Urinary Neurotransmitters as Biomarkers

Brainbow, by Lichtman, Livet, & Sanes (2008)

Happy New Year, everyone! In a previous post, we talked about using cytokines as biomarkers. In this post,  NeuroScience‘s David T. Marc, BS, Gottfried H. Kellermann, PhD & J. Fernando Bazan, PhD discuss the utility of urinary neurotransmitters as biomarkers.

In medicine, biomarkers are a powerful means to guide effective treatments; for instance, high cholesterol may identify patients at risk of cardiovascular events, and screening for HER2 expression helps pinpoint those breast cancer patients who are most likely to benefit from Herceptin treatment. While biomarkers are well-accepted in cardiovascular disease and oncology, neurological disorders lag in the availability of clinical biomarkers, notwithstanding that medications that alter neurological actions are widely used.

The few available neurological biomarkers are met with some with opposition, because most are not measured directly in the brain, but rather in blood, urine, and cerebrospinal fluid (CSF) (Fisar & Raboch, 2008). A common misconception is that the peripheral and central nervous systems (PNS and CNS) are dissociated (Elenkov et al., 2000) and therefore circulating neurotransmitters cannot be considered biomarkers of brain activity.

However, evidence suggests that there is significant molecular cross-talk between the PNS and CNS (Lechin, 2009; Salome et al., 2006). The brain-gut connection is a great example of this linkage. Nerves allow communication from the gut to the brain to signal satiety in the hypothalamus (Wang et al., 1998; Barrachina et al., 1997). Likewise, nerves leading from the brain to the gut can elicit changes in digestion (Janig & Morrison, 1986). Given these and other examples of PNS-CNS cross-talk, it’s clear that (1) neurotransmitters in the CNS can manipulate peripheral neurochemistry, and vice-versa (Berthoud & Neuhuber, 2000), and (2) CNS activity can arguably be inferred from peripheral neurotransmitter biomarker levels (Lechin et al., 1996).

The advantages of measuring neurotransmitters in urine, as compared to blood or CSF, include non-invasive specimen collection, stability of the sample, and over 60 years of documented clinical utility (Rosano et al., 1950). Early attempts to establish urinary neurotransmitters as biomarkers focused on the diagnoses of depression, anxiety, and attention-deficit-hyperactivity disorder (Pliszka et al., 1994; Zametkin et al., 1985; Kopin, 1984; Koslow et al., 1983). In our recent comprehensive review by Marc et al. in Neuroscience and Biobehavioral Reviews, we summarized peer-reviewed studies that clearly demonstrate the correlation of urinary neurotransmitters with clinical conditions and their ability to predict treatment outcomes, which can have a huge impact for managing patient care.

Many neurotransmitter-related disorders, as well as clinical interventions, affect neurotransmitter levels. Unfortunately, due to the spectral nature of these disorders, as well as frequent comorbidity, treatment success is difficult to achieve (Benazzi, 2006; Nemeroff, 2007). Comprehensive assessment of urinary neurotransmitters allows health care practitioners to improve health outcomes by better guiding the selection of specific interventions (Schwarz & Bahn, 2008; Le-Niculescu et al., 2008).

In an upcoming blog post, we’ll delve deeper into the idea that urinary neurotransmitters are biomarkers that reflect CNS activity, and introduce the concept of NeuroCircuitry. Briefly, NeuroCircuitry uses peer-reviewed literature and emerging systems biology databases and tools to model pathways by which PNS-CNS crosstalk occurs. The NeuroCircuitry model enhances the utility of peripheral neurotransmitter biomarkers in assessing CNS function and predicting responses to intervention, thus offering an even greater opportunity to guide individualized treatment selection.

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5 Responses to Urinary Neurotransmitters as Biomarkers

  1. Pingback: Mapping Neural Connections: The NeuroCircuitry Model | The NEI Connection

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  5. Dear Dr. Kellermann-
    I enjoyed your talk at the 2011 ILADS conference, and I am now attempting to understand how your company has determined what “normal” values for CNS neurotransmitters should be.

    My son Christopher recently completed the current NIH bipolar/ketamine efficacy trial as an in-patient at the NIH clinical center (a double-blind placebo/ketamine crossover infusion of 0.5 mg/kg of ketamine vs. normal saline over 40 minutes). His medical records do not suggest that neurotransmitter levels were measured pre or post treatment (but they may have been). NIH has reported a 71% positive response to ketamine in bipolar patients and 76% in MDD patients. As you are aware, Ketamine blocks the NMDA receptor from glutamate ingress and upregulates the AMPA receptor. NIH does not pretend to know why this has such a powerful anti-depressant effect, but is starting “mechanism of action” trials this year.

    There is little doubt that my son suffers from a significant chemical/neurotransmitter imbalance, but the question would seem to be: what is it, and how can it be corrected? If you can help me with this mystery, I would be grateful. I am very impressed with the work that your company is doing, and hope to understand it more fully as the year progresses. Thank you.

    Peter Brengel PA-C, MPAS, MBA

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