versão impressa ISSN 1516-4446
Rev. Bras. Psiquiatr. vol.32 no.1 São Paulo mar. 2010
Baixa frequência de transtorno bipolar, síndrome de desregulação dopaminérgica e punding em pacientes brasileiros com doença de Parkinson
Arthur KummerI; Fernando M. V. DiasI; Francisco CardosoII Antonio L. TeixeiraI
INeuropsychiatric Branch, Department of Internal Medicine, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte (MG), Brazil
IIMovement Disorders Clinic, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte (MG), Brazil
OBJECTIVE: To investigate the frequency of bipolar disorder, dopamine dysregulation syndrome and punding in Parkinson's disease patients from a Brazilian movement disorders clinic.
METHOD: One hundred patients underwent a comprehensive psychiatric examination composed of MINI-plus and specific questionnaires to investigate dopamine dysregulation syndrome and punding.
RESULTS: We identified, respectively, one and five Parkinson's disease patients with bipolar disorder type I and type II. All manic/hypomanic episodes occurred before Parkinson's disease onset. No patient was identified with dopamine dysregulation syndrome or punding.
CONCLUSION: The frequency of manic/hypomanic episodes seems to decrease with Parkinson's disease onset, and local environmental factors (e.g. drug availability) may be responsible for the low frequency of dopamine dysregulation syndrome and punding in Brazilian Parkinson's disease patients.
Descriptors: Parkinson disease; Bipolar disorder; Syndrome; Patients; Brazil
OBJETIVO: Investigar a frequência de transtorno bipolar, síndrome de desregulação dopaminérgica e punding em pacientes com doença de Parkinson de uma clínica de movimentos anormais no Brasil.
MÉTODO: Cem pacientes foram submetidos à avaliação psiquiátrica composta pelo MINI-Plus e questionários específicos para investigar síndrome de desregulação dopaminérgica e punding.
RESULTADOS: Identificamos, respectivamente, um e cinco pacientes com transtorno bipolar tipo I e tipo II. Todos os episódios maníacos/hipomaníacos ocorreram antes do início da doença de Parkinson. Nenhum paciente foi identificado com síndrome de desregulação dopaminérgica ou punding.
CONCLUSÃO: A frequência de episódios maníacos/ hipomaníacos parece declinar com o início da doença de Parkinson. Fatores ambientais locais (p.ex.: disponibilidade de drogas) podem ser responsáveis pela baixa frequência de síndrome de desregulação dopaminérgica e punding em pacientes brasileiros com doença de Parkinson.
Descritores: Doença de Parkinson; Transtorno bipolar; Síndrome; Pacientes; Brasil
The "monoaminergic theory" is considered an important biological basis for the comprehension of neuropsychiatric disorders.1 Parkinson's disease (PD), a degenerative condition resulting in predominantly dopamine depletion at pars compacta from substantia nigra, may provide relevant insights into this matter. Dysfunction of the dopaminergic neurotransmission may underlie the pathophysiology of some psychiatric disorders which have their frequency increased in PD.
Recently dopamine has been suggested to be involved in the neurobiology of bipolar disorder.2 A subgroup of PD patients undergoing therapy with high-dose dopaminergic agents can present the so-called Dopamine Dysregulation Syndrome (DDS). The core features of DDS are self-medication, levodopa-seeking and hoarding associated with disabling mood and behavioral changes.3 In DDS, mood dysregulation comprises alternation between depressed and elated affect, and is frequently associated with hypersexuality, aggression, pathological gambling, compulsive shopping and social isolation, resembling a bipolar-like syndrome.2-4 An additional behavioral disorder supposedly associated with changes in dopaminergic neurotransmission is punding, which consists of repetitive, stereotyped, aimless and disrupted behaviors related to the person's past work or hobby.5,6
In a previous study by our group we found that the lifetime frequency of bipolar I and II disorders in PD seems to be similar to that observed in the general population.7 By contrast, the prevalence of unipolar depression in PD was significantly increased.7 In the present study we investigated the frequency of bipolar disorder, DDS, and punding in a sample of Brazilian PD patients.
Patients and methods
One hundred (M/F: 56/44) outpatients with idiopathic PD were consecutively recruited from the Movement Disorders Clinic of the Universidade Federal de Minas Gerais (UFMG), Brazil. Patients with previous neurosurgery, other neurologic disorder, delirium or dementia were excluded. Dementia was diagnosed according to DSM-IV diagnostic criteria and to the score obtained in the Mini-Mental State Examination (MMSE) adapted for the Brazilian population.8
2. Clinical assessment
Demographic and clinical data were obtained. Neurological examination included the MMSE, the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn-Yahr Scale (HY), and the Schwab-England Scale of Activities of Daily Living (SES). Patients were examined in the "on" state. The UPDRS was used to assess PD severity and it included all of its subsections (I to IV). The HY was used to estimate disease stages, while disability in performing activities of daily living was assessed with the SES.
Patients underwent a standardized psychiatric examination, which included the Mini-International Neuropsychiatric Inventory (MINI-Plus), and structured questions related to the diagnosis of DDS and punding.
The MINI-Plus is an internationally validated short-structured diagnostic psychiatric interview,9 compatible with the DSMIV and ICD-10 criteria. DDS was investigated with the short screening questionnaire designed by Pezzella et al.,4 which was based on the diagnostic criteria for DDS published in the seminal paper by Giovannoni et al.10 In brief, the questions comprised the overuse of dopaminergic agonists or levodopa, associated with mood or behavioral changes. These questions were directed to both patients and their caregivers as suggested by the authors.4 We also asked questions related to behaviors suggestive of punding as proposed by Evans et al.5
The patients provided informed consent and the study was approved by the Ethics Committee of the UFMG (protocol CAAE-0048.0.203.000-06).
3. Statistical analysis
Descriptive statistics are presented with the corresponding 95% confidence interval.
A hundred PD patients participated in this study. No patient refused to participate. Patients had a mean age (standard deviation) of 56.8 (10.5) years and mean age of PD onset of 47.3 (11.4) years (Table 1). The mean disease duration was 9.5 (5.9) years. Seventy (70%) patients were taking levodopa (Table 2), with a mean (SD) dose of 608.5 (302.5) mg/day. Four additional patients (4%) had already used levodopa, but they had the drug withdrawn due to disabling dyskinesias. Another 46% were taking other dopaminergic agents (35% taking pramipexole and 11% taking bromocriptine). The mean daily levodopa equivalent unit dose5 was 560.4 (365.4).
Manic and hypomanic episodes were found in, respectively, one and five PD patients. A 95% confidence interval for manic episode was 0% to 2.95%, while this confidence interval for hypomania was 0.73% to 9.27%. These episodes were confirmed by patients' caregivers or relatives. All manic or hypomanic episodes occurred before disease onset and no further episodes were identified after PD development. However, among the six patients with manic/ hypomanic episodes we found three that presented depressive episodes after PD onset, and in two of them depression was controlled with sertraline without switching to mania. All PD patients with a history of bipolar disorder had motor fluctuations but with no related significant mood swings. Further clinical data of these patients are presented in Table 3.
No case of DDS or punding was diagnosed in the studied patients.
In the current study, we observed a frequency of bipolar I disorder of 1% and of bipolar II disorder of 5% in patients with PD. The frequency of bipolar disorders in the general population has been estimated to range from 1 to 5% by different studies,11,12 which is within the confidence intervals of our data. Moreover, we did not find any patient with DDS or punding.
Our results raise some intriguing issues. First, PD patients with a history of bipolar disorder did not present any further manic or hypomanic episodes after PD onset, although all of them were taking levodopa and two of them were taking an antidepressant. Thus, the prevalence of life-time bipolar disorder (i.e. manic/ hypomanic episodes) seems to be close to what is expected in the general population before PD onset, but the frequency of manic/ hypomanic episodes may decrease thereafter.
Second, not a single patient with DDS was identified in this cohort. This may suggest that the frequency of this syndrome may be lower in Brazilian patients. Of note, the frequency of DDS is estimated to be 4% in tertiary centers like ours.4,10 Phenomenology of DDS may be influenced by cultural and environmental factors as is its frequency.4 This lower frequency in our patients may be related to some of these environmental factors. Some drugs with a fast onset of action, including apomorphine, which may act as a catalyst for DDS,13 are not available in Brazil. Furthermore, our patients usually have difficulties affording dopaminergic agents or levodopa. Hence, they acquire medication in public pharmacies with a restrictive drug dispensation, preventing drug hoarding. It has been well established that drug availability is an important risk factor for drug abuse14 and this was not taken into account in previous studies investigating DDS. Although other risk factors, such as young-onset male patients and higher dopaminergic drug intake, are relevant for the clinician in preventing DDS,4 drug availability should be considered by health policy makers.
Dopamine may be involved in pathophysiology of bipolar disorder, as the frequency of manic/hypomanic episodes after PD onset seems to decrease. However, care should be taken in considering that a single monoamine is responsible for the heterogeneous phenotypes of neuropsychiatric disorders. For example, although dopamine plays a relevant role in schizophrenia, the frequency of psychosis in PD is not decreased and it is not necessarily related to dopamine replacement therapy.15 Also, bupropion, an antidepressant which increases synaptic dopamine and noradrenaline levels, is less prone to induce manic switches than sertraline and venlafaxine, antidepressants with smaller effect on dopaminergic neurotransmission.16 In PD, decreased dopaminergic levels may affect the frequency of manic and depressive episodes. Nevertheless, dopamine replacement therapy is not always able to treat non-motor symptoms of PD, and these patients respond to antidepressants with serotonergic mechanism of action. Thus, the relationships among neurotransmitters are far more complex than we can imagine.
Our study has some clear limitations. For instance, the patient diagnosed with bipolar I disorder was still taking a mood stabilizer. Furthermore, our screening for DDS was based on self-report of medicine usage which is not the "gold standard" in adherence monitoring.17 Our sample might also be considered too small to detect DDS and punding, especially taking into account that not many patients were in high-dose therapy of dopaminergic drugs. Nevertheless, a significant proportion of the patients enrolled in this study (50%) had early-onset PD, a well-known risk factor for these behavioral disorders,4 which may be considered as strength of this study. The prevalence of punding was initially estimated to be 14% within patients with high-dose therapy.5 Recently, this frequency was estimated at 1.4% in non-selected patients.6 We believe this later estimate is more accurate as we could not detect any patient with punding.
In conclusion, the frequency of manic/hypomanic episodes seems to decrease with PD onset. The small sample size and the low mean of daily levodopa equivalent unit dose may be responsible for the low frequency of DDS and punding in Brazilian PD patients but local environmental factors such as drug availability must also beconsidered in future studies as a potential determinant of the prevalence of DDS.
This work was partly funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.
1. Reis HJ, Guatimosim C, Paquet M, Santos M, Ribeiro FM, Kummer A, Schenatto G, Salgado JV, Vieira LB, Teixeira AL, Palotás A. Neurotransmitters in the central nervous system & their implication in learning and memory processes. Curr Med Chem. 2009;16(7):796-840. [ Links ]
2. Berk M, Dodd S, Kauer-Sant'anna M, Malhi GS, Bourin M, Kapczinski F, NormanT. Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand Suppl. 2007;434:41-9. [ Links ]
3. Kummer A, Maia DP, Salgado JV, Cardoso FE, Teixeira AL. Dopamine dysregulation syndrome in Parkinson's disease: a case report. Arq Neuropsiquiatr. 2006;64(4):1019-22. [ Links ]
4. Pezzella FR, Colosimo C, Vanacore N, Di Rezze S, Chianese M, Fabbrini G, Meco G. Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson's disease. Mov Disord. 2005;20(1):77-81. [ Links ]
5. Evans AH, Katzenschlager R, Paviour D, O'Sullivan JD, Appel S, Lawrence AD, Lees AJ. Punding in Parkinson's disease: its relation to the dopamine dysregulation syndrome. Mov Disord. 2004;19(4):397-405. [ Links ]
6. Miyasaki JM, Al Hassan K, Lang AE, Voon V. Punding prevalence in Parkinson's disease. Mov Disord. 2007;22(8):1179-81. [ Links ]
7. Kummer A, Cardoso F, Teixeira AL. Frequency of psychiatric disorders in young-onset Parkinson's disease does not differ from typical-onset Parkinson's disease. Parkinsonism Relat Disord. 2009;15(2):153-5. [ Links ]
8. Brucki SM, Nitrini R, Caramelli P, Bertolucci PH, Okamoto IH. Suggestions for utilization of the mini-mental state examination in Brazil. Arq Neuropsiquiatr. 2003;61(3B):777-81. [ Links ]
9. Amorim P. Mini International Neuropsychiatric Interview (MINI): validation of a short structured diagnostic psychiatric interview. Rev Bras Psiquiatr. 2000;22(3):106-15. [ Links ]
10. Giovannoni G, O'Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry. 2000;68(4):423-8. [ Links ]
11. Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, Kessler RC. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64(5):543-2. [ Links ]
12. Bauer M, Pfennig A. Epidemiology of bipolar disorders. Epilepsia. 2005;46(Suppl 4):8-13. [ Links ]
13. Lawrence AD, Evans AH, Lees AJ. Compulsive use of dopamine replacement therapy in Parkinson's disease: reward systems gone awry? Lancet Neurol. 2003;2(10):595-604. [ Links ]
14. Tarter RE, Vanyukov M, Kirisci L, Reynolds M, Clark DB. Predictors of marijuana use in adolescents before and after licit drug use: examination of the gateway hypothesis. Am J Psychiatry. 2006;163(12):2134-40. [ Links ]
15. Kummer A, Neves M, Lauar H, Cardoso F, Teixeira-Jr AL. Schizoaffective disorder and Parkinson's disease: a possible comorbidity? Rev Psiquiatr Clín. 2006;33(1):28-31. [ Links ]
16. Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE Jr, Kupka RW, Denicoff KD, Nolen WA, Grunze H, Martinez MI, Post RM. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163(2):232-9. [ Links ]
17. Grosset K, Grosset D: Hedonistic homeostatic dysregulation in Parkinson's disease and excess dopamine replacement therapy. Mov Disord. 2005;20(9):1230-1. [ Links ]
Arthur Kummer and Antonio Lucio Teixeira
Departamento de Clínica Médica, Faculdade de Medicina, UFMG
Av. Alfredo Balena, 190 - Santa Efigênia
30130-100 Belo Horizonte, MG, Brazil
Phone/Fax: (+55 31) 3409-2651
Submitted: May 14, 2009
Accepted: August 15, 2009