Urinary Neurotransmitter Analysis
Utility in depression management
Given the pervasiveness of anxiety and depression in today’s society and the limitations of the current standard of care for many patients, there is a need for reliable neurobiological assessments that objectively identify underlying biochemical abnormalities as plausible therapeutic targets. Measurement of neurotransmitters is an excellent candidate to serve as an objective framework of diagnosis, prognosis, and response to treatment in psychiatry; neurotransmitters can be measured in various biological fluids including blood serum, platelets, cerebral spinal fluid (CSF), saliva, and urine. Currently biomarkers for depression and anxiety are not utilized in standard medical practice, and tools upon which to base treatment decisions are restricted to the evaluation of subjective clinical symptoms. Without information yielded from objective testing, selection of the best treatment for each person with a mood disorder remains challenging, and is often determined through a time-consuming process of trial and error. Urinary neurotransmitter testing is rapidly becoming the preferred bodily fluid for objective neurobiological assessment since a) urine is the primary route of neurotransmitter elimination, and b) it is a non-invasive and cost effective testing method.
Introduction
The nervous system is the central control mechanism for nearly every bodily process. Within the nervous system neurotransmitters serve as chemical messengers for trillions of connections between the brain and target tissues, and they are essential for maintaining body homeostasis (Marc 2011). In response to prolonged stress however, the biological system begins to lose its ability to maintain chemical homeostasis; as a result, disease processes may be initiated (Lurie 1991). Imbalances in neurotransmission, due to excessive or deficient levels of certain neurotransmitters, are associated with depression, anxiety, insomnia, behavioral disorders, memory disorders, and a spectrum of other neurological disorders (Marc 2011). Since neurotransmitters are thought to play an integral role in mediating these disease processes, the measurement of specific imbalances may be of use in guiding targeted interventions that are aimed at correcting the individual excess or deficiency in question.
The importance of effectively assessing and treating depression cannot be overstated. The World Health Organization’s Global Burden of Disease Study places unipolar affective disorder among the 10 leading medical causes of disability in the world, second only to ischaemic heart disease (Murray 1997).
The current standard of care for depression is to embark upon a course of treatment, most likely a pharmaceutical intervention, based on its efficacy in randomized clinical trials, its specificity or “match” for the patient’s symptomatology, or the patient’s previous response(s) to treatment (Fava 2005). The patient is then monitored for a good outcome, allowing for course correction if there is no improvement. Both steps fundamentally rely on clinical findings and subjective data. Clearly, objective data would further enhance the medical assessment, if available (Holsboer 2008).
Clinical Utility of Biomarkers
As in any other disease state, a primary goal in the research of mental health disorders is the identification of specific biomarkers that could enhance the ability to develop targeted patient treatments in order to enhance patient management and to improve treatment success (Holsboer 2008).
Biomarkers are commonplace in most branches of medicine. For example, if a patient has cancer, heart failure or even a bladder infection, a medical practitioner will likely intervene with the appropriate laboratory testing before committing to any course of treatment. Tumor markers are used in oncology (Srinivas 2001), troponin is a biomarker in cardiology (Sato 2012), C-reactive protein (CRP) and Rheumatoid Factor (RF) are biomarkers in rheumatology (Dasgupta 2012), and prostatespecific antigen (PSA) is used in the detection and management of prostate cancer (Chang 2012). In the context of these conditions, biomarkers are important for diagnosis, early detection, patient monitoring, prognosis, prediction of safety and appropriate dosing.
With so many biomarkers available for other medical conditions, why is there no formalized biomarker in psychiatry? In the past, biomarkers for brain health assessments have been viewed as irrelevant to symptomatology because measures had included peripheral biological fluids (blood, urine, and saliva) as opposed to central nervous system markers, such as cerebrospinal fluid and brain tissue, which are far too costly and invasive to use in clinical practice (Roy 1988).
A common misconception about peripheral biochemistry is that it cannot serve as a biological indicator of central nervous system (CNS) activity due to the presence of the blood-brain-barrier, which limits the transport of neurotransmitters from the peripheral nervous system (PNS) to the CNS and vice versa. The CNS and PNS must not be viewed as separate entities, however. In reality, central neurotransmitters are carried to the periphery via specific blood brain barrier (BBB) transporters followed by renal filtration with subsequent excretion of neurotransmitters in the urine (Lechin 2006). A study by Lechin demonstrated that specific CNS nuclei can manipulate peripheral neurochemistry, and peripheral neurochemistry can affect central pathways (e.g. vagal afferents from periphery to CNS) (2006). The CNS and PNS also communicate via direct neuronal projections (Moreira 2011). Finally, animal studies have suggested a relationship between urinary and CNS neurotransmitters (Lynn-Bullock 2004).
The kidneys also have neurotransmitter transport mechanisms. Circulating neurotransmitters are filtered from the blood by nephrons and subsequently excreted in the urine through glomerular filtration and by active transport via organic cation transporters (OCT’s) (Moleman 1992). Two mechanisms of neurotransmitter transport in the kidneys have been well established: (1) monoamine neurotransmitters are excreted by ultrafiltration from arterial blood into the glomeruli, secreted in the proximal tubules, subsequently distributed through the collecting duct to the urinary bladder and excreted in the urine (Graefe 1997); (2) in the luminal and basolateral membranes of the renal proximal tubules, OCT2 is responsible for the reabsorption and secretion of endogenous compounds, including monoamine neurotransmitters (Koepsell 1998).
According to Cook, certain criteria must be met for a biomarker to be considered for psychiatric management (2008). First, the biomarker must be timely, clinically useful, and cost-effective. Second, the technology needed to assess the biomarker must be well tolerated by the target patient population. Third, methods that can be easily integrated into the practitioner’s current practice patterns are more likely to be accepted than those that require a major change in the delivery of care. Urine testing of neurotransmitters satisfies all three of these criteria.
Value of Urinary Neurotransmitter Testing
Many people, patients and practitioners alike, are familiar with the role of serotonin in depression (Genung 2012), and most antidepressant medications target the extracellular availability of serotonin and/or norepinephrine (Rozas 2009). Practitioners are less likely to investigate or address other important neurotransmitters/ neuromodulators involved in brain processes such as GABA, glycine, asparagine, glutamate, taurine, dopamine, epinephrine, norepinephrine, cortisol, phenylalanine, tyrosine, melatonin and histamine (Duncan 2012, Fu 2012, Hovelso 2012, Tamatam, 2012) (See Figures 1,2, and 3). The considerable variability in neurotransmitters/ neuromodulators may provide a possible explanation for why so many people using anti-depressant medications or supplements sometimes find little-to-no relief from their treatment (Eby 2010, Fournier 2010, Rozas 2009); in fact, sixty percent of cases of clinical depression are considered to be treatment-resistant (Eby 2010). The assessment of urinary neurotransmitter testing offers the possibility of improving treatment outcomes in these cases by allowing correction of the underlying imbalance. In addition, pharmacological based antidepressant intervention can take weeks or months to tweak and perfect, if indeed this can be achieved at all (Hamer 2011, Oyebode 2012, Waterreus 2012), and the use of biomarkers to select the most appropriate intervention and monitor treatment response may possibly expedite this process. Indeed, a current trend in psychiatry includes the selection of anti-depressants that address several targets at once, due to the modest to negligible efficacy of highly selective drugs (Razas 2009); and this trend speaks to the difficulty of correctly selecting highly selective agents based on symptomatology alone.
Studies show depression to be a long term, relapsing condition associated with significant tendency towards chronicity. Three quarters of patients with depression experience more than one episode of depression and the risk of recurrence is higher if the first episode occurs at a younger age and if there is a family history of depression (Hollon 2006). The risk of recurrence increases with each new episode and as the number of depressive episodes increases, the influence of life stress on recurrence wanes (Kendler 2000). Given these findings, the need for effective treatment in the first episode of depression is obvious (Palazidou 2012).
Targeted testing can help to determine exactly which neurotransmitter levels are out of balance, and in turn, which therapies are best suited for an individualized treatment plan (Holsboer 2008). There exists a welldeveloped body of literature correlating urinary levels of various neurotransmitter metabolites to mood disorders, the focus of the following review being depression. With objective evidence of the specific neurotransmitter imbalances of a particular patient, a clinician is much better equipped to individualize a treatment plan targeting the imbalances unique to each presenting case.
Neurotransmitter Assessment in Depression
Thirty-six depressed patients seen at the National Institute of Mental Health were assessed for urinary and cerebrospinal fluid (CSF) measures of dopamine and dopamine metabolites. Episodes of suicidality among the patients were documented five years later. Baseline CSF and urinary assessment of dopamine (and metabolites) was then compared. The team showed urinary measures of dopamine and metabolites to be a much more powerful predictor of suicide attempt than CSF measures (Roy 1994).
Seventy-five female patients with purging bulimia nervosa (BN) and 30 healthy controls were compared for psychopathology (impulsivity, borderline personality traits, depressive symptoms and self-defeating personality traits) and neurobiological parameters reflecting hypothalamicpituitary- adrenal axis activity (morning serum cortisol before and after dexamethasone) and monoamine activity (24-hour urinary excretion of norepinephrine, serotonin, dopamine, and their main metabolites: 3-methoxy-4- hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid). BN patients had lower 24-hour excretion of serotonin and dopamine than controls, as well as lower ability to suppress cortisol (Val-Leal 2011).
Roy and colleagues examined subsets of unipolar depressed patients and compared these subjects to non-depressed controls. They found that depressed patients had high urinary norepinephrine and its metabolite normetanephrine, but lower urinary output of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) compared to controls. They concluded that high urinary output of norepinephrine and normetanephrine reflected abnormal sympathetic nervous system activity and suggested that urinary neurotransmitter testing may be helpful in determining subsets of depression (Roy 1986). Other studies also confirmed these findings, which reported elevations in urinary norepinephrine output in depressed and anxious individuals (Grossman 1999, Koslow 1983, Roy 1988). Otte and colleagues likewise demonstrated elevated urinary excretion of norepinephrine in depressed patients, yet found no difference in levels of urinary dopamine and metabolites relative to healthy controls (Otte 2005).
Hughes (2004) observed that higher levels of depressive symptoms, as assessed by the Beck Depression Inventory (BDI), were associated with increased norepinephrine and cortisol excretion in the urine. In this study, ninety one women aged 47-55 years were evaluated and 24-hour urine collections were assayed for epinephrine, norepinephrine and cortisol. Depressed women (n=17, BDI scores >/=10) exhibited a 25% higher rate of urinary norepinephrine excretion than women with BDI scores <10 (n=74), P=.007. Higher levels of state anxiety were also related to greater NE excretion; likewise, cortisol excretion was related to both depression and anxiety. Interestingly, depression and anxiety symptoms were unrelated to urinary epinephrine excretion.
Of tremendous significance to a discussion of the clinical utility of assessment of urinary neurotransmitter levels is the response of these levels to various types of treatment; do abnormal levels of urinary neurotransmitters correct themselves following various treatments for depression, natural or prescription? Do treatment responders differ in the impact of treatment to urinary levels of neurotransmitters from treatment non responders?
Nichkova et al (2012) evaluated the clinical utility of a novel ELISA for the measurement of serotonin in urine from depressed subjects and from subjects under antidepressant therapy. Results demonstrated significantly lower serotonin levels in depressed patients (87.53±4.89 μg/g Cr; n=60) than in non-depressed subjects (153.38±7.99 μg/g Cr). This study also demonstrated that urinary excretion of serotonin in depressed individuals significantly increased after antidepressant treatment by the dietary supplement 5-HTP and/or selective serotonin re-uptake inhibitor. Similarly, a double-blind, placebocontrolled, block-randomized, two-way crossover study designed to assess vascular safety administered 20 mg/d of the SSRI paroxetine. Urinary serotonin excretion increased significantly (89%) when compared to placebo 24-hours after oral administration (Kotzailias 2004).
Thirty-six un-medicated depressed patients were assigned to one of four groups; placebo, fluoxetine, duloxetine, or St John’s Wort. At baseline and following eight weeks of treatment, patients were assessed for urinary levels of melatonin. As anticipated, all three antidepressant treatments significantly increased urinary melatonin levels, while placebo had no effect (Carvalho 2009).
Thirty- five subjects aged 55-75 were assigned to receive tryptophan- fortified cereal (60mg per 30g cereal) and followed for a three- week period. Tryptophan increased sleep efficiency, actual sleep time, immobile time, and decreased total nocturnal activity, sleep fragmentation index, and sleep latency. Urinary 6-sulfatoxymelatonin (melatonin metabolite), and 5-hydroxyindoleacetic acid (serotonin metabolite) levels increased respectively. Anxiety and depression symptoms were also improved (Bravo 2012). A novel tart-cherry product has similarly been shown to reduce urinary levels of cortisol and increase urinary levels of 5-hydroxyindoleacetic acid, suggesting a role for the cherry in stress control/ mood regulation (Garrido 2012).
Of note is an investigation by Linnoila and colleagues (1984). After a series of studies evaluating urinary catecholamine levels in depressed patients, and their response to treatment, the team followed a small subset of depressed patients (21) regarding urinary serotonin and 5-hydroxyindoleacetic acid (5-HIAA). Three of the patients suffered from rapid cycling bipolar disorder (RCBD), a rare and difficult to treat variant of bipolar. The patients with RCBD demonstrated quite dramatically elevated levels of urinary serotonin and 5-HIAA, that were corrected upon administration of lithium. This small sample of patients suggests low levels of urinary serotonin correlate to depression, while elevated levels of urinary serotonin may correlate to mania and mood cycling.
Conclusions
Overall, urinary neurotransmitter analysis can be a useful tool in clinical assessment and treatment for depression as well as other mood based disorders. The urinalysis is cost-effective, timely, non-invasive, and can easily be incorporated into any clinical practice. The ability to identify abnormality across specific areas of the catecholamine pathway, the serotonin pathway, and the GABA pathway allows the integrated healthcare provider to tailor a treatment plan to the specific areas identified. There exists a formulary of 30-40 medicines most integrated healthcare providers call upon for management of depression and other affective disorders. Trials evaluating the impact of such medicines on urinary neurotransmitter assessment among depressed patients would be of tremendous value.
References
Bravo R, Matito S, Cubero J, Paredes SD, Franco L, Rivero M, Rodríguez AB, Barriga C. Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans. Age (Dordr). 2012 May 24.
Carvalho LA, Gorenstein C, Moreno R, Pariante C, Markus RP. Effect of antidepressants on melatonin metabolite in depressed patients. J Psychopharmacol. 2009 May;23(3):315-21.
Chang RT, Kirby R, Challacombe BJ. Is there a link between BPH and prostate cancer? Practitioner. 2012 Apr;256(1750):13-6
Cook IA. Biomarkers in psychiatry: Potentials, pitfalls, and pragmatics. Primary Psychiatry. 2008;15(3):54-59. April 2008. http://www.primarypsychiatry.com/aspx/articledetail. aspx?articleid=1477
Dasgupta B, Cimmino MA, Maradit-Kremers H et al 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis. 2012 Apr;71(4):484-92.
Duncan J, Johnson S, Ou XM. Monoamine oxidases in major depressive disorder and alcoholism. Drug Discov Ther. 2012 Jun;6(3):112-22.
Eby GA 3rd, Eby KL. Magnesium for treatment-resistant depression: a review and hypothesis. Med Hypotheses. 2010 Apr;74(4):649-60.
Fava GA, Ruini C, Rafanelli C. Sequential treatment of mood and anxiety disorders. J Clin Psychiatry. 2005. Nov;66(11):1392-400.
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010 Jan 6;303(1):47-53.
Fu XY, Lu YR, Wu JL, Wu XY, Bao AM. [Alterations of plasma aspartic acid, glycine and asparagine levels in patients with major depressive disorder] [Article in Chinese]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2012 Mar;41(2):132-8.
Fullagar S, O’Brien W. Problematizing the neurochemical subject of antidepressant treatment: The limits of biomedical responses to women’s emotional distress. Health (London). 2012 Jun 6.
Garrido M, Espino J, González-Gómez D, Lozano M, Barriga C, Paredes SD, Rodríguez AB. The consumption of a Jerte Valley cherry product in humans enhances mood, and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine. Exp Gerontol. 2012 Aug;47(8):573-80.
Gaynes BN, Rush AJ, Trivedi M, Wisniewski SR, Balasubramani GK, Spencer DC, Petersen T, Klinkman M, Warden D, Schneider RK, Castro DB, Golden RN. A direct comparison of presenting characteristics of depressed outpatients from primary vs. specialty care settings: preliminary findings from the STAR*D clinical trial. Gen Hosp Psychiatry. 2005 Mar- Apr;27(2):87-96.
Genung V. Understanding the neurobiology, assessment, and treatment of substances of abuse and dependence: a guide for the critical care nurse. Crit Care Nurs Clin North Am. 2012 Mar;24(1):117-30.
Graefe KH, Friedgen B, Wolfel R, Bossle F, Russ H,Schomig E. 1,1_- Diisopropyl-2,4_-cyanine (disprocynium24), a potent uptake 2 blocker, inhibits the renal excretion of catecholamines. Naunyn Schmiedebergs Arch. Pharmacol. 1997;356:115–125.
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(1): 21-27.
Hamer M, Batty GD, Marmot MG, Singh-Manoux A, Kivimäki M. Anti-depressant medication use and C-reactive protein: results from two population-based studies. Brain Behav Immun. 2011 Jan;25(1):168-73.
Hollon SD, Shelton RC, Wisniewski S, Warden D, Biggs MM, Friedman ES, Husain M, Kupfer DJ, Nierenberg AA, Petersen TJ, Shores-Wilson K, Rush AJ. Presenting characteristics of depressed outpatients as a function of recurrence: preliminary findings from the STAR*D clinical trial. J Psychiatr Res. 2006 Feb;40(1):59-69.
Holsboer F. How can we realize the promise of personalized antidepressant medicines? Na Rev Neurosci. 2008;9(8): 638-646.
Hovelsø N, Sotty F, Montezinho LP, Pinheiro PS, Herrik KF, Mørk A. Therapeutic potential of metabotropic glutamate receptor modulators. Curr Neuropharmacol. 2012 Mar;10(1):12-48.
Hughes JW, Watkins L, Blumenthal JA, Kuhn C, Sherwood A. Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. J.Psychosom. Res. 2004;57(4): 353-358.
Kahane A. Urinary Neurotransmitter Analysis as a Biomarker for Psychiatric Disorders. Townsend Letter. January 2009
Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘kindling’ hypothesis. Am J Psychiatry 2000;157:1243–51
Koepsell H, Busch A, Gorboulev V, Arndt P. Structure and Function of Renal Organic Cation Transporters. News Physiol Sci. 1998 Feb;13:11-16.
Koslow SH, Maas JW, Bowden CL, Davis JM, Hanin I, Javaid J. CSF and urinary biogenic amines and metabolites in depression and mania. A controlled, univariate analysis. Arch Gen Psychiatry. 1983 Sep;40(9):999- 1010.
Kotzailias N, Marker M, Jilma B. Early effects of paroxetine on serotonin storage, plasma levels, and urinary excretion: a randomized, double-blind, placebo-controlled trial. J.Clin.Psychopharmacol. 2004;24(5): 536-539.
Lechin F, van der Dijs B. Central nervous system circuitry and peripheral neural sympathetic activity responsible for essential hypertension. Curr Neurovasc Res. 2006 Nov;3(4):307-25.
Lepschy M, Rettenbacher S, Touma C, Palme RG. Excretion of catecholamines in rats, mice and chicken. J Comp Physiol B. 2008 Jul;178(5):629-36.
Linnoila M, Miller TL, Bartko J, Potter WZ. Five antidepressant treatments in depressed patients. Effects on urinary serotonin and 5-hydroxyindoleacetic acid output. Arch Gen Psychiatry. 1984 Jul;41(7):688-92.
Lurie S. Psychological issues in treatment of the “chemical imbalance”. Am J Psychother. 1991;45:348-358.
Lynn-Bullock CP, Welshhans K, Pallas SL, Katz PS. The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats. J Chem Neuroanat. 2004 May;27(2):129-38.
Maj M, Pirozzi R, Formicola AM, Bartoli L, Bucci P. Reliability and validity of the DSM-IV diagnostic category of schizoaffective disorder: preliminary data. J Affect Disord. 2000 Jan-Mar;57(1-3):95-8.
Marc DT, Ailts JW, Campeau DC, Bull MJ, Olson KL. Neurotransmitters excreted in the urine as biomarkers of nervous system activity: validity and clinical applicability. Neurosci Biobehav Rev. 2011 Jan;35(3):635-44.
Moleman P, Tulen J, Blankestijn P, Man in’t Veld A, Boomsma F. Urinary excretion of catecholamines and their metabolites in relation to circulating catecholamines.Six-hour infusion of epinephrine and norepinephrine in healthy volunteers.Arch. Gen. Psychiatry. 1992; 49, 568–572.
Moreira TS, Takakura AC, Damasceno RS, Falquetto B, Totola LT, Sobrinho CR,
Ragioto DT, Zolezi FP. Central chemoreceptors and neural mechanisms of cardiorespiratory control. Braz J Med Biol Res. 2011 Sep;44(9):883-9.
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: global burden of disease study. Lancet. 1997;349:1498– 504.
Nichkova MI, Huisman H, Wynveen PM, Marc DT, Olson KL, Kellermann GH. Evaluation of a novel ELISA for serotonin: urinary serotonin as a potential biomarker for depression. Anal Bioanal Chem. 2012 Feb;402(4):1593-600.
Oyebode F, Rastogi A, Berrisford G, Coccia F. Psychotropics in pregnancy: safety and other considerations. Pharmacol Ther. 2012 Jul;135(1):71-7.
Okumura T, Nakajima Y, Matsuoka M, Takamatsu T, 1997. Study of salivary catecholamines using fully automated column-switching highperformance liquid chromatography. J. Chromatogr. B Biomed. Sci. Appl. 694, 305–316.
Otte C, Neylan TC, Pipkin SS, Browner WS, Whooley MA. Depressive symptoms and 24-hour urinary norepinephrine excretion levels in patients with coronary disease: findings from the Heart and Soul Study. Am J Psychiatry. 2005 Nov;162(11):2139-45.
Palazidou E. The neurobiology of depression. British Medical Bulletin. 2012; 101: 127–145
Rozas I. Improving antidepressant drugs: update on recently patented compounds. Expert Opin Ther Pat. 2009 Jun;19(6):827-45.
Roy A, Pickar D, Karoum F, Linnoila M. Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression.Arch. Gen. Psychiatry. 1988;45, 849–857.
Roy A, Pickar D, Douillet P, Karoum F, Linnoila M. Urinary monoamines and monoamine metabolites in subtypes of unipolar depressive disorder and normal controls. Psychol Med. 1986;16(3): 541 546.
Roy A, Pollack S. Are cerebrospinal fluid or urinary monoamine metabolite measures stronger correlates of suicidal behavior in depression? Neuropsychobiology. 1994;29(4):164-7.
Sato Y, Fujiwara H, Takatsu Y. Cardiac troponin and heart failure in the era of high-sensitivity assays. J Cardiol. 2012 Aug 3.
Schwarz E, Bahn S. The utility of biomarker discovery approaches for the detection of disease mechanisms in psychiatric disorders. Br J Pharmacol. 2008;153Suppl 1: S133-S136.
Srinivas PR, Kramer BS, Srivastava S. Trends in biomarker research for cancer detection. Lancet Oncol. 2001 Nov;2(11):698-704.
Tamatam A, Khanum F, & Bawa, AS. Genetic biomarkers of depression. Indian J Hum Genet. 2012 Jan-Apr; 18(1): 20–33.
Waterreus A, Morgan VA, Castle D, Galletly C, Jablensky A, Di Prinzio P, Shah S. Medication for psychosis – consumption and consequences: The second Australian national survey of psychosis. Aust N Z J Psychiatry. 2012 Aug;46(8):762-73.
