A new systematic review published in JAMA Network on October 14, 2019, finds that the risk of Parkinson's disease (PD) is significantly higher in people who have been diagnosed with bipolar disorder (BD). Patients who have BD should, therefore, be investigated for PD if any features of this condition appear, without ascribing it to the effects of the antipsychotic medication that they are taking.
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The researchers systematically reviewed and performed a meta-analysis of seven studies, which included more than one million participants who had a diagnosis of BD, to detect the incidence of idiopathic PD in this group. They found that the odds of developing PD were more than three times higher in this group than the odds in the general population.
PD is a neurological disorder that presents with both muscular and other symptoms – resting tremor, the paucity of movements, rigidity, and unstable posture. In many patients with PD, disorders of mood may be the first symptom to appear, almost 10 years earlier than the first muscle-related symptom.
BD is a mood disorder that sets in at an average of 20 years and persists over the long term. Its predominant feature is the recurrence of episodes of depression and mania or of depression and hypomania, classified as BD 1 and BD 2, respectively. Both genetic and environmental factors play a role in the development of this disorder.
The drug levodopa, which increases dopamine levels in the brain, can cause manic or hypomanic symptoms in BD, while dopamine antagonists improve the symptoms. Some evidence suggests an increase in dopamine receptors in the brain coinciding with the occurrence of mania.
BD is treated with lithium and antipsychotic drugs, as well as anti-seizure drugs, among others. Some of these agents cause drug-induced parkinsonism, a syndrome that closely mimics PD. However, some patients with BD may have PD that is misdiagnosed as a drug reaction, leading to inappropriate management. This is all the more likely in that PD onset is typically in older individuals.
BD is also more common, perhaps, in individuals who have PD, and hence the current study explored the association of these conditions.
One study with over 73,000 patients comprised about 1,200 BD patients, the rest having other psychiatric conditions. Over the next six years, those with BD were at a fivefold risk of PD.
In another study comparing lithium with antidepressant use in BD, lithium use in isolation increased PD risk or the risk of using an antiparkinson drug by 68% in patients who had not had parkinsonian symptoms over the last five years, compared to unipolar depression patients on antidepressants – even though the latter group is known to have an increased risk of PD.
Other studies also reflect an increased risk of PD in the group with BD, though data quality is uneven in some of them. Further analysis using only studies with valid data, and excluding studies with a high risk of bias, continued to show a higher chance of subsequent PD diagnosis in patients with BD. This risk remained higher in subgroups followed up for more or less than nine years.
Both BD and PD are the result of altered dopamine levels in the brain. Whatever underlying phenomenon is causing the cyclicity of BD, it is associated with the reduced expression of dopamine sensitivity with depressive symptoms, followed by the upregulation of dopamine receptors leading to mania. As the cycle persists, it may result in an overall persistent lowering of dopamine activity, which is typical of PD. This could well explain why PD develops in BD patients over time.
Another supporting bit of evidence is the recognized existence of mood changes in PD, which correlate with the control of symptoms or lack of them, with the current stable dose of PD medication. Off-time refers to the period of the day when the symptoms fail to respond to medication, while on-time means adequate control is achieved. It is known that manic symptoms are common in the on-time phase and depressive symptoms during the off-time phase.
Lithium is the base drug in the treatment of BD and can itself cause parkinsonian symptoms along with other drugs used in this condition. Simply recognizing this association should lead to greater efforts to recognize and mitigate Parkinson-like symptoms, whether due to PD or drug-induced parkinsonism.
The distinctions are also important: BD is not linked to actual physical break down of neurons, and the on-time off-time mood fluctuations in PD are not the same as the much longer mood changes in BD, in which other neurotransmitters are also involved.
BD thus acts as a high-risk population that should be screened for the development of PD. Further research should concentrate on finding the common genetic factors for both conditions, if any, the increased risk of PD with other environmental and genetic contributors, and whether BD is indeed an earlier marker of an underlying degenerative condition of the brain. Better study design, using larger cohorts, clearly defined criteria rather than self-reported or database diagnoses, and longer follow-up periods to capture the later age of onset of PD would help greatly to find answers to these questions.
Risk of developing Parkinson disease in bipolar disorder: a systematic review and meta-analysis. Patrícia R. Faustino, Gonçalo S. Duarte, Inês Chendo, Ana Castro Caldas, Sofia Reimão, Ricardo M. Fernandes, José Vale, Michele Tinazzi, Kailash Bhatia, & Joaquim J. Ferreira. JAMA Network October 14, 2019. doi:10.1001/jamaneurol.2019.3446. https://jamanetwork.com/journals/jamaneurology/fullarticle/2752486