Neurotransmitter Testing – Giving a Diagnostic Edge in Treating Mood Disorders
Mental health disorders affect millions of people in the United States and profoundly contribute to the burden of disease in society. The National Alliance of Mental Illness reports that nearly 7% of American adults live with major depression and approximately 18% live with anxiety disorders such as panic disorder, obsessive compulsive disorder, post traumatic stress disorder, generalized anxiety disorder, and phobias. (1)Mood disorders are the third most common cause of hospitalization in the U.S. for individuals aged 18 to 44 . The top-prescribed and top-selling prescription drugs in the U.S. in 2014 included antipsychotics, antidepressants, and attention-deficit disorder drugs.
The current treatment paradigm in addressing poor brain health relies on diagnostic tools that encompass the evaluation of clinical signs and symptoms. Despite the lack of testable biomarkers for mood disorders, for many patients, treatments can generally be effective. However, even after treatment frequent relapse episodes can still occur. Furthermore, a large number of patients suffer from treatment-resistant depression3. Therefore, selection of the best therapeutic regimen for each patient remains a challenge, and is often discovered through a time-consuming process of trial and error. Also, no single approach works for everyone with any one disorder.
Targeted neurotransmitter testing can help health care practitioners achieve a diagnostic edge beyond the traditional psychological inventory by identifying specific i mbalances i n n eurotransmitter l evels. B ased o n n eurotransmitter test results, practitioners can identify specific biochemical heterogeneities for each particular patient, and objectively monitor therapeutic responses during and after intervention. Neurotransmitter testing objectively enhances medical assessment and represents a major advance in the personalization of the treatment of mood disorders.
Why We Test Neurotransmitters
The etiology of mood disorders is profoundly complex and likely encompasses many different types of neurotransmitters, how they achieve balance in the brain and in the gut axis, and how they each interplay with other hormone systems throughout the body. Appropriate balancing of neurotransmitter signals allows the body to maintain equilibrium. When brain and peripheral neurochemistry become unbalanced, the body will struggle to re-establish physiological integrity, which may present in the form of suboptimal psychological well-being. Excessive or deficient levels of certain neurotransmitters in both the brain and in the periphery are associated with a spectrum of neurobiological disorders, such as depression and anxiety. The measurement of specific imbalances may be a very effective neurobiological tool in guiding targeted intervention, aimed at addressing the individual excess or deficiency in question.
Is Testing Neurotransmitters in Urine Accurate
The importance of effectively assessing and treating mood disorders cannot be overstated. Objectivity is a key element to the therapeutic approach to mood disorders. Currently, the standard of care dictates a trial and error pharmaceutical approach is taken with each patient based on both self and clinician assessments. However, without information yielded from objective clinical testing, selection of the most effective treatment for each particular patient with a mood disorder continues to be a challenge. While this may prove effective for some patients, the potential for harm during those interim treatment failures is a real concern for clinicians and patients alike.
Urinary neurotransmitter testing is performed with the goal that therapeutic interventions may be introduced to address, alleviate, and improve a patient’s well-being and has a breadth of data to support the efficacy of the test in clinical practice (see Table on next page). Evaluation of neurotransmitter levels in urine provides valuable information about the heterogeneity of patient biochemistry, epigenetics, and how the body functions as a whole.
Although the urine test is not a direct measure of brain neurotransmitter levels, it provides relevant information with respect to neurotransmitter regulation in the brain, which can be altered by treatment. The levels in urine often parallel levels in the central nervous system, and the test may therefore assist in the selection of patients with mood issues who might respond to specific pharmaceutical or over-the-counter treatment interventions 58,59. In other words, the test provides a means to glean a functional systemic perspective regarding each neurotransmitter in the periphery, which ultimately operates under the control of the brain.
How do Neurotransmitters end up in urine?
Some neuro- transmitters are produced in the brain and transported across the blood-brain barrier into blood, and others are produced in the periphery (e.g., norepinephrine and epinephrine). Nephrons, the functional units of the kidney, filter circulating neurotransmitters or their precursors from the blood into urine (60)
For some neurotransmitters, urinary measurements correlate with levels in the central nervous system (e.g., glutamate, PEA), and for others, what ends up in urine is only reflective of peripheral biosynthesis (e. g., serotonin, GABA, dopamine, norepinephrine, epinephrine). Regardless of production origin, neurotransmitter excretion reflects the overall systemic neurotransmitter tone, dysregulation of which may contribute to disease states. The ability to identify abnormality across specific areas of the catecholamine and PEA, GABA/ glutamate, serotonin, histamine, and glycine pathways allows healthcare providers to develop a tailored treatment plan to the specific areas associated with imbalance.
What You should Know before you run a Urinary Neurotransmitter Test
- The neurotransmitter test assumes proper kidney function. Neurotransmitter levels are reported in μg/g creatinine, where creatinine is measured from the same sample. This test should not be used in individuals with compromised renal function.
- The sample can become very dilute due to increased fluid consumption during the day. Therefore, on the day of testing, individuals should restrict their liquid intake to normal consumption.
- On the day of testing, individuals are advised to refrain from consuming alcohol, nicotine, bananas, pineapple, and walnuts as they may interfere with testing.
Neurotransmitter | High Levels in Urine | Low Levels in Urine |
Serotonin is the “housekeeping” molecule – promotes healthy sleep, regulates appetite, improves mood, supports healthy digestive function and so much more. 5-HIAA is a metabolite. | Serotonin is high in depression4,5 and with 5HTP use6, and is implicated in anxiety, dysbiosis, irritability, and low libido. | Serotonin is decreased in autism spectrum disorder7, depression8, with oral contraceptives9,10 and may be associated with anxiety, low mood, irritability, and sleep disturbances. |
GABA functions as the major inhibitory neurotransmitter, induces relaxation and reduces anxiety. | GABA is elevated in sleep apnea11, ovarian cancer12, and is suspected in anxiety, excessive need for sleep, foggy thinking, and lethargy. | Low GABA is implicated in anxiety, sleep difficulties, adrenal distress and hypothalamic pituitary adrenal axis feedback dysfunction. Low GABA levels are associated with disorders like ADHD and Tourette syndrome13. |
Glycine plays a dual role as a neurotransmitter and an amino acid that serves as a building block to proteins. | Clinically, high glycine levels are suspected in anxiety and may be associated with insufficient vitamin B status and/or methylation events. | Glycine levels are low in diabetes14, hypothyroidism15, obesity16, and after intense exercise17, Clinically, low glycine levels are suspected in depression. |
Glutamate functions as the major excitatory neurotransmitter and metabolic fuel throughout the body. | Glutamate is high in celiac disease18 | Glutamate is low in patients with migraines20. Clinically, low glutamate is implicated in depression, chronic fatigue, lack of concentration, low energy levels, and sleep disturbances. |
Histamine is a neurotransmitter and immuno-modulator. | Histamine is high in cystitis21, flushing disorder22, food allergies23, polycythemia24 and pregnancy25. High histamine may implicate allergies, depression, headaches, migraines, OCD, and sleep difficulties. | Low histamine is associated with fatigue, low libido, low productivity, mild depression, tension headaches, and weight gain. |
PEA serves as a biomarker for ADHD. | PEA is elevated in individuals with bipolar major affective disorder26, anxiety and insomnia27, phenylketonuria28 and with methylphenidate treatment29. | PEA is low in patients with autistic spectrum disorder30, ADHD29,31,32, depression33, and inattentiveness34,35. |
Dopamine serves as the reward and pleasure center in the brain, and messenger of the sympathetic nervous system in the periphery. DOPAC and HVA are metabolites. | High dopamine is reported in patients with high in anxiety36, stress37, paroxysmal hypertension38, primary aldosteronism39, PTSD40, and mercury toxicity41. | Dopamine is low in Alzheimer’s disease42, anorexia nervosa43, fibromyalgia44, hypertension45, periodic limb movement disorder46, sleep disturbances47, hypoadrenergic orthostatic hypotension48. |
Epinephrine and norepinephrine regulate the “fight or flight” response. Normetanephrine is a norepinephrine metabolite, and VMA is a norepinephrine and epinephrine metabolite. | Epinephrine and norepinephrine levels are high in patients with anxiety49,50, ADHD34,35, bipolar disorder51, depression52, hyperglycemia53, sleep apnea11, PTSD40, and stress54,55. | Epinephrine and norepinephrine levels are low in Alzheimer’s disease42, metabolic syndrome56, and obesity57. |
Neurotransmitters You Should Know About
There are many neurotransmitters in the body. The primary messengers are divided into two groups.
Excitatory Neurotransmitters:
- Dopamine, generally regarded as the brain’s pleasure and reward center, plays the central role in addiction, improves attention, focus and motivation, and modulates movement control
- Epinephrine and Norepinephrine regulate the “fight or flight” response, elevated blood pressure and heart rate,stimulate wakefulness and reduce digestive
- Glutamate functions as the “on” switch in the brain. It’s the major excitatory neurotransmitter that decreases sleep, optimizes learning, memory and mood and improves libido.
- Histamine plays a role in the body as a neurotransmitter that increases metabolism, promotes wakefulness and suppresses appetite.
- PEA (phenylethylamine) promotes energy, elevates mood, regulates attention, aggression and serves as a biomarker for ADHD.
- Serotonin, generally regarded as the “happiness molecule,” contributes to the feeling of calm and well-being that eases depression and anxiety, supports sleep and decreases appetite
Inhibitory Neurotransmitters:
- GABA functions as the “off” switch in the brain. It’s the major inhibitory neurotransmitter that improves mood, relieves anxiety and promotes sleep.
- Glycine plays a dual role as a neurotransmitter and amino acid that serves as a building block to proteins, improves sleep quality, calms aggression and serves as an anti-inflammatory agent.
- Serotonin, generally regarded as the “happiness molecule,” contributes to the feeling of calm and well-being that eases depression and anxiety, supports sleep and decreases appetite.
Neurotransmitter Imbalance & Chronic Conditions
Numerous neurotransmitter imbalances may cause persistent health concerns:
- Anxiety & Depression: Imbalances are often associated with Glutamate (panic attacks), PEA, Histamine, Serotonin, as well asEpinephrine and
- Fatigue: An imbalance between excitatory and inhibitory neurotransmitters is
- Impulsivity: GABA, Dopamine and Serotonin are three chemical messengerscommonly linked to disorders like ADD, ADHD and
- Insomnia: Glutamate, Histamine, Dopamine, GABA and Serotonin are severalchemical messengers often linked to sleep disturbances and
- PMS or PMDD: Imbalances such as Serotonin, Dopamine, Norepinephrine and GABA are often
- Do you often feel worried or anxious?
- Is your mood low – do you struggle to be happy?
- Are you prone to panic attacks – heart racing, difficulty breathing?
- Do you struggle with impulsivity issues?
- Do you have issues with addictions – food, medications, drugs or alcohol?
- Have you been diagnosed with a mental health disorder?
- Are you easily agitated, or prone to irritation and impatience?
- Do you harbor negative or critical feelings?
- Do you have a gloomy outlook or pessimistic thoughts?
- Do you feel overwhelmed by life or feel like your life is out of control?
- Do you find it hard to get out of bed most mornings?
- Is it impossible for you to get going without coffee or sugary drinks/foods?
- Do you often feel “tired and wired”?
- Do you often have sleep disturbances, restlessness or bad dreams?
- Do you have repetitive behaviors – like handwashing, cleaning or checking and straightening objects?
- Are you prone to hyperactivity or poor concentration?
- Do you get symptoms of excessive moodiness, tears, anger or depression around your period?
Common neurotransmitter-related causes of health issues often involve the following scenarios:
Neurotransmitter imbalances are often associated with anxiety and depression, specifically Glutamate (panic attacks), PEA, Histamine, Serotonin, as well as Epinephrine & Norepinephrine. Learn how Epinephrine & Norepinephrine affect chronic stress.
An imbalance between excitatory and inhibitory neurotransmitters can lead to persistent fatigue.
GABA, Dopamine and Serotonin are three chemical messengers commonly linked to disorders like ADD, ADHD & OCD.
Imbalances in Glutamate, Histamine, Dopamine, GABA and Serotonin are often linked to sleep disturbances and insomnia.
Imbalances in Serotonin, Dopamine, Norepinephrine and GABA are often involved in cases of PMDD (pre-menstrual dysphoric disorder) and severe PMS.
We will also go over recommendations for a treatment plan and the cost.
A treatment plan often Focuses on the Following.
Disclaimer: At-home lab testing is not intended to diagnose, treat, cure or prevent any disease and is not meant as a substitute for or alternative to information from your medical doctor.
References :
- National Alliance on Mental Illness. Mental Illness. Facts and Numbers. 2013.
- Brooks M. Top 100 Most Prescribed, Top-Selling Drugs. Medscape 2014.
- Eby GA, III, Eby KL. Magnesium for treatment-resistant depression: a review and hypothesis. Med Hypotheses 2010;74:649-60.
- Mitani H, Shirayama Y, Yamada T, Kawahara R. Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:531-4.
- Audhya T, Adams JB, Johansen L. Correlation of serotonin levels in CSF, platelets, plasma, and urine. Biochim Biophys Acta. 2012;1820:1496-501.
- Joy T, Walsh G, Tokmakejian S, Van Uum SH. Increase of urinary 5-hydroxyindoleacetic acid excretion but not serum chromogranin A following over-the-counter 5-hydroxytryptophan intake. Can J Gastroenterol. 2008;22:49-53.
- Gevi F, Zolla L, Gabriele S, Persico AM. Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism. Mol Autism. 2016;7:47.
- Nichkova MI, Huisman H, Wynveen PM, et al. Evaluation of
- a novel ELISA for serotonin: urinary serotonin as a potential biomarker for depression. Anal Bioanal Chem 2012;402:1593- 600.
- Shaarawy M, Fayad M, Nagui AR, Abdel-Azim S. Serotonin metabolism and depression in oral contraceptive users. Contraception. 1982;26:193-204.
- Var C, Keller S, Tung R, et al. Supplementation with vitamin B6 reduces side effects in Cambodian women using oral contraception. Nutrients. 2014;6:3353-62.
- Kheirandish-Gozal L, McManus CJ, Kellermann GH, et al. Urinary neurotransmitters are selectively altered in children with obstructive sleep apnea and predict cognitive morbidity. Chest 2013;143:1576-83.
- Nicholson-Guthrie CS, Guthrie GD, Sutton GP, Baenziger JC. Urine GABA levels in ovarian cancer patients: elevated GABA in malignancy. Cancer Lett 2001;162:27-30.
- Perlmutter D, Loberg K. Brain Maker. The Power of Gut Microbes to Heal and Protect Your Brain – for Life. Little, Brown and Company, Hachette Book Group, 2015.
- Sasaki M, Sato K, Maruhama Y. Rapid changes in urinary serine and branched-chain amino acid excretion among diabetic patients during insulin treatment. Diabetes Res Clin Pract. 1988;5:219-24.
- Friedrich N, Pietzner M, Cannet C, et al. Urinary metabolomics reveals glycemic and coffee associated signatures of
- thyroid function in two population-based cohorts. PLoS One. 2017;12:e0173078.
- Ahmad MS, Alsaleh M, Kimhofer T, et al. Metabolic Phenotype of Obesity in a Saudi Population. J Proteome Res. 2017;16:635-44
- Corsetti R, Barassi A, Perego S, et al. Changes in urinary amino acids excretion in relationship with muscle activity markers over a professional cycling stage race: in search of fatigue markers. Amino Acids. 2016;48:183-92
- Marko AM, Gerrard JW, Buchan DJ. Glutamic acid derivatives inadult celiac disease. II. Urinary total glutamic acid excretion. Can Med Assoc J 1960;83:1324-5.
- Belanger R, Chandramohan N, Misbin R, Rivlin RS. Tyrosine and glutamic acid in plasma and urine of patients with altered thyroid function. Metabolism 1972;21:855-65.
- Ragginer C, Lechner A, Bernecker C, et al. Reduced urinary glutamate levels are associated with the frequency of migraine attacks in females. Eur J Neurol 2012;19:1146-50.
- el-Mansoury M, Boucher W, Sant GR, Theoharides TC. Increased urine histamine and methylhistamine in interstitial cystitis. J Urol. 1994;152:350-3.
- Myers G, Donlon M, Kaliner M. Measurement of urinary histamine:development of methodology and normal values. J Allergy Clin Immunol. 1981;67:305-11.
- Raithel M, Hagel A, Albrecht H, et al. Excretion of urinary histamine and N-tele methylhistamine in patients with gastrointestinal food allergy compared to non-allergic controls during an unrestricted diet and a hypoallergenic diet. BMC Gastroenterol. 2015;15:41.
- Horakova Z, Keiser HR, Beaven MA. Blood and urine histamine levels in normal and pathological states as measured by a radiochemical assay. Clin Chim Acta. 1977;79:447-56.
- Harrison VC, Peat G, de Heese HV. Fetal growth in relation to histamine concentration in urine. J Obstet Gynaecol Br Commonw. 1974;81:686-90.
- Karoum F, Linnoila M, Potter WZ, et al. Fluctuating high urinary phenylethylamine excretion rates in some bipolar affective disorder patients. Psychiatry Res 1982;6:215-22.
- DeLisi LE, Murphy DL, Karoum F, et al. Phenylethylamine excretion in depression. Psychiatry Res 1984;13:193-201.
- Reynolds GP, Seakins JW, Gray DO. The urinary excretion of 2-phenylethylamine in phenylketonuria. Clin Chim Acta. 1978;83:33-9.
- Kusaga A, Yamashita Y, Koeda T, et al. Increased urine phenylethylamine after methylphenidate treatment in children with ADHD. Ann Neurol 2002;52:372-4.
- Kusaga A. [Decreased beta-phenylethylamine in urine of children with attention deficit hyperactivity disorder and autistic disorder]. No To Hattatsu. 2002;34:243-8.
- Baker GB, Bornstein RA, Rouget AC, et al. Phenylethylaminergic mechanisms in attention-deficit disorder. Biol Psychiatry 1991;29:15-22.
- Irsfeld M, Spadafore M, Pruss BM: Beta-phenylethylamine, a small molecule with a large impact. Webmedcentral 2013;4:pii 4409.
- Sabelli HC, Fawcett J, Gusovsky F, et al. Urinary phenyl acetate: a diagnostic test for depression? Science. 1983;220:1187-8. 34. Faraone SV, Bonvicini C, Scassellati C. Biomarkers in the diagnosis of ADHD–promising directions. Curr Psychiatry Rep 2014;16:497.
- Scassellati C, Bonvicini C, Faraone SV, Gennarelli M: Biomarkers and attention-deficit/hyperactivity disorder: a systematic review 866.600.1636 | [email protected] | zrtlab.com and meta-analyses. J Am Acad Child Adolesc Psychiatry 2012;51:1003-19.
- Field T, Diego M, Hernandez-Reif M, et al. Prenatal dopamine and neonatal behavior and biochemistry. Infant Behav Dev. 2008;31:590-3.
- Ghaddar A, Omar KH, Dokmak M, et al. Work-related stress and urinary catecholamines among laboratory technicians. J Occup controlled, univariate analysis. Arch Gen Psychiatry 1983;40:999-1010.
- Kuchel O, Buu NT, Larochelle P, et al. Episodic dopamine 77. discharge in paroxysmal hypertension. Page’s syndrome revisited. Arch Intern Med. 1986;146:1315-20.
- Ishiguro T, Shimamoto K, Sakamoto T, et al. Renal dopaminergic activity in patients with primary aldosteronism. Hypertens Res. 1995;18 Suppl 1:S193-S5.
- Yehuda R, Southwick S, Giller EL, et al. Urinary catecholamine excretion and severity of PTSD symptoms in Vietnam combat veterans. J Nerv Ment Dis 1992;180:321-5. Houston MC. Role of mercury toxicity in hypertension, cardiovascular disease, and stroke.
- J Clin Hypertens (Greenwich) 2011;13:621-7. Liu L, Li Q, Li N, et al. Simultaneous determination of catecholamines and their metabolites related to Alzheimer’s disease in human urine.
- J Sep Sci 2011;34:1198-204. Van Binsbergen CJ, Odink J, Van der Beek EJ, et al. Biogenic amines in anorexia nervosa: circadian rhythm in urinary excretion and influence of posture and physical task load on plasma catecholamines. Psychosom Med 1991;53:440-52.
- Riva R, Mork PJ, Westgaard RH, et al. Catecholamines and heart rate in female fibromyalgia patients. J Psychosom Res 2012;72:51-7.
- Gill JR, Jr., Grossman E, Goldstein DS. High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension. Hypertension. 1991;18:614-21.
- Cohrs S, Guan Z, Pohlmann K, et al. Nocturnal urinary dopamine excretion is reduced in otherwise healthy subjects with periodic leg movements in sleep. Neurosci Lett 2004;360:161-4.
- Seay JS, McIntosh R, Fekete EM, et al. Self-reported sleep disturbance is associated with lower CD4 count and 24-h urinary dopamine levels in ethnic minority women living with HIV. Psychoneuroendocrinology 2013;38:2647-53.
- Kuchel O, Buu NT, Hamet P, et al. Orthostatic hypotension: a posture-induced hyperdopaminergic state. Am J Med Sci. 1985;289:3-11.
- Paine NJ, Watkins LL, Blumenthal JA, et al. Association of depressive and anxiety symptoms with 24-hour urinary catecholamines in individuals with untreated high blood pressure. Psychosom Med 2015;77:136-44.
- Hughes JW, Watkins L, Blumenthal JA, et al. Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J Psychosom Res 2004;57:353-8.
- Koslow SH, Maas JW, Bowden CL, et al. CSF and urinary biogenic amines and metabolites in depression and mania. A
- Holzman C, Senagore P, Tian Y, et al. Maternal catecholamine levels in midpregnancy and risk of preterm delivery. Am J Epidemiol 2009;170:1014-24.
- Fujiwara K, Tsukishima E, Kasai S, et al. Urinary catecholamines and salivary cortisol on workdays and days off in relation to job strain among female health care providers. Scand J Work Environ Health 2004;30:129-38.
- Lee ZS, Critchley JA, Tomlinson B, et al. Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese. Metabolism 2001;50:135-43.
- Grossman F, Potter WZ. Catecholamines in depression: a cumulative study of urinary norepinephrine and its major metabolites in unipolar and bipolar depressed patients versus healthy volunteers at the NIMH. Psychiatry Res 1999;87:21-7.
- Troisi RJ, Weiss ST, Parker DR, et al. Relation of obesity and diet to sympathetic nervous system activity. Hypertension. 1991;17:669- Health 2014;55:398-404.
- Landsberg L, Troisi R, Parker D, et al. Obesity, blood pressure, and the sympathetic nervous system. Ann Epidemiol 1991;1:295-303.
- Ravindran AV, Bialik RJ, Brown GM, Lapierre YD. Primary early onset dysthymia, biochemical correlates of the therapeutic response to fluoxetine: II. Urinary metabolites of serotonin, norepinephrine, epinephrine and melatonin. J Affect Disord. 1994;31:119-23.
- Maas JW, Koslow SH, Katz MM, et al. Pretreatment neurotransmitter metabolite levels and response to tricyclic antidepressant drugs. Am J Psychiatry. 1984;141:1159-71.
- Pestana M, Jardim H, Correia F, et al. Renal dopaminergic mechanisms in renal parenchymal diseases and hypertension. Nephrol Dial Transplant. 2001;16 Suppl 1:53-9.