dose of dopamine agonists. Patients with ICB were further classified as having ICD or DDS based on the J-QUIP subscore. General linear models were used to compare gray matter volume and functional connectivity (FC) of the NAcc, caudate, and putamen between the ICB and non-ICB groups and between patients with ICD and those with DDS. ResultsWe found no significant differences in gray matter volumebetween the ICB and non-ICB groups or between patients with ICD and those with DDS. Compared with the non-ICB group, the FC of the right NAcc in the ICB group was lower in the bilateral ventromedial prefrontal cortex and higher in the left middle occipital gyrus. Furthermore, patients with DDS showed higher FC between the right putamen and left superior temporal gyrus and higher FC between the left caudate and bilateral middle occipital gyrus than patients with ICD. In contrast, patients with ICD exhibited higher FC between the left NAcc and the right posterior cingulate cortex than patients with DDS. ConclusionsThe functionally altered network between the right NAcc and ventromedial prefrontal cortex was associated with ICB in PD. In addition, the surrounding cortico-striatal networks may differentiate the behavioral characteristics of patients with ICD and those with DDS.

Dopamine dysregulation syndrome after prescription of dopamine agonists: a case report

IntroductionWe present the case of a 65-year-old woman with multiple and chronic psychosomatic symptoms. Due to motor impairments she was diagnosed in 2009 with Parkinson’s Disease (PD) by the neurology department and empirical treatment with levodopa was prescribed. However, the patient increased her levodopa intake by three times the recommended dose. The patient presented many adverse effects, including psychotic symptoms, that were interrupted after the levodopa intake was ended during a two month internament in a psychiatric unit. Dopamine dysregulation syndrome (DDS) is a condition in which patients with PD increase their levodopa intake without an objective worsening of motor symptoms. Higher-than-prescribed doses are taken by patients who develop tolerance and dependence to dopaminergic agonists.ObjectivesTo analyse the prevalence of DDS, its diagnosis and treatment as well as the identification of risk factors.MethodsA case report is presented alongside a review of the relevant literature regarding DDS.ResultsThe available evidence suggests that the main risk factors for DDS are a history of mood disorders and behavioural disorders, but more studies are needed. Given that DDS is considered a rare adverse effect, physicians usually overlook voluntary dose increase by patients.ConclusionsDDS, even though uncommon, has severe adverse effects such as dependence and acute psychosis. Before prescription of dopamine agonists, individual risk factors (such as psychiatric comorbidities or history of substance abuse) should be assessed. Also, patients and families should be informed and trained in alarm signs detection. Further studies would be justified to determine DDS prevalence, early diagnosis and treatment.DisclosureNo significant relationships.

Management of Parkinson’s disease challenged by co-morbid drug abuse

IntroductionParkinson’s disease (PD) is a neurologic degenerative condition with complex neuropsychiatric manifestations which can be challenging to manage and greatly impact quality of life and prognosis.ObjectivesThe description of this case aims to highlight the complex interaction between PD, drug-abuse and impulse control disorder (ICD).MethodsClinical information was obtained through patient interviewing and medical records consulting. A literature review on the topic was conducted.ResultsWe report the case of a 52-years-old male with PD diagnosed at the age of 45, presenting with rigidity of right limbs and freezing of gait. He had a history of multiple substance-abuse: hashish, heroin and cocaine, with cessation of all substances by the age of 40. The patient responded well to antiparkinsonian medication initially, but needed frequent adjustments and developed ICD secondary to dopamine agonists, presenting pathological gambling and hypersexuality. At 47 he restarted using cocaine stating that it diminished the motor symptoms. Motor symptoms worsened and became partially responsive to medication. Pharmacologic options were limited due to ICD. He developed dopamine dysregulation syndrome, abusing dopaminergic drugs and requesting multiple prescriptions. Deep brain stimulation surgery was proposed, but the patient was deemed unfit for the procedure after two separate psychiatric evaluations, mainly because of behaviour and social problems in relation to sustained cocaine abuse and personality disorder. Attempts to stop drug abuse were unsuccessful despite several interventions by addiction psychiatry.ConclusionsCo-occurrence of PD, substance-abuse and personality disorder poses as a therapeutic challenge conditioned by pharmacological iatrogenesis and behavioural disturbances, requiring a multidisciplinary and individualized approach.DisclosureNo significant relationships.

Emergencies in Parkinsonism

Patients with Parkinsonism may present acutely to the ED with serious and even life-threatening conditions. Although falls are a common presentation in advanced Parkinsonism, early presentations with falls should alert the clinician that the patient might have a Parkinson syndrome other than Parkinson’s disease itself, including autonomic neuropathy causing orthostatic hypotension. Patients may present with neuroleptic malignant syndrome, acute psychosis, marked hypokinesis, freezing gait, aspiration pneumonia, dysphagia, serotonin syndrome, dopamine dysregulation syndrome and intestinal pseudo-obstruction. An inpatient admission is necessary for investigation and observation of these patients. We present a case of a patient who presented with an uncommon side effect of a common medication used for Parkinsonism.

Impulse control disorders, dopamine dysregulation syndrome and sex dysfunction in Parkinson's disease.

Hypersexuality (HS), characterized by an aberrant, compulsive and inappropriate sexual drive, is an underreported and undermanaged complication of the treatment with dopamine agonists in patients with Parkinson's disease (PD). HS is part of the spectrum of impulse control disorders (ICDs). The failure to control these addictive behaviors is distressing for the patient and it is associated with important consequences. Reports of the prevalence of HS showed different results, due to the lack of standardized diagnostic criteria, but also due to the embarrassment or guilt feelings that patients experience regarding their sexual behaviors. Overall, it is considered that HS may occur in 1.92-22.8% of PD patients and the main risk factors involved could be male sex and genetic susceptibility. The pathophysiology of HS is unknown, but several degenerative mechanisms were proposed, involving dopaminergic, serotoninergic and noradrenergic pathways in cerebral regions responsive for planning and rewarding. There are no standardized tools for the assessment of HS in PD patients; however, several scales and questionnaires were developed with the aim of screening and rating the severity of ICDs, including HS. The management of HS is challenging. Discontinuation or reducing the dopaminergic treatment was effective in some cases, but it might lead to worsening of the motor function. A multidisciplinary approach is mandatory to manage the other associated aspects, such as psychological and social consequences of HS.

Validation of the Chinese Version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease.

Background: Impulse control and related disorders (ICRDs) have gained recognition as a severe complication of Parkinson's disease (PD) and are connected to poor quality of life and devastating financial and social problems. This study aimed to evaluate the usefulness of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) and estimate the risk factors for ICRDs in Chinese patients with PD.Methods: 207 PD patients were assessed using the QUIP and evaluated for PD motor and nonmotor symptoms. ICRDs were diagnosed via interviews of patients or their caregivers, and the clinical characteristics of patients with and without ICRDs were compared.Results: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the C-QUIP were 95.0, 83.4, 38.0, 99.4, and 84.5%. The prevalence of each disorder among participants diagnosed via interview was pathological gambling (0.5%), hypersexuality (1.9%), compulsive shopping (1.0%), binge eating (3.9%), hobbyism (1.9%), punding (0.5%), walkabout (0.5%), and dopamine dysregulation syndrome (2.9%). PD patients with ICRDs had longer PD duration, higher Hoehn and Yahr stage, Non-Motor Symptoms Scale (NMSS), and Hamilton-Depression Rating Scale (HAMD). Also, they received a larger total daily levodopa equivalent dose (LED), levodopa dosage, and dopamine agonist only LED (DA-LED) than did PD patients without ICRDs.Conclusions: Given its psychometric properties, the C-QUIP is a valid and rapid screening instrument for assessing of ICRDs in PD patients. Higher Hoehn and Yahr staging, NMSS and HAMD scores, a larger mean LED and levodopa dosage are risk factors for ICRDs.

P.042 Dopamine Dysregulation Syndrome in Parkinson’s Disease and its Management with Advanced Therapies

Background: Dopamine Dysregulation Syndrome (DDS) is an adverse non-motor complication of dopamine replacement therapy in Parkinson’s Disease. The current literature on DDS is limited, and it remains underdiagnosed and challenging to manage. Methods: We performed a retrospective chart review and classified patients according to risk factors that have been identified in the literature, UPDRS scores, intervention and outcome. Univariate analyses were performed to quantify these characteristics. Results: Prior psychiatric illness was identified in 70% of patients, impulse control disorder in 89% and substance abuse in 3.7%. Interventions included reduction of dopamine therapy (88.9%), deep brain stimulation (DBS) of the subthalamic nucleus (STN, 48.1%) or globus pallidus interna (GPi, 7.4%), and levodopa-carbidopa intestinal gel (LCIG) infusion (11.1%). Baseline UPDRS IV before treatment and MDS III after treatment were not significant between intervention groups (p=0.09 and p=0.13 respectively). Overall 88.9% patients improved at follow up, with medication only (75%), STN DBS (100%), GPi DBS (100%) and LCIG (33%). Relapse rate was 18.2%, in the STN group only. Conclusions: Our results suggest that GPi DBS, in concurrence with dopaminergic medication reduction, is the most effective intervention. STN DBS might be also beneficial although the associated medications reduction causes DDS relapse in a subgroup of patients.

Impulsive conditions in Parkinson's disease: A pharmacosurveillance-supported list

Background“Impulse Control Disorders” are behavioral conditions (e.g., gambling, hypersexuality), which are increasingly reported as reactions to dopamine agonists in Parkinson's disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease focuses only on 6 behaviors. Nonetheless, impulsivity could affect the entire range of human practices. Because of their heterogeneity and undefined boundaries, it is not clear what conditions should be considered as Impulse Control Disorders. This results in poorly standardized scientific literature and underdiagnosis. ObjectiveWe aimed to create a comprehensive list of possible manifestations of drug-induced Impulse Control Disorders in Parkinson's disease and test it on pharmacosurveillance data. MethodsPubMed was used to identify reviews in English about Impulse Control Disorders in Parkinson's disease. Mentioned conditions were charted and translated to the lexicon of MedDRA, ICD-11, and DSM-5. The relevant MedDRA terms were used to test potential association with dopamine agonists on the FDA Adverse Event Reporting System. Results50 reviews published between 2001 and 2020 were identified. 66 conditions were collected as possible Impulse Control Disorders. Pathological gambling, shopping, eating and sexuality, dopamine dysregulation syndrome, hobbyism and punding were the most frequently mentioned, together with leisure activities, body-focused compulsivity, disruptive, impulse control and conduct disorders, and substance abuse. All these conditions were disproportionately reported with dopamine agonists, except for substance abuse. ConclusionsWe defined a potential extended list of ICDs, which, along with its conversion to international taxonomies, can support the identification of drug-induced conditions in pharmacovigilance archives, as well as monitoring processes in clinical practice.

Does antiretroviral therapy alter the course of Parkinson's disease in people living with HIV?

South Africa has the world's largest antiretroviral programme which has resulted in an increase in life expectancy in persons living with HIV. Parkinson's disease (PD) is an age-related neurodegenerative disorder. No data has been published in this setting with regards to the interaction between PD and people infected with HIV. This was a retrospective study which matched two HIV non-infected PD patients to one HIV-infected patient with PD. Patients with secondary causes of Parkinsonism were excluded. Demographic, clinical and laboratory data were extracted from the charts. Hoehn and Yahr scale was used to assess PD severity. Twenty PD patients were recruited from 1 January 2008 to 31 October 2020 and were diagnosed with HIV for a median of 72 months. The median age at onset of PD was 52 years. All patients were on antiretroviral therapy. There were no statistically significant differences in the levodopa equivalent daily dose, clinical phenotype, impulse control disorders (ICDs) and frequency of a positive family history between the two groups. HIV-infected patients had a higher frequency of dopamine dysregulation syndrome. At the end of follow-up, 3 (15%) PLH-PD had moderate to severe PD compared to 16 (40%) of PD controls. The OR of having moderate to severe PD in HIV non-infected PD patients was 4. Persons living with HIV and Parkinson's disease present with PD symptoms at a younger age, progress slower to a severe stage and respond well to dopaminergic replacement therapy.

Changing Gears - DBS For Dopaminergic Desensitization in Parkinson's Disease?

In Parkinson's disease, both motor and neuropsychiatric complications unfold as a consequence of both incremental striatal dopaminergic denervation and intensifying long-term dopaminergic treatment. Together, this leads to 'dopaminergic sensitization' steadily increasing motor and behavioral responses to dopaminergic medication that result in the detrimental sequalae of long-term dopaminergic treatment. We review the clinical presentations of 'dopaminergic sensitization', including rebound off and dyskinesia in the motor domain, and neuropsychiatric fluctuations and behavioral addictions with impulse control disorders and dopamine dysregulation syndrome in the neuropsychiatric domain. We summarize state-of-the-art deep brain stimulation, and show that STN-DBS allows dopaminergic medication to be tapered, thus supporting dopaminergic desensitization. In this framework, we develop our integrated debatable viewpoint of "changing gears", that is we suggest rethinking earlier use of subthalamic nucleus deep brain stimulation, when the first clinical signs of dopaminergic motor or neuropsychiatric complications emerge over the steadily progressive disease course. In this sense, subthalamic deep brain stimulation may help reduce longitudinal motor and neuropsychiatric symptom expression - importantly, not by neuroprotection but by supporting dopaminergic desensitization through postoperative medication reduction. Therefore, we suggest considering STN-DBS early enough before patients encounter potentially irreversible psychosocial consequences of dopaminergic complications, but importantly not before a patient shows first clinical signs of dopaminergic complications. We propose to consider neuropsychiatric dopaminergic complications as a new inclusion criterion in addition to established motor criteria, but this concept will require validation in future clinical trials. ANN NEUROL 2021;90:699-710.

New pharmacological and neuromodulation approaches for impulsive-compulsive behaviors in Parkinson's disease.

A significant proportion of patients with Parkinson's disease (PD) display a set of impulsive-compulsive behaviors at some point during the course of illness. These behaviors range from the so-called behavioral addictions to dopamine dysregulation syndrome, punding and hoarding disorders. These behaviors have been consistently linked to the use of dopaminergic medications used to treat PD motor symptoms (dopamine agonists, levodopa, and other agents) and less consistently to neuromodulation techniques such as deep brain stimulation (DBS). Since there are still no approved treatments for these conditions, their pharmacological management is still a big challenge for clinicians. We conducted an extensive review of current pharmacological and neuromodulation literature for the management of impulsive-compulsive disorders in PD patients. Pharmacological treatment approaches for impulsive-compulsive behaviors and DDS in PD patients include reduction of levodopa (LD), reduction/cessation of dopamine agonist (DA), and initiation of infusion therapies (apomorphine infusion and duodopa). Also, atomoxetine, a noradrenergic agent approved for the treatment of attention deficit hyperactivity disorder, showed some interesting preliminary results but there is still a lack of controlled longitudinal studies. Finally, while DBS effects on impulsive-compulsive disorders are still controversial, non-invasive techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation) could have a potential positive effect but, again, there is still a lack of controlled trials. Managing impulsivity and compulsivity in PD patients is still a non-evidence-based challenge for clinicians. Controlled trials on promising approaches such as atomoxetine and non-invasive neuromodulation techniques are needed.