dopamine dysregulation syndrome ( dds ) , originally described as  hedonistic homeostatic dysregulation  by giovannoni et al . , is a disturbance that may complicate long - term dopamine replacement therapy ( drt ) of parkinson 's disease ( pd ) . patients with dds develop an addictive pattern of drt use , self - administering doses of dopaminergic drugs in excess of those required to control their motor symptoms . patients demand drug escalation and a compulsive drt seeking and intake is developed , taking larger levodopa doses than prescribed . they justify the overuse of antiparkinsonian drugs , despite being very dyskinetic , to avoid the nonmotor aspects related to  off attempts made by physicians to reduce drt doses are received with resistance and commonly are unsuccessful . dds has been related to levodopa and potent short - acting dopamine agonists as subcutaneous apomorphine , but it also can occur with other dopamine agonists . the compulsive use of drt may lead to negative social behaviours such as hoarding medication . dds may encompass other psychomotor pathologies due to antiparkinsonian therapy as punding  complex meaningless stereotyped and repetitive motor behaviours  and impulse control disorders , such as pathological gambling , hypersexuality , compulsive shopping , and binge eating . dds is probably underdiagnosed because patients may not complain of their behaviour and physicians may forget to ask about that . there are no large epidemiological studies about the prevalence of dds in the general pd population . the prevalence of dds in patients attending parkinson 's disease centers is 3 - 4% [ 1 , 3 ] . the dds diagnostic criteria proposed by giovannoni et al .   in his seminal paper were ( a ) pd with documented levodopa responsiveness ; ( b ) need for increasing doses of drt in excess of those normally required to relieve parkinsonian symptoms and signs ; ( c ) pattern of pathological use : expressed need for increased drt in the presence of excessive and significant dyskinesias despite being  on  , drug hoarding or drug seeking behaviour , unwillingness to reduce drt , and absence of painful dystonias ; ( d ) impairment in social or occupational functioning : fights , violent behaviour , loss of friends , absence from work , loss of job , legal difficulties , arguments or difficulties with family ; ( e ) development of hypomaniac , maniac , or cyclothymic affective syndrome in relation to drt ; ( f ) development of a withdrawal state characterized by dysphoria , depression , irritability , and anxiety on reducing the level of drt ; ( g ) duration of disturbance of at least 6 months . pezzella et al . used the following selection criteria for dds : ( a ) pd with documented levodopa responsiveness ; ( b ) need to increase doses of drt beyond those normally required to relieve parkinsonian symptoms and signs ; ( c ) pattern of pathological use of drt ( chronic medication abuse , excluding occasional dosage increase while experiencing a sudden off or preparing for a social event ) and current mood disorders ( depression , anxiety , hypomaniac state , euphoria ) , behavioural disorders ( pathological gambling , obsessional shopping , hypersexuality , aggression , social isolation ) , or alteration of the perception of the on state ( walkabouts , stereotypies ) . impulsivity and sensation and novelty - seeking personality traits have been found in patients with pd and dds [ 46 ] . it has been also noticed that young - onset pd patients are more vulnerable to develop this syndrome . other reported risk factors are male gender , previous history of substance abuse ( alcohol , drugs , etc . ) , higher dopaminergic drug intake , and presence of depressive symptoms [ 47 ] . recently , engagement in a creative or artistic profession has been described as an additional risk factor for developing dds . it has been suggested that parkin gene mutations ( park2 ) may be a risk factor for developing dds [ 9 , 10 ] . d2-like  receptor family genes could play a role in the pathogenesis of dds . in pet studies with [ 11c]-raclopride , parkin - positive medicated patients have been reported to show a significant decrease of d2 striatal receptors in comparison with idiopathic pd medicated patients and with age - matched healthy controls . many pd patients with dds fulfil dsm - iv criteria for substance dependence because of the negative effect that the pathological use of medication has on their social , psychological , and physical functioning . based on this model , patients with dds may use dopaminergic drugs to avoid dysphoric off states . however , the model that may better explain the pathophysiology of dds is the incentive - sensitization theory [ 4 , 7 ] . this theory of addiction postulates that compulsive drug use modifies dopaminergic neurotransmission in the nucleus accumbens and related reward circuitry involving the mesocorticolimbic dopamine system . this neuroadaptation on the accumbens - related circuitry makes the system sensitized to the psychomotor effects of drugs . thus , the potential addictive pattern of antiparkinsonian drugs may be related to their effect on the reward system . some experimental data on the activation of accumbens - related reward - seeking pathways by drt suggested that antiparkinsonian drugs share some properties with addictive psychostimulants as amphetamine . there is evidence of sensitization of the ventral striatum reward system by pet imaging with [ 11c]-raclopride in pd patients with dds who had enhanced levodopa - induced ventral striatal dopamine release compared with levodopa - treated patients with no compulsive drug use . thus , pd patients with more pronounced mesolimbic dopaminergic denervation , involving the ventral striatum ( nucleus accumbens ) , may be prone to develop compulsive behaviours after dopaminergic treatment [ 11 , 12 ] . deep brain stimulation of the subthalamic nucleus ( stn - dbs ) is an established therapy for advanced pd patients with motor complications . bilateral continuous high - frequency stimulation of the stn improves motor disability by 3367% , motor fluctuations by 7383% , and levodopa - induced dyskinesias by 5588% and permits a 4080% reduction in the doses of antiparkinsonian medication , compared with the preoperative state . however , adverse neurocognitive , mood , and behavioral changes may appear after stn - dbs . despite the motor improvement of patients who underwent stn - dbs , its effect on nonmotor symptoms of parkinson 's disease , especially neurobehavioral disorders as impulse control disorders , punding , and the relationship between stn - dbs and dds in patients with parkinson 's disease remains unclear . while some authors described a complete resolution of the behaviour disorder after stn - dbs [ 1619 ] , others found no improvement or even worsening of dds postoperatively . furthermore , de novo dds may appear as a complication of stn - dbs [ 14 , 1921 ] . to our knowledge , there are 9 pd patients with dds reported in the literature who improved or resolved after stn - dbs [ 1619 ] . described two patients with preoperative dds that resolved immediately after surgery without recurrence of the compulsive medication use in successive years . described a pd patient suffering from severe dds necessitating in - ward psychiatric management , who , following stn - dbs and medication reduction , had a rapid and dramatic resolution of dds and associated psychiatric symptoms . reported one patient who had also a great improvement of dds within the first month after surgery . lim and colleagues described three resolved dds cases after stn - dbs and other two patients that improved their behaviour after the procedure . postoperative dds improvement may be related to the reduction of dopaminergic agents allowed by surgery [ 16 , 19 , 22 ] . decreasing the pulsatile administration of levodopa may decrease the experience of negative emotional states and reduce the abnormal sensitization of motivational symptoms associated with the mesolimbic system . however subthalamic nucleus deep brain stimulation may not influence dds evolution or even can worsen it . interestingly , dopamine dysregulation syndrome can also appear for the first time after deep brain stimulation of the subthalamic nucleus . we reviewed the literature searching for reports of pd patients in whom dds appeared within 12 months of stn - dbs . to our knowledge , at least , 7 cases have been reported [ 14 , 1921 ] . the first patient with postoperative dds was reported by houeto et al . in 2002 , a 61-year - old man with personal history of alcohol misuse and bipolar disorder before the onset of the disease . the motor outcome after surgery was good ( updrs iii improved by 86% ) , although daily levodopa dose was reduced only by 12% . three years later , the same group published a five - year followup of 37 pd patients treated with stn - dbs in their center . they reported 3 patients addicted to levodopa treatment as permanent adverse effect related to medical treatment , bilateral stn - dbs , or progression of the disease . lim and colleagues reported in 2009 two patients with dds which apparently appeared for the first time after bilateral stn - dbs . however , one of the reported cases is not considered in this paper since dds occurred 8 years after surgery in the context of a battery failure . we have recently reported three pd patients who developed dds within a year after surgery . the first case was a 47-year - old woman who underwent stn - dbs for a 10-year history of pd complicated with motor fluctuations and disabling dyskinesias . she had been treated with different antiparkinsonian drugs , including subcutaneous infusion of apomorphine . after dbs , off periods were significantly reduced , dyskinesias decreased , and medical treatment was reduced by 50% ( apomorphine infusion was stopped ) . six months after surgery , despite her motor improvement , her husband reported a compulsive intake of levodopa . the patient justified the overuse because  she felt herself as empty of energy .  in addition , she exhibited binge eating . therapeutic approaches included pramipexole withdrawal , dbs adjustments , and addition of quetiapine and lorazepam , but five years after surgery she continued to overuse levodopa . the second case was a 59-year - old man with a 7-year history of pd complicated with motor fluctuations and mild depressive symptoms . before surgery he was treated with high doses of levodopa plus multiple boluses of subcutaneous apomorphine . despite the clinical motor improvement after stn - dbs , four months after surgery , the patient kept injecting himself apomorphine to avoid anxiety , depressive mood , and fear sensation . addition of quetiapine , citalopram , and dbs parameter adjustments did not resolve the behaviour , and dds persisted four years after surgery . the third patient was a 45-year - old man with pd since the age of 30 , without previous psychiatric history who underwent stn - dbs surgery for severe motor fluctuations . a month after stn - dbs procedure , he started drinking high quantity of caffeine - rich beverages ( coke ) and developed hypersexuality . two months later he admitted taking double dose of pramipexole than prescribed because he felt he  needed  it . hypersexuality and compulsive coke drinking disappeared , but the patient became apathetic and began to overuse levodopa . in these cases dbs disconnection was tried , but switching off dbs led to rapid deterioration of their motor function in a matter of hours , a situation which was not tolerated by the patients . a definite causal relationship with stn - dbs can not be made since the outcome of dds after discontinuing dbs could not be assessed besides , dds could have appeared in the evolution of the patients ' disease independently of the surgical treatment . however , the temporal relationship between stn - dbs surgery and the onset of dds suggests that stn - dbs might have played a role in the appearance of dds . one possible explanation for the appearance or worsening of dds after stn - dbs could be misplacement of the electrodes in the medial zone of the stn , which corresponds to its limbic territory   and is related to motivational and emotional aspects of behavior [ 23 , 24 ] . this explanation , however , seems unlikely since in all reported patients the motor outcome of the surgery was as expected after stimulation of the dorsolateral sensorimotor part of the stn . however , due to the small size of the stn , stimulation with electrode contacts located mainly within the sensorimotor territory can result in the spread of current to associative and limbic areas as well as to surrounding structures . computational modelling to measure the volume of activated tissue during dbs is currently being investigated [ 25 , 26 ] . several neuroimaging studies have found that stn - dbs induced metabolic modifications in cortical and subcortical structures related to limbic and associative circuits [ 2628 ] . thus , the spread of stimulation to associative and limbic areas of the stn may underlie the appearance of dds after dbs surgery . impulse control disorders such as pathological gambling have also been reported after dbs [ 29 , 30 ] as well as impulsive behaviour during high - conflict decisions   and apathy . indeed , besides dds , most of the patients developed other behavioural addictions such as pathological gambling and abnormal sexual behaviour , binge eating , punding , and compulsive shopping . on the other hand , the psychostimulant effect of stn - dbs [ 33 , 34 ] seems an unlikely explanation for de novo dds after surgery . the seemingly paradoxical occurrence of either improvement or worsening of dds after stn - dbs or , furthermore , the de novo appearance of this addictive behaviour may be related to individual differences in the extent of mesolimbic dopaminergic denervation [ 22 , 35 ] . pet studies comparing pd patients with postoperative apathy after dopamine agonist withdrawal with nonapathetic patients have revealed areas of increased [ 11c]-raclopride binding potential values in the orbitofrontal , dorsolateral , prefrontal , and posterior cingulate cortices as well as other subcortical structures including the amygdala and the ventral striatum bilaterally in the apathetic group , thus suggesting the existence of different nonmotor phenotypes .   reward - seeking behavior is mediated by the amygdala and nucleus accumbens , both of which receive dopaminergic projections from the ventral tegmental area . thus , pd patients with more pronounced mesolimbic dopaminergic denervation involving the ventral striatum ( nucleus accumbens ) may be prone to developing compulsive behaviours after dopaminergic treatment [ 5 , 12 ] .   this might be the case of de novo dds patients , in whom the combined effect of dopaminergic replacement therapy ( albeit reduced after surgery ) and dbs on the limbic territory of the stn could have led to hyperstimulation of the mesolimbic system , thus precipitating the onset of dds . the clinical management of dds is challenging , particularly when appears after stn - dbs . despite a good postoperative motor outcome , most patients overused dopaminergic drugs not because they felt pleasurable effects but to avoid anxiety , dysphoria , and other nonmotor symptoms [ 2 , 21 , 37 ] . preoperative recognition of dds and other impulse control disorders is correlated with a better outcome of these behaviours after dbs , whereas lack of recognition , poor motor benefit , and higher dopaminergic medication doses after surgery were associated with persistence or even new cases of dds . changes in stimulation parameters , attempts to reduce the dose of dopaminergic drugs , and the addition of antipsychotics and/or antidepressants may not be helpful . the outcome of dds after stn - dbs was poor in the majority of reported cases [ 14 , 1921 ] . a large and rapid reduction in dopamine replacement therapy with withdrawal of dopaminergic agonists may induce apathy and severe depression in many patients , whereas a more conservative approach may precipitate dds in some cases .   identifying vulnerable patients to develop dds seems of paramount relevance . young - onset pd , male gender , previous history of substance abuse , impulsive sensation seeking personality , presence of depressive symptoms , and artistic professions have been considered risk factors for dds [ 48 ] as well as treatment with high doses of dopaminergic medication and rapid acting dopaminergic drugs [ 47 ] . perhaps detailed neuropsychological evaluations using scales such as quip ( questionnaire for impulsive and compulsive disorders in parkinson 's disease )   or pet studies to detect cases of severe denervation of the mesolimbic dopaminergic system   may be useful tools to identify potential dds patients . perhaps the use of computational modelling [ 25 , 26 ] , when it becomes available , could help elucidate the best set of stimulation parameters for individual patients . nevertheless , it seems advisable to avoid a hyperdopaminergic state during the postoperative period , since high doses of dopaminergic medication added to stn - dbs therapy may predispose to developing dds in vulnerable patients . further research should be undertaken in order to identify patients who are vulnerable to dds and to define the most appropriate postoperative management .
dopamine dysregulation syndrome is a complication of the dopaminergic treatment in parkinson 's disease that may be very disabling due to the negative impact that compulsive medication use may have on patients ' social , psychological , and physical functioning . 
 the relationship between subthalamic nucleus deep brain stimulation and dopamine dysregulation syndrome in patients with parkinson 's disease remains unclear . 
 deep brain stimulation may improve , worsen , or have no effect on preoperative dopamine dysregulation syndrome . 
 moreover , dopamine dysregulation syndrome may appear for the first time after deep brain stimulation of the subthalamic nucleus . 
 the outcome of postoperative dopamine dysregulation syndrome is poor despite stimulation and medication adjustments . 
 here we review the phenomenology and neurobiology of this disorder , discuss possible mechanisms that may underlie the diverse outcomes of dopamine dysregulation syndrome after subthalamic nucleus deep brain stimulation , and propose management strategies .