Bipolar disorder, a precursor of Parkinson's disease?
Transtorno bipolar, um precursor da doença de Parkinson?
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor findings such as resting tremor, bradykinesia and rigidity. Non-motor features of PD have received greater attention in the past two decades owing to their recognized contribution to disability.1
Wider biological changes occur in PD and include increased oxidative and nitrosative stress, immune-inflammatory processes, tryptophan catabolites and alterations in serotoninergic and melatoninergic pathways.2
Mood disturbance, and especially major depressive disorder, is a common non-motor condition in PD, with an average prevalence of 25-40% in outpatient settings.3
Bipolar disorder (BD) is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression.4
Recently, some studies have demonstrated the association between BD and PD; however, although there is some knowledge about risk factors associated with BD in PD (5), little is known about its pathophysiology,the mechanisms involved in BD or whether it can be considered a non-motor symptom or comorbidity of PD
Case report and literature revision.
We describe a case of PD in the context of BD: GJV, a 43-year-old male, was referred to our service in 2014 with a history of depression since 2003 and maniac episode after antidepressant treatment without mood stabilizer. After this episode, although adequately treated with mood stabilizing drugs including lithium (for a few months, subsequently withdrawn after diarrhea), anticonvulsants (valproate and carbamazepine) and atypical antipsychotics (risperidone and quetiapine), he never returned to a euthymic state. On his first visit, while in use of venlafaxine 300 mg and quetiapine 300 mg, he reported depression and had noticed tremor in his right hand the previous year. He had right persistent, involuntary resting tremor, bradykinesia and rigidity. Single-Photon Emission Computed Tomography (SPECT) using the radiotracer TRODAT disclosed a right striatum of 0.84 (0.64-1.0) and left striatum <0.20 (0.64-1.0) compatible with PD (Figure 1). After PD treatment with levodopa medication 500 mg/day and pramipexole 2 mg/day, the psychiatric disease was stabilized using venlafaxine 75 mg/day and lamotrigine 100 mg/day. We believe that the PD treatment helped promote mood stabilization
Figure 1. Single-Photon Emission Computed Tomography (SPECT) of patient using the radiotracer TRODAT showing right striatum of 0.84 (0.64-1.0) and left striatum <0.20 (0.64-1.0), suggestive of Parkinson's disease.
Parkinson's disease is a neuropsychiatric disorder characterized by both motor and non-motor symptoms. Depression is probably the most common non-motor symptom in PD.3
DSM-IV-defined major depressive disorder occurs in 17% of PD patients and minor depression in 22%.6,7
Cannas et al. (2002) described five patients with PD and BD, but their patients developed the psychiatric disorder a few years after starting dopaminergic therapy in the presence of a mild motor disability and a mild cognitive impairment. BD was diagnosed retrospectively by examining all available clinical data, the typical history and DSM-IV criteria.8
Although one of the manifestations of bipolar disorder is depression, a 2010 study in Brazil found a prevalence of Bipolar I Disorder of 1% and of Bipolar II Disorder of 5% in patients with PD, with no difference to the rate of bipolar disorders found in the general population.9
In recent years, there has been increased reporting of cases of BD and PD, but still without an exact correlation of cause or consequence. Several mechanisms are involved in BD and PD neurodegeneration, such as inflammatory process, cytokines, epigenetic alterations and neurotransmission dysfunction, which will be the focus of our discussion. Dopamine, PD and BD: the dopamine (DA) system has been demonstrated to be a particularly age-sensitive neurotransmitter network. During the course of normal aging, the number of DA neurons, receptors, and transporters declines.10-14
As the DA system has a central role in higher-order cognitive functions, a correlative triad among aging, DA integrity, and cognition may be proposed.15
Several lines of evidence implicate the dopaminergic system in the pathogenesis of both maniac and depressive episodes and increased dopaminergic function has been consistently found after long-term treatment with antidepressants.16
In a 2005 study, Leszczynska-Rodziewicz et al. found no significant association between the polymorphisms of dopamine receptors, type D2, and bipolar affective disorder in a Polish population.17
Dopamine has been implicated in the neurobiology of BD,18
however, we must consider that a single monoamine is responsible for the heterogeneous phenotypes of this neuropsychiatric disorder. For example, there is no decreased frequency of psychosis in PD and, even though dopamine plays a relevant role in schizophrenia, psychosis is not necessarily related to dopamine replacement therapy.19
BD, and particularly dementia in late-life bipolar disorder, was initially considered as comorbid Alzheimer's disease (AD).20
In 2016, Forlenza et al. investigated whether cognitively impaired older adults with BD might have a profile of CSF biomarkers similar to that reported in dementia and in MCI due to AD, i.e., lower concentrations of Aþ1-42 and higher concentrations of T-tau and P-Tau.21
Their analysis of CSF failed to support the supposition of a common biological signature associated with cognitive deterioration in BD and AD. The phenotypic endpoint of PD is classically associated with loss of dopaminergic neurons in the substantia nigra, with many susceptibility genes and environmental factors being associated with PD.22
Dopaminergic degeneration is a hallmark of PD, which causes various symptoms affected by corticostriatal circuits. Although dopaminergic degeneration is the most important pathologic marker of PD, it is followed by various types of functional progressive degeneration in the whole brain involving the limbic system and neocortex.23
Several studies have reported that non-motor symptoms such as cognitive dysfunction in PD were related to widespread cortical atrophy in frontoparietal, limbic and cerebellum areas.24-26
Anterior striatal dopaminergic denervation is related to non-motor symptoms including sensory, neuropsychiatric and cognitive functions.27-29
Glutamate and BD: BD has been consistently associated with glutamatergic system abnormalities.30,31
Pharmacological studies reinforce the association between BD and the glutamatergic system by reporting that first line agents to treat BD, such as lithium, valproate, carbamazepine, and lamotrigine, also modulate the glutamatergic system.32
Soeiro-de-Souza et al., 2013, evaluated glutamate levels in the Anterior Cingulate Cortex (ACC) and found that BD subjects during euthymia had higher glutamate levels compared with healthy controls.33
ACC shares extensive anatomical connections with the amygdala; subiculum; hypothalamus; accumbens; ventral tegmental area; substantia nigra; raphe; locus coeruleus; periaqueductal gray; and brainstem autonomic nuclei, and other areas of the orbitomedial pre-frontal cortex.34,35
These structures are implicated in the modulation of emotional behavior, raising the possibility that abnormal synaptic interactions between these areas and the ACC may contribute to disturbances in emotional processing or regulation.36
Serotonin, PD and BD: the serotonergic hypothesis is one of the few hypotheses attempting to link the pathophysiology of PD with an increased risk of depression.37
and maybe BD. The evidence supporting this hypothesis are:  serotonergic activity is reduced in PD;38
 animal studies have shown that serotonin has the ability to inhibit the release of dopamine from the striatum, where it could be concluded that the reduction in serotonergic activity leads to less inhibition and an increased level of dopamine;37
and  reduction inserotonergic tone is a known risk factor for depression. It is likely that many biochemical pathways may cause PD, DA and BD, expressed differently in the beginning and end. The serotonergic hypothesis explains cases where BD is the initial picture.
In conclusion, although serotonin is not clearly involved in the pathophysiology of PD and the serotonergic hypothesis remains controversial, our case report supports the association between PD and BD. The development of mood disorders related to serotonin may be an inadequate adaptation to prevent the emergence of the parkinsonian picture.
All authors contributed significantly to, and are agreement with, the content of this manuscript.
1. Jankovic J & Tolosa E (Editors). Parkinson's Disease & Movement disorders. Fifth Edition, Philadelphia, USA. Luppincott Eillianms & Wilkins; 207.
2. Anderson G, Seo M, Berk M, Carvalho AF, Maes M. Gut Permeability and Microbiota in Parkinson's Disease: Role of Depression, Tryptophan Catabolites, Oxidative and Nitrosative Stress and Melatoninergic Pathways. Curr Pharm Des. [Epub ahead of print].
3. Leentjens AFG. Depression in Parkinson's Disease: Conceptual Issues and Clinical Challenges. J Geriatr Psychiatry Neurol. 2004;17(3):120-6.
4. Belmaker RH. Bipolar disorder. N Engl J Med. 2004;351(5):476-86.
5. Leentjens AFG, Scholtissen B, Vreeling FW, Verhey FRJ. The Serotonergic Hypothesis for Depression in Parkinson's Disease: an Experimental Approach. Neuropsychopharmacol. 2006;31(5):1009-15.
6. American Psychiatric Association. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 2000.
7. Reijnders JSAM, Ehrt U, Weber WEJ, Aarsland D, Leentjens AFG. A systematic review of prevalence studies of depression in Parkinson's disease. Mov Disord. 2008;23(2):183-9.
8. Cannas A, Spissu A, Floris GL, Congia S, Saddi M V, Melis M, et al. Bipolar affective disorder and Parkinson's disease: a rare, insidious and often unrecognized association. Neurol Sci. 2002;23 Suppl 2:S67-8.
9. Kummer A, Dias FM V, Cardoso F, Teixeira AL. Low frequency of bipolar disorder, dopamine dysregulation syndrome, and punding in Brazilian patients with Parkinson's disease. Rev Bras Psiquiatr. (São Paulo). 2010;32(1):62-5.
10. McGeer PL, Itagaki S, Akiyama H, McGeer EG. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol. 1988;24(4):574-6.
11. Rinne JO, Lönnberg P, Marjamäki P. Age-dependent decline in human brain dopamine D1 and D2 receptors. Brain Res. 1990;508(2):349-52.
12. Suhara T, Fukuda H, Inoue O, Itoh T, Suzuki K, Yamasaki T, et al. Age-related changes in human D1 dopamine receptors measured by positron emission tomography. Psychopharmacol. 1991;103(1):41-5.
13. Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991;114(Pt 5):2283-301.
14. Volkow ND, Wang GJ, Fowler JS, Ding YS, Gur RC, Gatley J, et al. Parallel loss of presynaptic and postsynaptic dopamine markers in normal aging. Ann Neurol. 1998;44(1):143-7.
15. Bäckman L, Nyberg L, Lindenberger U, Li S-C, Farde L. The correlative triad among aging, dopamine, and cognition: current status and future prospects. Neurosci Biobehav Rev. 2006;30(6):791-807
16. Bonhomme N, Esposito E. Involvement of serotonin and dopamine in the mechanism of action of novel antidepressant drugs: a review. J Clin Psychopharmacol. 1998;18(6):447-54.
17. Leszczyńska-Rodziewicz A, Hauser J, Dmitrzak-Weglarz M, Skibińka M, Czerski P, Zakrzewska A, et al. Lack of association between polymorphisms of dopamine receptors, type D2, and bipolar affective illness in a Polish population. Med Sci Monit. 2005;11(6):CR289-295.
18. Berk M, Dodd S, Kauer-Sant'anna M, Malhi GS, Bourin M, Kapczinski F, et al. Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand Suppl. 2007;(434):41-9.
19. Kummer A, Maia DP, Salgado JV, Cardoso FEC, Teixeira AL. Dopamine dysregulation syndrome in parkinson's disease. Case report. 2006;64:1019-22.
20. Nunes P V, Forlenza O V, Gattaz WF. Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007;190:359-60.
21. Forlenza O V, Aprahamian I, Radanovic M, Talib LL, Camargo MZ, Stella F, et al. Cognitive impairment in late-life bipolar disorder is not associated with Alzheimer's disease pathological signature in the cerebrospinal fluid. Bipolar Disord. 2016;18(1):63-70.
22. Wirdefeldt K, Adami H-O, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol. 2011;26 Suppl 1:S1-58.
23. Del Tredici K, Rüb U, De Vos RAI, Bohl JRE, Braak H. Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol. 2002;61(5):413-26.
24. Beyer MK, Janvin CC, Larsen JP, Aarsland D. A magnetic resonance imaging study of patients with Parkinson's disease with mild cognitive impairment and dementia using voxel-based morphometry. J Neurol Neurosurg Psychiatry. 2007;78(3):254-9.
25. Camicioli R, Gee M, Bouchard TP, Fisher NJ, Hanstock CC, Emery DJ, et al. Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism. Parkinsonism Relat Disord. 2009;15(3):187-95.
26. Nishio Y, Hirayama K, Takeda A, Hosokai Y, Ishioka T, Suzuki K, et al. Corticolimbic gray matter loss in Parkinson's disease without dementia. Eur J Neurol. 2010;17(8):1090-7.
27. Cao H, Xu X, Zhao Y, Long D, Zhang M. Altered brain activation and connectivity in early Parkinson disease tactile perception. AJNR Am J Neuroradiol. 2011;32(10):1969-74.
28. Polito C, Berti V, Ramat S, Vanzi E, De Cristofaro MT, Pellicanò G, et al. Interaction of caudate dopamine depletion and brain metabolic changes with cognitive dysfunction in early Parkinson's disease. Neurobiol Aging. 2012;33(1):206.e29-39.
29. Rektorova I, Srovnalova H, Kubikova R, Prasek J. Striatal dopamine transporter imaging correlates with depressive symptoms and tower of London task performance in Parkinson's disease. Mov Disord. 2008;23(11):1580-7.
30. Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des. 2009;15(14):1595-611.
31. Manji H. Bcl-2: A key regulator of affective resilience in the pathophysiology and treatment of severe mood disorders. Biol Psychiatry. 2008;63(Suppl 1):243S.
32. Yatham LN, Kennedy SH, Schaffer A, Parikh S V, Beaulieu S, O'Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11(3):225-55.
33. Soeiro-de-Souza MG, Salvadore G, Moreno RA, Otaduy MCG, Chaim KT, Gattaz WF, et al. Bcl-2 rs956572 Polymorphism is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder. Neuropsychopharmacol. 2013;38(3):468-75.
34. Ongür D, Ferry AT, Price JL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460(3):425-49.
35. Drevets WC, Ongür D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry. 1998;3(3):220-6, 190-1.
36. Ongür D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA. 1998;95(22):13290-5.
37. Mayeux R. The "serotonin hypothesis" for depression in Parkinson's disease. Adv Neurol. 1990;53:163-6.
38. Chen CP, Alder JT, Bray L, Kingsbury AE, Francis PT, Foster OJ. Post-synaptic 5-HT1A and 5-HT2A receptors are increased in Parkinson's disease neocortex. Ann N Y Acad Sci. 1998;861:288-9.
1. MD PhD. Clínica de Urologia - UROMED, Marília, SP, Brazil
2. MD. Department of Neuroscience and Behavior, Faculty of Medicine of Ribeirão Preto, USP, SP, Brazil
3. MD PhD. Department of Neuroscience and Behavior, Faculty of Medicine of Ribeirão Preto, USP, SP, Brazil
Rua Carlos Botelho, 520
17516-190 Marília SP - Brazil
Received October 11, 2016.
Accepted in final form November 16, 2016.
Disclosure: The authors report no conflicts of interest.
This study was conducted at the Clínica de Urologia - UROMED, Marília, SP, Brazil.