NEUROTRANSMITTERS IN HEALTH AND DISEASE— Overview and Update

1. NEUROTRANSMITTERS IN HEALTH AND DISEASE—Overview and Update Barb Bancroft RN, MSN, PNP CPP Associates Chicago IL www.barbbancroft.com

2. In the mid-nineteenth century, advocates of physical causes for mental illness recommended bloodletting, purging, cold-water immersion, and various tonics and medications (primarily opium and opium derivatives) as treatment. • Others believed that mental disorders were caused by inappropriate mothering; it was thought impossible for patients to recover while at home. Part of the treatment was to place the patients in a mental asylum. To simplify management, many of these patients were restrained in straight-jackets and manacles and chains.

3. NEUROTRANSMITTERS • Indolamines Serotonin (5-hydroxytryptamine, or 5-HT)—the most ubiquitous neurotransmitter of all) Melatonin • Catecholamines (Sympathetic Nervous System) Dopamine (DA) Norepinephrine (NE) • Acetylcholine (Parasympathetic Nervous System) • GABA (Gamma-amino-butyric acid )(inhibitory) • Glutamate (excitatory) • Nicotine • Cannabinoids

4. The supporting “cast” • Neurotransmitters don’t work as a separate molecule…neurotransmitters need receptors, neurotransmitters need to be metabolized via various enzymes, neurotransmitters need to be “taken back-up” into cells in a timely fashion, the information needs to be transported via pathways…SO, we will be talking about all of the supporting “cast” so to speak… • RECEPTORS, ENZYMES, GLIAL CELLS, PATHWAYS

5. For example, serotonin receptors • Serotonin receptors for example…known as 5-HT (hydroxytryptamine)—and there are MANY of them…5-HT1 through 5HT7, with many subtypes…5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F; 5-HT2A, 5-HT2B, 5-HT2C; 5-HT3; 5-HT4; 5HT-5A; 5-HT6; 5-HT7 • 5-HT1C does not exist, and the 5-HT5B only exists in mice

6. Serotonin Receptors • Drugs that affect serotonin either boost the receptors or block the receptors…agonists or antagonists • 5-HT1A—if you activate it you will be anxious; if you block it you will reduce anxiety—Buspirone (Buspar) is a blocker of this receptor • 5-HT2C—blocking this receptor results in increased food intake and weight gain; “atypical” antidepressants such as olanzapine (Zyprexa), clozapine (Clozaril) • 5-HT1B, 1D, 1F—ifyou boost these receptors vasoconstriction will occur; the “triptans” are used for the treatment of acute migraine headaches**

7. The “triptans”--5-HT1B/1D/1Fagonists- • Sumatriptan (Imitrex)(64-70% response rate at 2°) (Treximet—Imitrex (85 mg) + naprosyn (500 mg) • Naratriptan(Amerge)(fewer HA recurrences than Imitrex)(45% response rate at 2 hours) • Zolmitriptan (Zomig, Zomig ZMT)* (dissolves) • Rizatriptan (Maxalt,Maxalt MLT)* (dissolves) • Almotriptan (Axert)(dec. chest pain, tightness, pressure) • Eletriptan (Relpax)—faster acting than oral Imitrex • Frovatriptan (Frova) (longest half-life)(45% response rate at 2°)

8. WARNING: Triptans and coronary heart disease • Triptans stimulate the 5-HT1B receptors on coronary arteries and result in vasoconstriction. This may become clinically significant in patients with underlying coronary artery disease or vasospastic disease—the triptans are contraindicated in patients with CAD • FYI: More than 50% of neurologists and 75% of headache specialists have migraines

9. Serotonin…historical highlights • 1st discovered as a protein in serum (sero) in 1948, but the Italians actually initially discovered it in the gut in 1933 and called it “enteramine”

10. Historical highlights… • 1958—Serotonin’s ability to contract a rat’s uterus was found to be antagonized by LSD • And, the question begs to be asked… “Who gives a…”

11. Serotonin • The bigger question needs to be asked…why were they using LSD in a rat’s uterus? • Triggered research into the role of LSD in causing hallucinations (dopamine/serotonin) and into LSD’s schizophrenic-like effect (serotonin/dopamine)

12. Serotonin (a.k.a. 5-HT, or 5-hydroxytryptamine)… • Serotonin is the most ubiquitous neurotransmitter of all • It’s found in the central and peripheral nervous systems, it is located in the GI tract, platelets • ~95% of all serotonin in the body is “enteric” or in the GUT • Involved in a wide variety of clinical conditions including…

13. Digression: The Second Brain...serotonin and the gut • Drugs such as SSRIs that increase serotonin in the brain and improve mood, also increase the release of serotonin in the GI tract—increasing gastric motility and the release of serotonin from the duodenum • Side effects—nausea and diarrhea (use Imodium) • Irritable bowel syndrome—brain-butt connection • The histologic changes found in the CNS are also found histologically in the bowel…HUH?

14. Functions of serotonin • Happiness • Sociability/boosts self-esteem/overcomes shyness • Social phobias • Makes you full and feel sleepy • Impulsive eating disorders such as bulimia • Impulse control • Helps to control pain pathways • Nausea, vomiting, gastric motility • Generalized anxiety disorder and panic attacks • Aggression • Extreme violence • Premenstrual dysphoric disorders • Migraines • Penile erections (ejaculation, specifically)

15. Boosts self-esteem/overcome shyness • College fraternity members w/ highest ranking and most friends had 20-40% higher serotonin levels • Stroke patients and SRIs (i.e., Prozac)—improved compliance w/ rehab

16. Boosts self-esteem • Remove dominant chimpanzee from group • Give a subordinate male fluoxetine (Prozac) • The subordinate took charge, made friends, organized alliances, and became the top banana.

17. Social phobias—off-the-beaten-path phobias • Arachibutyrophobia—fear that peanut butter may stick to the roof of the mouth • Erythrophobia—the fear of blushing • Peladophobia—the fear of bald people • Coulrophobia—a debilitating fear of clowns • Bromidrosiphobia—the morbid fear of body odor • Albutophobia—the fear of bathing (this phobia reared its ugly head with a vengeance after Alfred Hitchcock’s movie, “Psycho”.) • Hellenologophobia—the fear of complex science terminology

18. Plays a role in impulsive eating disorders such as bulimia nervosa • Bulimia (be aware of girls with Type 1 diabetes and bulimia) • Binge-eating disorder • Anorexia (?) • Boosting serotonin boosts impulse control • Helps to control binge eating disorders • Fluoxetine (Prozac) • Paroxetine (Paxil)

19. Levels of serotonin activity are abnormally high in anorexics—linked to feelings of anxiety and obsessional thinking, classic traits of anorexia; dopamine levels are also high— “addicted to starvation” (autoimmune? Genetics?)

20. Serotonin—boost mood, boosts self-esteem (“E”, XTC, Ecstasy gives this one a jolt…long term use may deplete the serotonin-containing neurons) Anxiety, panic attacks

21. Aggression--Premenstrual dysphoric disorder • A breakdown product of progesterone, allopregnanolone, acts on receptors for GABA—has a calming effect; fluoxetine (Prozac/Sarafem) specifically increases allopregnanolone

22. Penile erection • Low serotonin is presumed to be a major part of the cause of premature ejaculation • SSRIs are used to treat this condition

23. Serotonin and depression • “The FDA this week approved the first-ever transdermal patch for the treatment of depression. Simply remove the backing and press the patch firmly over your mother’s mouth.” ---Tina Fey, on Saturday Night Live (March 2006)

24. Serotonin, estrogen and menstrual migraines • During low estrogen states such as menses (the sudden drop of estrogen triggers migraines) • Or during the placebo week of oral contraceptives, serotonin levels decrease and the headaches occur • How about using an estrogen patch 7 days prior to menses, or OC without the placebo week? • (Lybrel (Wyeth)—first FDA-approved low-dose combination oral contraceptive taken 365 days per year) • During high estrogen states, ie, pregnancy, serotonin rises and headaches decrease

25. Mirror neurons • Is happiness contagious? • Is depression contagious? • Mom’s and babies… • Nature vs. Nurture

26. Serotonin and depression • Depressed women have 53% less serotonin in the pleasure centers of their limbic system than men • Increased rates of classic depression in women and this gender difference starts at puberty

27. What do women do when we’re depressed? We eat!

28. What do we eat? • In addition to increasing serotonin in the brain, chocolates (boost)anandamide—a substance that closely resembles marijuana (“ananda” in Sanskrit means “bliss”… • Bliss is a 1 lb bag of M & M’s…

29. Carbohydrates facilitate the entry of tryptophan (the amino acid required to produce serotonin) into the brain • CHO’s also increase the release of insulin from the pancreas and bingo, you put on weight • Especially with more than 125 grams of carbohydrates per day

30. Implications for low-carb diets • Dr. Atkin’s, South Beach • Is she really that happy? NOOOOOOOOO • Females without carbs—no energy, depressed, and constipated with halitosis • Men love their red meat – why? (meat contains tyramine, the precursor to the catecholamines—norepinephrine and dopamine)

31. The numbers don’t lie… • From the early 1960s to 2002, the mean weight for men and women aged 20-74 increased 24pounds and the mean height increased approximately 1 inch • During 1999-2002, the mean weight of men over 20 years of age was approximately 190 pounds and the mean height was approximately 5’9” • Among women, the mean weight was approximately 163 pounds and the mean height was approximately 5’4” (US Dept. of Health and Human Services, CDC, National Center for Health Statistics, 2004; Available http://www.cdc.gov/nchs/data/ad/ad347.pdf)

32. Weight loss drugs • The weight loss drugs target the satiety center in the hypothalamus—boost serotonin that tells you – “stop eating, you’re full” • Redux and Fenphen increased serotonin in the satiety center • Meridia (sirbutamine)—prevented the re-uptake of serotonin in the satiety center—weak; removed from the market on October 8, 2010 due to the risk (ever so slight) of severe cardiovascular events

33. Drugs for weight loss… • OFF LABEL use of some drugs—metformin (Glucophage), topiramate (Topomax) • Some new drugs are awaiting approval by the FDA • NEW possibility but not FDA approved yet…lorcaserin, a selective serotonin 5-HT2C agonist, is in phase III clinical trials—helps to lose weight and MAINTAIN weight loss • NO increased risk for valvular heart disease like fenphen

34. Guys don’t “crave carbs”…they have plenty of self-esteem… • They think they look like this today…and they DID in the 1960’s

35. Serotonin makes you happy in the mesolimbic system of the brain • The number ONE class of drugs prescribed today for depression are the serotonin reuptake inhibitors (SRIs) or the SSRIs Selective SRIs

36. The SRI’s (serotonin reuptake inhibitors)… • 1987—the first selective serotonin reuptake inhibitor was “unleashed” and we all know that drug as fluoxetine, Prozac (Lilly) (longest t½) • Sertraline (Zoloft)(1992)—shortest t½; excellent choice for elderly depressed patient; may also be useful for mild irritability and aggression

37. SRIs (Serotonin Reuptake Inhibitors) • Paroxetine (Paxil)(1992) ++drug interactions; adrenergic effects=tremor—14.7% @ 40 mg/d); most anticholinergic • Citalopram (Celexa)(2000)—most selective affinity for HT receptors; useful for mild irritablity and aggression • Escitalopram(2002)(as above) (Lexapro)(#12 of the top selling drugs in 2009)**fewest SE of all SRIs—new use: reduce the number of hot flashes (TAMOXIFEN)

38. New antidepressant approved • VilazodoneHCl (Viibryd)—a combined selective SRI and sertonin 1A receptor partial agonist • Rx—Major Depressive Disroder • No sexual dysfunction, no significant weight gain • Nausea, diarrhea, vomiting, insomnia • Boxed warning for an increased risk of suicide in 18-24 y.o.

39. Depression in children • Prozac is still the only drug approved by the FDA for the treatment of depression in children and adolescents • Prozac has a longer t½ life; Makes withdrawal more gradual and, it also • Keeps levels steady if a dose is missed (teenagers in particular often miss or skip doses) • More later…

40. Give antidepressants time to work! 3-5 weeks…but monitor closely during this time • Why does it take so long for anti-depressants to work? • How long should your patients stay on antidepressants? • (P.S. escitalopram/Lexapro may ease depressive and anxiety symptoms more quickly than the other SRIs—in some cases by the end of week one)

41. Neurogenesis--1998 • Dr. Spickerman • Antidepressants • Statin drugs • What else boosts neurogenesis? • Exercise and meditation

42. Other antidepressants inhibit the re-uptake of both serotonin and norepinephrine--SNRIs • Other antidepressants inhibit the reuptake of both serotonin & norepinephrine and are called the SNRIs (Venlafaxine/Effexor)(1997); duloxetine (Cymbalta) and desvenlafaxine (Pristiq)(2005) • Used for depression • Other indications are numerous—more later

43. P.S. the “old” antidepressants known as TCAs (tricyclic antidepressants) • Amitriptyline (Elavil) • Nortriptyline (Pamelor, Norpramin) • Also boost serotonin and norepinephrine but they are not referred to as SNRIs… • More later about the clinical uses of the “old” TCAs…

44. Other antidepressants • Wellbutrin (bupropion)—boosts dopamine (energizing and also boosts sex drive; no weight gain) • Remeron (mirtazepine)—boosts norepinephrine (lots of weight gain)

45. The SRIs—side effects • Increasing serotonin may result in decreased dopamine • Dopamine gives you some zip to your doo-dah in the bedroom • SRIs may result in anorgasmia, loss of libido and premature ejaculation • What can you do? Zoloft—short half-life • Add Wellbutrin (or switch to Wellbutrin) or amantadine (Symmetrel) to boost dopamine • Yohimbine? NO; OTC’s? • Estratest?

46. Other side effects of SSRIs—lesser known, but important • Inhibit platelets—bleeding • Bruxism—increase serotonin, decrease dopamine results in jaw clenching at night • RLS—increased serotonin, decrease dopamine, increases leg movement • SIADH—dilutional hyponatremia

47. A new eating disorder (not yet officially recognized by the DSM, but…) • Orthorexia—obsession about eating the “right thing”, the “perfect diet”—fixate on eating foods that make you feel pure and healthy • Overly concerned about preparation techniques—washing foods multiple times and sterilizing utensils • Food obsessions hinder ADL; strict rules and beliefs about food may lead them to become socially isolated; orthorexics may become intolerant of other people’s view about food and health (Dr. Steven Bratman)

48. Other conditions with decreased serotonin…(and increased norepinephrine)—poor self-esteem, lack of impulse control • Chronic alcohol abuse (also decreases dopamine) • Chronic child abuse (mental, physical, sexual)--PTSD • Closed head injuries--PTSD • anabolic steroids (“roid rage) • Low cholesterol levels--aggression • Exposure to lead as a child--aggression • When serotonin re-uptake inhibitors are used, serotonin levels increase, thinking becomes clearer

49. Notes on the use of SRIs • Used for patients with OCD, binge-eating, PTSD, aggression • Child abuse/spousal abuse—the P’s ↓ aggressive levels by 25%; gives time to reflect—reflective delay; size up situation and prevents immediate reaction

50. Do anti-depressants work for everyone? • NO • Psychotherapy is definitely beneficial • What else can you do?