Neurobiology of Norepinephrine & The Role of SNRI in Depression

1. Neurobiology of Norepinephrine&The Role of SNRI in Depression The Mind Body Clinical Story of an Intriguing Neurotransmitter Rakesh Jain, MD, MPH Associate Clinical Professor University of Texas Medical School Houston, Texas USA

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3. What is it? Norepinephrineis a catecholamine [an organic compound that has a catechol (benzene with two hydroxyl side groups) and a side-chain amine.]with multiple roles including as a hormone and a neurotransmitter. And Why We Care? The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on adrenergic receptors in: Amygdala Cingulate gyrus Cingulum Hippocampus Hypothalamus Neocortex Spinal cord Striatum Thalamus Some Brainstem nuclei Cerebellum

4. What is it’s function? Neurotransmitter: One of the most important functions of norepinephrine is its role as theneurotransmitter released from the sympathetic neurons affecting the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions.1 Hormone: As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled.2 Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. It increases the brain's oxygen supply.3 Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus coeruleus.4 Drug: When norepinephrine acts as a drug, it increases blood pressure by increasing vascular tone (tension of vascular smooth muscle) through α-adrenergic receptor activation; a reflex bradycardia homeostatic baroreflex is overcome by a compensatory reflex preventing an otherwise inevitable drop in heart rate to maintain blood pressure. http://en.wikipedia.org/wiki/Norepinephrine. Retrieved 2013-02-04 1. Guyton, Arthur; Hall, John (2006). "Chapter 10: Rhythmical Excitation of the Heart". In Gruliow, Rebecca (Book). Textbook of Medical Physiology (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc.. p. 122. ISBN0-7216-0240-1; 2. Tanaka2000 Tanaka M, et al. (2000). Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. doi:10.1016/S0014-2999(00)00569-0; 3. The Hormone Foundation. "The Endocrine System & Types of Hormones.“; 4. HenekaMT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc NatlAcadSci U S A. 17:6058–6063 doi:10.1073/pnas.0909586107PMID 20231476

5. The Life Cycle of NE – And Therapeutic Opportunities Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination, either by degradation of Norepinephrine (NE) or by uptake by surrounding cells. • Biosynthesis • Vesicular transport • Release • Receptor binding • Termination • Uptake • Degradation http://en.wikipedia.org/wiki/Norepinephrine. Retrieved 2013-02-04

6. Where Does NE Come From ? • Norepinephrine is synthesized by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system from the amino acid tyrosine. Sperner-Unterweger B, et al. Progg Neuro-Psychopharm Bio Psych 2012.

7. Mechanism: Uptake Uptake: Extracellular uptake of norepinephrine into the cytosol is done either presynaptically (uptake 1) or by non-neuronal cells in the vicinity (uptake 2). Furthermore, there is a vesicular uptake mechanism from the cytosol into synaptic vesicles. 1. Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167; 2. Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

8. Mechanism: Degradation Norepinephrine degradation. Enzymes are shown in boxes.1 Degradation: In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are: • Normetanephrine (via the enzyme catechol-O-methyl transferase, COMT) • 3,4-Dihydroxymandelic acid (via monoamine oxidase, MAO) • Vanillylmandelic acid (3-Methoxy-4-hydroxymandelic acid), also referred to as vanilmandelate or VMA (via MAO) • 3-Methoxy-4-hydroxyphenylethylene glycol, "MHPG“ or "MOPEG" (via MAO) • Epinephrine (via PNMT) 2 Flower R, Rang HP, Dale MM; Ritter JM. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

9. Adrenergic Receptor Classification Alpha 1A Alpha 1B Alpha 1 Alpha Alpha 2 Alpha 2A Noradrenergic Receptors Alpha 2B Beta 1 Alpha 2B Beta Beta 2 Beta 3

10. Focus on the Alpha Family Of Noradrenergic Receptors • Currently, three Alphasubtypes, designated Alpha 1, Alpha 2, and Alpha 3, have been cloned and pharmacologically characterized • The mammalian heart expresses primarily Alpha 1 (75–85%), a substantial number of Alpha 2 can be detected in cardiac tissue • The Alpha 2 are primarily expressed in cells other than cardiac myocytes (e.g. endothelial cells, fibroblasts, and vascular smooth cells) Post SR, et. al. Annu Rev. Pharmacol. Toxicol 1999.39:343-60

11. Alpha -2 Receptors are Very Important in Mental Health A A B B C C • Most prevalent subtype in the PFC, also located in the locus ceruleus1 • Critical to PFC functioning1 • Attention • Behavior • Emotions • Associated with sedative and hypotensive effects1,2 • Least prevalent subtype3 • Most concentrated in the thalamus3 • Associated with sedative effects1 • Much less prevalent than A; present in cortex and locus ceruleus3 • Associated with sedative and hypotensive effects1 Alpha-2 agonists have varying degrees of affinity for the three alpha-2 receptor subtypes 1. Arnsten AFT, et al. J Child AdolescPsychopharmacol. 2007;17:393-406; 2. Franowicz JS, Arnsten AFT. Psychopharmacology. 2002;162:304-312; 3. MacDonald E, et al. Trends Pharmacol Sci. 1997;18:211-219.

12. Transmission of Neuronal Signal is Modulated by the α-2A Receptor NE presynaptic terminal Excitatory signal Reuptake transporter Postsynaptic neuron NE a2A receptor Ion channel Wang M, et al. Cell. 2007;129:397-410.

13. But, Alpha 2 Receptor Agonism, Which is Distributed in the Body too, may Lead to Insulin resistance Gribble FM. N Engl J Med. 2010 Jan 28;362(4):361-2

14. Turning Our Attention to Beta Adrenergic Receptors: Focus on Beta 1 Distribution Ablad B. et al Drugs. 1976;11 SUPPL 1:100-11; Minneman PK et al. AnnuRevNeurosci. 1981;4:419-61

15. Turning Our Attention to Beta Adrenergic Receptors: Focus on Beta 2 Adrenergic Receptor Distribution Ablad B. et al Drugs. 1976;11 SUPPL 1:100-11; Minneman PK et al. AnnuRevNeurosci. 1981;4:419-61

16. Adrenergic Receptors – a True Brain-Body Distribution & Function The primary regulators of adipose tissue lipolysis, are the catecholaminesbind to the alpha 2, beta 1, beta 2, and beta 3 adrenergic receptors. • The alpha 2 receptor couples with Gi-proteins to inhibit lipolysis • while the beta receptors couple with Gs-proteins to stimulate lipolysis. • The beta 1 receptor may mediate low level catecholamine stimulation • the beta 3 receptor, which is activated by higher levels of catecholamines, may deliver a more sustained signal Carey GB Adv Exp Med Biol. 1998;441:157-70

17. Adipose Tissue and NE Receptors • Beta 1 receptor may mediate low level catecholamine stimulation, • Beta 2 receptor may mediate intermediate level catecholamine stimulation • Beta 3 receptor, which is activated by higher levels of catecholamines, may deliver a more sustained signal Carey GB Adv Exp Med Biol. 1998;441:157-70

18. Noradrenergic Beta 3 Receptor – Critical Role on Obesity and Lipolysis • If genetic polymorphisms of gene coding for Beta 3 Receptors are present, an individual is at higher risk for visceral fat, metabolic syndrome, aggravated lipid metabolism, and elevated blood pressure • Beta 3 stimulation leads to thermogenesis. Beta 3 receptors are mainly located on adipose cell membranes • Beta 3 appears crucial for two tasks – a) thermogenesis and b) lipolysis. Therefore its critical for body weight management Oguri K, et. al Acta Paediatr. 2013 Jan 3. doi: 10.1111/apa.12149 Birerdinc A. et al ProgLipid Res. 2013 Jan;52(1):51-61. doi: 10.1016/j.plipres.2012.08.001

19. Could Noradrenergic Dysfunction Lead to Obesity? Launois-Bensaudesyndrome Interestingly, treatment with a salbutamol (a beta-2 agonist) – a noradrenergic drug, lead to adipose tissue reduction and weight loss Leung NW. Et al. ClinEndocrinology 1987. 27(5):60106

20. Brain Aspects of Norepinephrine (NE)

21. Monoamine Innervation of Prefrontal Cortices A B Robbins TW, Arnsten AF. Annu Rev Neurosci. 2009;32:267-287

22. NE and LC firing: tonic and phasic activity • Two firing patterns from the LC - tonic and phasic. • Tonic firing is steady-state, background firing that occurs at rest (awake and alert). • In depression, low tonic firing correlates with fatigue, cognitive dullness. • Chronic stress and depression with low tonic activity and low inhibitory auto regulation allows excessive phasic NE firing. • Phasic firing occurs in response to a strong stimulus. It correlates with threat or a significant stressor. Result of robust NE firing. • Increases vigilance. • Enhances sensorimotor reflex responses. • Increases acoustic startle reflex. • Reduces immobility. • Primes the “fight or flight” response. • Associated with anxiety and panic disorders. 1. Morilak DA, Frazer A. Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioral effects in depression and anxiety disorders. Int J Neuropsychopharm. 2004;7:193-218

23. Several Neurotransmitters Are Involved in Regulating Mood Serotonin Norepinephrine Anxiety, irritability Energy, interest Impulsivity Mood, emotion,cognitive function Sex, appetite, aggression Motivation Drive Pleasure Dopamine Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. Cambridge, UK: Cambridge Univ Press; 2000:152.

24. Brain Regions and MDD Symptoms: Possible Role of Serotonin Pathways Psychomotor symptoms Raphe nuclei Loss of interest or pleasure Changes in mood Suicidal behavior Suicidal ideation Loss of weight or appetite Trouble sleeping Arango V et al. Brain Res. 1995;688:121-33. Houdouin F et al. Brain Res. 1991;565:48-56; Hrdina PD et al. Brain Res. 1993;614:37-44; Leibowitz SF et al. PharmacolBiochemBehav. 1990;37:735-42. Nolte J, Angevine JB Jr. The Human Brain in Photographs and Diagrams. 2nd ed. 2000; Talbot PS, Cooper SJ. Neuropsychopharmacol. 2006;31:1757-67. Walsh SL, Wagner GC. J Pharmacol Exp Ther. 1992;263:617-26; Zangen A et al. Psychopharmacol. 2001;155:434-39.

25. Brain Regions and MDD Symptoms:Possible Role of Norepinephrine Pathways Cognitive dysfunction dlPFC H C Physical fatigue Insomnia/hypersomnia Loss of weight or appetite Locus coeruleus SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor Avery RA et al. Neuropsychopharmacol. 2000;23:240-9; Kuratsune H et al. NeuroImage. 2002;17:1256-65. Kurose Y, Terashima Y. Brain Res. 1999;828:115-8. Mao ZM et al. Biol Psychiatry. 1999;46:1259-65; Nolte J, Angevine JB Jr. The Human Brain in Photographs and Diagrams. 2nd ed. 2000; Vetrivelan R et al. Neurosci. 2006;139:1141-51. Watson M, McElligott JG. Brain Res. 1984;296:129-38.

26. Propagation of Synapse How Increasing Norepinephrine Availability can Improve Attention and Working Memory Presynaptic neuron Reuptake transporter Postsynaptic neuron  Extraneuralcatecholamineconcentration Pharmacological block on Re-uptake Catecholamines in the extraneuronal space Closed HCN Channel HCN=hyperpolarization-activated cyclic nucleotide-gated 1) ArnstenA. Expert Rev Neurother.2010;10(10):1595-1605; 2) Wang M, et al. Cell.2007;129(2):397-410.

27. Functional Connectivity Across the “Big Three” Monoamine Systems:Serotonin, Norepinephrine, and Dopamine 5-HT α1 + D2 5-HT1A + - DA NE α2 D2 - - 5-HT1B α2 α2 Interneuron5-HT2A for NE neurons5-HT2C for DA neurons D2 PostsynapticNeuron Kennedy SH et al. J Affect Disord. 2011;132(Suppl 1):S21-S23; Trivedi MH et al. J Clin Psychiatry. 2008;69(2):246-258.

28. Interactions Between 5-HT and NE Cortex/Hippocampus 5-HT1B(-) 2(-) 2(-) 5-HT2(-) NA 5-HT1A(-) 2(-) 5-HT Locus Coeruleus 1(+) Raphé Nucleus Gupta RK, et al. Aust N Z J Psychiatry. 2003;37(2):190-195.

29. SSRIs Induced NE “over-regulation andthe “noradrenergic cluster” Core symptoms of depression which respond less well or more slowly to SSRIs-1,2 • Lassitude • Loss of energy • Retardation of thoughts and actions • Concentration difficulties, loss of alertness • Loss of interest, anhedonia, emotional indifference or blunting • Sleep difficulties, sometimes worsened by SSRIs • Appetite loss, sometimes worsened by SSRI nausea Bech P et al. Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects of four fixed citalopram doses compared to placebo in patients with major depression. Psychopharmacology 2002;163:20-25. Wade A, et al. The onset of effect for escitalopram and its relevance for the clinical management of depression. Current Med Res Opin. 2006;22:2101-2110.

30. Increased NE turnover in MDD r = 0.40, p = 0.007 MHPG ng/ml Time A:BDI Time B: BDI 144 subjects (44 men, 100 women) were reassessed by the BDI. Baseline sMHPG levels in men with a BDI score of ≤9 at time A and a BDI score of ≥10 at time B Watanabe et al, 2012, Int J Geriatr Psychiatry; 27: 321–326.

31. Stress and inflammation in MDD IL-1, TNF-, IL-6 Psychosocial stress, social isolation, personality factors A IL-6 IL-10, TGF- Major depression sickness behavior Euthymia Stress resilience G HPA - axis c k t Immunoregulation i - IL-10, TGF- /-AR IL-1, NE TNF-, IL-6 NF-B 7nAChr GR ACh TLR Infection, tissue trauma, neoplasm GCs Macrophage Raison et al, Arch Gen Psychiatry. 2010;67(12):1211-1224

32. NE – via Locus Ceruleus, Impacts Microglia & Controls Neuro-inflammation NE stimulation of microglia suppresses cytokine and chemokine production NE stimulation increases microglia migration and phagocytosis Alzheimer's Disorder – there is LC degeneration and decreased NE in forebrain Heneka MT PNAS 2010. 107(13):6058-6063

33. NE – Its Critical Role on Optimum Astrocyte, Microglia and Neuronal Health O’Donnel J, et.alNeurochem Res 2012. 37:2496-2512

34. In Depressed Humans, Norepinephrine Producing LC (Locus Ceruleus) Have Impaired Astrocytes • Normal vs Depressed – Post mortem study • Gene expression using quantitative end-point polymerase chain reaction conducted with laser-captured astrocytes from locus ceruleustissue from matched pairs of • psychiatrically healthy controls(open symbols) • men with major depressive disorder(closed symbols). • Both SLC1A3 and SLC1A2 are glutamate related genes Szebeni CK, et al. J of Psychiatric Neuroscience 2013. DOI: 10:1503/jpn.120110

35. NE and Major Depression:Diagnostic and Therapeutic Implication

36. one of these required apathy/ loss of interest depressed mood Constructing a Diagnosis: The Categorical Approach weight/ appetite changes sleep disturbances psychomotor fatigue four more of these required guilt executive dysfunction worthlessness suicidal ideation Stahl’s essential psycopharmacology: neuroscientific basis and practical applications, 3rd edition, Cambridge University Press, 2008

37. Change in NE turnover after SSRI treatment Associations between the percent changes in pMHPG levels and the percent improvement in HRSD scores before and 4 weeks after paroxetine treatment. 41 inpatients who met the DSM-IV criteria for major depressive disorder scored at least 15 on the HRSD. Shinkai et al, J ClinPsychopharmacol 2004;24:11–17

38. Antidepressants Are Not Created Equal: Differential Effects on Retardation HDRS item 8==Retardation score. Includes slowness of thought and speech, impaired concentration and decreased motor activity. Schecter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Dis. 2004;83:233-236

39. Proof Of Concept – a NE Medication Can Improve Both Depression and Fatigue LY2216684 (Edivoxetine) is a potent, Norepinephrine Reuptake Inhibitor (NRI) VAS-F scores N = 217 *p < 0.05 ** p < 0.01 Probability of Remission (%) Severity of overall fatigue during past week p = .008 Fatigue interference with daily activities during past week p = .024 Week of Treatment Estimated Probability of Montgomery-Asberg Depression Rating Scale (MADRS) Remission (Repeated Measures Analysis) B. Pangallo et al. Journal of Psychiatric Research 45 (2011) 748e

40. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Edition. 2000:254. How Norepinephrine Interacts With Serotonin: Role of Receptors Presynaptic Alpha 2 Autoreceptor 5-HT Neuron Postsynaptic Alpha 2 Hetero Receptor Release the5-HT brake Alpha 1 Receptor Alpha 2 Antagonist 5-HT Step on 5-HT Accelerator NE NE Neuron

41. Normal mood Reduced positive affect Increased negative affect - - - - - + + + + + depressed mood guilt/disgust fear/anxiety hostility irritability loneliness depressed mood loss of happiness (joy) loss of interest/pleasure loss of energy/enthusiasm decreased alertness decreased self-confidence NE dysfunction NE dysfunction 5HT dysfunction DA dysfunction Targeting More than One Mechanism – Does That Offer Any Further Help ? Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 3rd Ed. NY, NY: Cambridge UnivPress; 2008.

42. Even Treatments Such as Deep Brain Stimulation (DBS) work via NE / DA / 5HT Animal study of DBS (Deep Brain Stimulation) of Nac (Nucleus Accumbens) and Examination of neurotransmitter elevation in OFC (Orbitofrontal Cotrex) Clearly, all the neurotransmitters are impacted even by therapies for resistant depression – such as DBS Dijk A et.al J Neurochemistry 2012. 123:897-903

43. Norepinephrine &Neurobiology of Exercise Disease Structure Function CNS • External Input • Visual • Olfactory • Acoustic • Gustatory • Somatosensory Cognitive Controls Hippocampus, Cortex Repair Plasticity Protection Neurogenesis Transcription NA, 5-HT,GABA, Glutamate, Glycine BDNF/TrkB ERK/CREB NFKB Learning & Memory Alzheimer’s Dementia • Behavior • Social • Sexual • Coping • Addictive • Escape • Fight & Flight • Stress • Sleep • Ingestive Schizophrenia Executive Controls Prefrontal & Cingulate Cortex Depression Emotional Controls Amygdala, Prefrontal Cortex Sleep Disorders Motivational Controls Reward,Wanting,Selection Hypothalamus, Accumbens, VTA Internal Feedback “Consequences of exercise” Obesity DA ↓ Parkinson’s Disease ↑ ROS Motor Controls Motor Cortex Striatum, Brainstem, Cerebellum, Spinal Cord Energy Balance Diabetes ANS & Endocrine Systems Humoral Factors Neural Primary Afferents CVD Muscle Cardiovascular Consequences Immune Control Immune Disorder “Exercise” Metabolic Consequences Liver, WAT, Pancreas Gastrointestinal Control IBD, Constipation Colon Cancer Thermal Consequences ANS, autonomic nervous system; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; CREB, cyclic adenosine monophosphate response element-binding protein; CVD, cardiovascular disease; DA, dopamine; ERK, extracellular signal-regulated kinase; 5-HT, 5-hydroxytryptamine; GABA, gamma amino butyric acid; IBD, inflammatory bowel disease; NA, noradrenaline; NFκB, nuclear factor of kappaB; ROS, reactive oxygen species; TrkB, tyrosine residue kinase receptor-type 2; VTA, ventral tegmental area; WAT, white adipose tissue. Dishman RK et al. Obesity. 2006;14(3):345-356.

44. Streeter CC et al. Med Hypotheses. 2012;78(5):571-579. Meditation/Yoga: As a Mind-Body Intervention Mean thalamic GABA levels in participants with Major Depressive Disorder (MDD) and low back pain (LBP) (n=2) compared to normal participants (n=19) before (Scan 1) and after (Scan 2) a 12-week yoga intervention Vagal-GABA Circuits Key GABA-R, gamma aminobutyric acid receptorsAutonomic, GABA and other neurotransmitter pathwaysHypothalamic pituitary adrenal axis neuroendocrine pathways Prefrontal Cortex GABA-R ThalamusGABA-R InsulaGABA-R HypothalamusGABA-R Pituitary Amygdala GABA-R Hippocampus GABA-R Parabrachial NucleusGABA-R PeriaqueductalGABA-R Adrenal Brainstem Nuclei Nucleus TractusSolitariusGABA-R Nucleus Ambiguus GABA-R Dorsal Medial Nucleus GABA-R Vagal Efferents Vagal Afferents Pharynx, Larynx, Lungs Cardiac Gastrointestinal

45. Cognition: Presence of Norepinephrine Can Exert Objective Changes in Cognition(desvenlafaxine as an example) Reddy S, st al. Presented at the 2011 CPNP Annual Meeting, May 1-4, 2011, Phoenix, Arizona.

46. Cognition: Role Various Receptors Play in Various Aspects of Cognition and Memory O’Donnel J, et.alNeurochem Res 2012. 37:2496-2512

47. NE Containing Anti-Depressants Show Wide Spectrum of Symptoms & Wellness CoverageFocus on SDS and WHO-5 Guico-Pabia CJ, et al. Poster Presentation, American Academy of Nurse Practitioners, 2010

48. First-Line Antidepressants: Guidelines APA = American Psychiatric Association; TCA = tricyclic antidepressant; MAOI = monoamine axidase inhibitor; DNRI = dopamine norepinephrine reuptake inhibitor American Psychiatric Association. Am J Psychiatry. 2010;[in press]. Lam RW, et al. J Affect Disord. 2009;117(Suppl 1):S26-S43.

49. Remission Rates with SSRIs vs. SNRIs Debate: What is the Latest? A meta-analysis of head-to-head SSRIs vs. SNRIs trials Remission as the outcome measured Odds Ratio IV, Random, 95% CI 1.5 1 0.5 In (odds ratio) 0 500 600 100 200 300 400 -0.5 -1 -1.5 5 Number of Patients in Each Trial (N) 0.2 0.5 1 2 Favors SSRIs Favors SNRIs SNRI remission rates were 5.7% higher Machado M et al. J Clin Pharm Ther. 2010;35(2):177-188.

50. A Reciprocal & Positive Relationship Between Medication Induced NE / DA Increase and Exercise • Fatigue and Impaired Cognitive Function are often linked to NE/ DA neurotransmission • Physical Activity Improves these neurotransmitters • However, a a depressed individual the presence of a NE / DA medication may reduce fatigue and improve motivation to increase odds of patient exercising • Norepinephrine/ Dopamine Facilitation • Physical Exercise Stenman E, Lilja A. Medical Hypothesis 2013. (80):47-49