Costello Harry, Schrag Anette-Eleonore, Howard Robert, Roiser Jonathan P
Institute of Cognitive Neuroscience, University College London, London, UK.
Division of Psychiatry, University College London, London, UK.
medRxiv. 2023 Jun 30:2023.06.30.23292073. doi: 10.1101/2023.06.30.23292073.
Depression in Parkinson's disease (PD) is common, disabling and responds poorly to standard antidepressant medication. Motivational symptoms of depression, such as apathy and anhedonia, are particularly prevalent in depression in PD and predict poor response to antidepressant treatment. Loss of dopaminergic innervation of the striatum is associated with emergence of motivational symptoms in PD, and mood fluctuations correlate with dopamine availability. Accordingly, optimising dopaminergic treatment for PD can improve depressive symptoms, and dopamine agonists have shown promising effects in improving apathy. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known.
We hypothesised that there would be dissociable effects of dopaminergic medications on different depression symptom dimensions. We predicted that dopaminergic medication would specifically improve motivational symptoms, but not other symptoms, of depression. We also hypothesised that antidepressant effects of dopaminergic medications with mechanisms of action reliant on pre-synaptic dopamine neuron integrity would attenuate as pre-synaptic dopaminergic neurodegeneration progresses.
We analysed data from a longitudinal study of 412 newly diagnosed PD patients followed over five years in the Parkinson's Progression Markers Initiative cohort. Medication state for individual classes of Parkinson's medications was recorded annually. Previously validated "motivation" and "depression" dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging.
Linear mixed-effects modelling was performed across all simultaneously acquired data points. Dopamine agonist use was associated with relatively fewer motivation symptoms as time progressed (interaction: β=-0.07, 95%CI [-0.13,-0.01], p=0.015) but had no effect on the depression symptom dimension (p=0.6). In contrast, monoamine oxidase-B (MAO-B) inhibitor use was associated with relatively fewer depression symptoms across all years (β=-0.41, 95%CI [-0.81,-0.01], p=0.047). No associations were observed between either depression or motivation symptoms and levodopa or amantadine use. There was a significant interaction between striatal DAT binding and MAO-B inhibitor use on motivation symptoms: MAO-B inhibitor use was associated with lower motivation symptoms in patients with higher striatal DAT binding (interaction: β=-0.24, 95%CI [-0.43, -0.05], p=0.012). No other medication effects were moderated by striatal DAT binding measures.
We identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists may be effective for treatment of motivational symptoms of depression. In contrast, MAO-B inhibitors may improve both depressive and motivation symptoms, albeit the latter effect appears to be attenuated in patients with more severe striatal dopaminergic neurodegeneration, which may be a consequence of dependence on pre-synaptic dopaminergic neuron integrity.
帕金森病（PD）中的抑郁很常见，会导致功能障碍，且对标准抗抑郁药物反应不佳。抑郁的动机性症状，如冷漠和快感缺失，在PD抑郁中尤为普遍，并预示着对抗抑郁治疗反应不佳。纹状体多巴胺能神经支配的丧失与PD中动机性症状的出现有关，情绪波动与多巴胺可用性相关。因此，优化PD的多巴胺能治疗可改善抑郁症状，多巴胺激动剂在改善冷漠方面已显示出有前景的效果。然而，抗帕金森药物对抑郁症状维度的不同影响尚不清楚。
我们假设多巴胺能药物对不同的抑郁症状维度有可分离的影响。我们预测多巴胺能药物将特异性改善抑郁的动机性症状，但对其他症状无效。我们还假设，作用机制依赖于突触前多巴胺神经元完整性的多巴胺能药物的抗抑郁作用会随着突触前多巴胺能神经变性的进展而减弱。
我们分析了帕金森病进展标志物倡议队列中412名新诊断的PD患者进行的为期五年的纵向研究数据。每年记录各类帕金森病药物的用药状态。先前验证的“动机”和“抑郁”维度源自15项老年抑郁量表。使用重复的纹状体多巴胺转运体（DAT）成像测量多巴胺能神经变性。
对所有同时获取的数据点进行线性混合效应建模。随着时间的推移，使用多巴胺激动剂与动机症状相对较少相关（交互作用：β=-0.07，95%CI[-0.13，-0.01]，p=0.015），但对抑郁症状维度无影响（p=0.6）。相比之下，在所有年份中，使用单胺氧化酶-B（MAO-B）抑制剂与抑郁症状相对较少相关（β=-0.41，95%CI[-0.81，-0.01]，p=0.047）。未观察到抑郁或动机症状与左旋多巴或金刚烷胺使用之间的关联。纹状体DAT结合与MAO-B抑制剂使用对动机症状有显著交互作用：在纹状体DAT结合较高的患者中，使用MAO-B抑制剂与较低的动机症状相关（交互作用：β=-0.24，95%CI[-0.43，-0.05]，p=0.012）。纹状体DAT结合测量未调节其他药物作用。
我们确定了多巴胺能药物与PD中不同抑郁维度之间的可分离关联。多巴胺激动剂可能对治疗抑郁的动机性症状有效。相比之下，MAO-B抑制剂可能改善抑郁和动机症状，尽管在纹状体多巴胺能神经变性更严重的患者中，后一种作用似乎减弱，这可能是依赖于突触前多巴胺能神经元完整性的结果。
