Dopamine dysregulation syndrome in Parkinson’s disease

Dopamine dysregulation syndrome in Parkinson’s disease Giovanni Fabbrini

Progression of Parkinson’s disease Handicap PreS Motor complications Non motor symptoms Honey Moon * Symptoms 25 yrs

Long term dopamine replacement therapy (DRT): motor complications • Motor fluctuations • Wearing-off • On-off • Delayed-on • Drug resistant-off • Involutary movements • Dyskinesias • Dystonias

Long term dopamine replacement therapy (DRT): non motor complications • Restlesness and insomnia • Aggression • Hypomania • Hypersexuality • Impulsivity • Vivid dreaming Similar to those seen after excessive use of stimulants such as cocaine and amphetamine

Compulsive dopamine replacement therapy • Patients who take DRT far beyond that needed to treat their motor disability • Complain of intolerable motor and affective symptoms • Ignore drug schedules • Feel “on” only when severely dyskinetics • Drug seeking behaviour • Impairment of social, occupational, familial functioning Giovannoni et al, JNNP, 2000

Compulsive dopamine replacement therapy = Hedonistic homeostatic dysregulation syndrome in Parkinson’s disease? • Neuropsychological behavioral disorder associated with substance misuse and addiction. • Dopamine replacement therapy in PD attenuates motor symptoms. • DRT may stimulate dopaminergic pathway linked to the brain’s reward system, implicated in addiction • Stimulation of these pathways may initiate hedonistic homeostatic dysregulation in rare patients.

Compulsive DRT: analysis of case reports • More common in men with young onset disease • Predisposing factors: • Past medical history remarkable for alcohol or illegal drug abuse • Affective disorders Quinn et al, 1983; Vogel et al, 1983; Priebe et al, 1984; Nausieda et al, 1985; Tack et al, 1988; Uitti et al, 1989; Soyka et al, 1992; Weinman et al, 1995; Spigset et al, 1997; Courty et al, 1997; Merims et al, 2000; Geschwandtner et al, 2001; Serrano-Duenas, 2002; Muller et al, 2002; Houeto et al, 2002; Giovannoni et al, 2000

Compulsive DRT: analysis of case reports • May be seen with L-dopa and dopamine agonists • More frequent with acute rescue drugs, such as dispersible levodopa or subcutaneous apomorphine • All cases described had L-dopa induced dyskinesias (moderate-severe) Quinn et al, 1983; Vogel et al, 1983; Priebe et al, 1984; Nausieda et al, 1985; Tack et al, 1988; Uitti et al, 1989; Soyka et al, 1992; Weinman et al, 1995; Spigset et al, 1997; Courty et al, 1997; Merims et al, 2000; Geschwandtner et al, 2001; Serrano-Duenas, 2002; Muller et al, 2002; Houeto et al, 2002; Giovannoni et al, 2000

Compulsive DRT: controlled studies PD + DRT PD controls Age at PD onset 43 56 Males 80% 59% LDE dose 2000 700 Evans et al. Neurology 2005;65:1570

Compulsive DRT: frequency of motor and non motor complications % Evans et al. Neurology 2005;65:1570

Mov Disord 2005;20:77-81

Demographics • 202 consecutive patients over a two months period (tertiary referral center) • 114 males/88 females • Mean age: 68.1 (42-89) years • Mean disease duration: 7.3 (1-30) years • Mean HY score: 2.2 (I-IV)

Inclusion Criteria for compulsive DRT • PD patients with documented levodopa responsiveness • Need for increasing doses of DRT in excess of those normally required to relief parkinsonian symptoms • Pattern of pathological use of DRT

Criteria for compulsive DRT • mood disorders: depression, anxiety, hypomanic state, euphoria • behavioural disorders: pathological gambling, obsessional shopping, hypersexuality, aggression, social isolation • alteration of the perception of the on state, walkabouts, punding Overall frequency of compulsive DRT = 3.4% (n=7)

COMPARISON BETWEEN PATIENTS WITH OR WITHOUT HEDONISTIC HOMEOSTATIC DYSREGULATION MATCHED FOR CLINICAL AND DEMOGRAPHIC VARIABLES

COMPARISON BETWEEN PATIENTS WITH OR WITHOUT HEDONISTIC HOMEOSTATIC DYSREGULATION MATCHED FOR CLINICAL AND DEMOGRAPHIC VARIABLES * * % * HHD + HHD - *p< 0.05 Mov Disord 2005;20:77-81

COMPARISON BETWEEN PATIENTS WITH OR WITHOUT HEDONISTIC HOMEOSTATIC DYSREGULATION MATCHED FOR CLINICAL AND DEMOGRAPHIC VARIABLES * * % * p<0.05 HHD + HHD - Mov Disord 2005;20:77-81

Behavioral phenomena associated with compulsive DRT • Punding: intense fascination with the repetitive manipulations, examination, cataloguing, and endless sorting of objects of common use, engagement in extended monologues devoid of content. Lawrence et al, 2003

Punding • First described in amphetamine addicts. • Derived from the swedish slang, literally: “block-head” • Described with substantially all stimulants • The punder is aware of the obtuse nature of the behavior but even self-injury from the stereotypies do not abort it.

Punding (some anedoctal reports) • Swedish motorcyclist gang (amphetamine users) who drove 200 times around the same block of houses….. • Bathing in a tub all day long…. • Hold a note or a phrase of music for hours… • Filing the nails until they bled…

Punding in PD • Obsession with rock and wood collection… • Obsessed with photography, dismantled 5 cameras… • Repetitively writing poetry, fill pockets with useless objects, dismantle electronic objects… • Gardener fanatic… • Excessive paper shiffling… • Repetitively sort buttons… • others Evans et al, Mov Disord 2004;19:397-405

Behavioral phenomena associated with compulsive DRT • Altered appetite: compulsive eating during “on” phases, sometimes food craving, food bingering. • Hypersexuality: increased in libido. Possible compulsive masturbation, exhibitionism, paraphilias, repeated demand for sexual intercourse Lawrence et al, 2003

Behavioral phenomena associated with compulsive DRT • Heightened aggression • Craving: patients may adopt strategies (even simulation of akinetic crisis) to access additional medication. • Withdrawal: sadness, inertia, fear, anxiety, sweating, nausea • Delirium, psychosis • Pathological gambling and shopping Lawrence et al, 2003

Pathological gambling in PD • Prevalence in general population: • 0.42%USA National Survey (J Clin Psychiatry 2005;66:564 • 1%(Gambling in Ontario. Addition Research Foundation 2004) • Prevalence in Parkinsonian patients: • 4.4% Mov Disord 2006;21:2206 (Ldopa) • 8.0% Mov Disord 2006;21:2206 (DA agonists) • 7.2% Neurology 2006;66:1750

Pathological gambling in PD • 11 patients (9M, 2 W), age range 35-68 • 4 patients with dyskinesias • 5 patients on psychoactive drugs (antidepressant 4, quetiapine 1) • All on DA agonists (8 also on levodopa) Dodd ML. Arch Neurol 2005;62:1-5

Pathological gambling in PD and dopamine dysregulation syndrome. Analysis of published case series • PG + DDS = 18 cases • PG without DDS = 53 cases • Unspecified = 106 cases Dodd ML. Arch Neurol 2005;62:1-5

Examples of pathological gambling in PD • Slot machines • Casino attendance • Lottery/scratch cards • Internet gambling • Horse racing • Bingo • Interactive television

Compulsive DRT use Substance dependence disorder? Addiction? Or Difficulties in controlling behavior Compulsion to take substances Continue use despite consequences DRT may be maladaptative Avoiding being unmedicated

Dopamine dysregulation syndrome. Hypothesis • Dopamine replacement therapy activate reward pathways. • Dopamine replacement therapy activates feeling of pleasure. • Hedonistic homoeostatic dysregulation (desire to avoid unpleasant withdrawal symptoms).

Dopamine dysregulation syndrome. Hypothesis • Habit (learning mechanisms). • Incentive sensitisation theory (progressive neuroadaptation in DA projections to the accumbens related circuitry).

Common effects of drugs of abuse • Increase dopaminergic transmission to the NAc after acute administration • Sensitization of the dopamine system • Hyperfunctional CRF system (activated during withdrawal from any drug) • Hypofrontality (glutamatergic influences)

Limbic circuitry Red arrows indicate glutamatergic pathways; black arrows indicate GABAergic pathways; blue arrows indicate dopaminergic pathways.

General hypothesis concerning the functions of midbrain DA cells in the development of addiction/relapse • Reward or changes in the positive incentive value of stimuli. • Reward prediction signal and role in reward-based learning. • Signaling “incentive salience”, or adaptations in the mesolimbic DA system leading to “wanting” (craving) drugs, not necessarily “liking” them.

Long-term potentiation at excitatory synapses on VTA dopamine neurons but not GABAergic neurons. The presence of LTP at excitatory synapses in VTA strengthens the hypothesis that this process could play a crucial role in the onset of sensitization. Ann Review Physiology, 2004

Psychostimulants and commonly abused drugs enhance excitatory synapses on midbrain DA cells Saal et al, Neuron 2003;37:577-582

Chronic L-DOPA treatment of Parkinsonian rats restores LTP and blocks depotentiation in dyskinetic rats. HFS induces LTP in sham-operated rats but not in 6-OHDA animals. (b) Chronic L-DOPA treatment restored LTP in both dyskinetic and non-dyskinetic Parkinsonian rats. (c) Synaptic depotentiation induced by LFS was present in non-dyskinetic rats, but was lost in dyskinetic animals. Picconi et al, Nat Neurosci 2003;6:501

Effect of a single Ldopa dose on % reduction in striatal 11C raclopride binding in control PD vs DDS patients Evans et al, Ann Neurol 2006;59:852-858

Differences in 11C raclopride binding potential after a single dose of Ldopa between control PD and DDS patients Pattern correlates with measures of “wanting” but not with measures of “liking” the drug Evans et al, Ann Neurol 2006;59:852-858

Implications for management. Prevention • Minimize the risk of developing compulsive DRT • Know your patient! • Use the lowest possible doses of dopaminergic agents in individual “at risk”

Implications for management if compulsive DRT is already established • Avoid intermittent apomorphine • Reduce DRT • Atypical antipsychotics • Antidepressant • Drug addiction rehabilitation programme • In our experience, prognosis is poor!

Compulsive DRT-Conclusions • Although uncommon, it is important to be aware of its existence. • Milder forms may occur. • In our popolation, we identified 7 cases (prevalence of 3.4 %). This is a similar figure to the one obtained by the British authors who first reported this syndrome in PD. • In our and others’ series, it seems to be associated with family history for neuropsychiatric disorders, sleep diorders, hallucinations, disturbed mood and DA-agonist use. • Further studies are needed in different populations

Complicated Parkinson’s disease • Motor fluctuations • Dyskinesias • Hallucinations • Excessive daytime somnolence • Dopamine dysregulation syndrome An interaction between disease and treatment

NMDA receptor-dependent LTP has been demonstrated at excitatory synapses on midbraindopamine neurons (36, 91, 92). Importantly, while excitatory synapses on dopamine cells undergo LTP, it appears that excitatory synapses on VTA GABAergic neurons do not (Figure 2) (36). The presence of LTP at excitatory synapses in VTA strengthens the hypothesis that this process could play a crucial role in the onset of sensitization. Figure 2 Long-term potentiation at excitatory synapses on VTA dopamine neurons but not GABAergic neurons. LTP was induced by pairing 1-Hz afferent stimulation with depolarization of the postsynaptic neuronal membrane to +10 mV for 200 stimuli. (A) LTP in the average of nine dopamine cells. (B) No LTP after pairing in the average of six GABAergic cells. Experiments carried out in the presence of 100 μM picrotoxin.

Teorie sulla addiction • Dati animale • Dati uomo • Dati PET

Dopamine dysregulation syndrome in Parkinson’s disease