NEUROTRANSMITTERS IN HEALTH AND DISEASE— Overview …

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Transcript NEUROTRANSMITTERS IN HEALTH AND DISEASE— Overview …

NEUROTRANSMITTERS IN HEALTH
AND DISEASE—
Overview and Update
Barb Bancroft RN, MSN, PNP
CPP Associates
Chicago IL
www.barbbancroft.com
• 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.
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
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
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, 5HT1E, 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
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—if you boost these receptors
vasoconstriction will occur; the “triptans” are used
for the treatment of acute migraine headaches**
The “triptans”--5-HT1B/1D/1F agonists• 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°)
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
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”
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…”
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)
Serotonin (a.k.a. 5-HT, or 5hydroxytryptamine)…
• 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…
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?
Functions of serotonin
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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)
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
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.
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
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)
• 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?)
Anxiety, panic
attacks
• Serotonin—boost
mood, boosts selfesteem (“E”, XTC,
Ecstasy gives this
one a jolt…long term
use may deplete the
serotonin-containing
neurons)
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
Penile erection
• Low serotonin is presumed to be a major part
of the cause of premature ejaculation
• SSRIs are used to treat this condition
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)
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
Mirror neurons
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Is happiness contagious?
Is depression contagious?
Mom’s and babies…
Nature vs. Nurture
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
What do women do when we’re
depressed? We eat!
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…
• 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
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)
The numbers don’t lie…
• From the early 1960s to 2002, the mean weight for
men and women aged 20-74 increased 24 pounds
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)
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
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
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
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
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
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)
New antidepressant approved
• Vilazodone HCl (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.
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…
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)
Neurogenesis--1998
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Dr. Spickerman
Antidepressants
Statin drugs
What else boosts neurogenesis?
Exercise and meditation
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
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…
Other antidepressants
• Wellbutrin (bupropion)—boosts dopamine
(energizing and also boosts sex drive; no
weight gain)
• Remeron (mirtazepine)—boosts
norepinephrine (lots of weight gain)
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?
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
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)
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
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
Do anti-depressants work for everyone?
• NO
• Psychotherapy is definitely beneficial
• What else can you do?
Hang around with people that make you
happy…mirror neurons
Get out in the sun!
• Vitamin D and depression—reduced 25 (OH)D
levels –depressed patients averaged 37 ng/L,
non-depressed—46 ng/L
• Depression rates have increased over the last
century
• Humans have reduced their light exposure
How?
• Via urbanization (tall buildings and pollution reduce
UVB)
• Industrialization (working inside reduces UVB
exposure)
• Cars (glass totally blocks UVB)
• Clothes (even light clothing blocks UVB)
• Sunblock
• Misguided medical advice to never let the sunlight
touch your unprotected skin
• (Vitamin D Council, National Institutes of Mental
Health, 2011)
Will vitamin D supplements help?
• Ongoing research using D3 (cholecalciferol),
not D2 (ergocalciferol)
• 400 IU and 800 IU have been shown to
positively improve affect
• Larger doses have been shown to improve
depression scales
• More research…could help, doesn’t harm
Exercise…
• Boosts serotonin
• Boosts endorphins (for up to 24 hours after
exercise)
• Builds new neurons
Anti-depressants and pain
management (neuropathic pain)
• Boosting serotonin
and NE in the descending pain pathways helps treat
neuropathic pain
• Amitriptyline (Elavil)
• Nortriptyline (Norpramin)
• Venlafaxine (Effexor)
• Duloxetine (Cymbalta)*
• *has just been approved for the treatment of
musculoskeletal pain)
Other drugs for neuropathic pain
• And then, there’s always gabapentin
(Neurontin) and pregabalin (Lyrica), and
topiramate (Topamax)—more on these drugs
later
• Neurontin and Norpramin together have been
shown to be quite effective when neither drug
works alone (Lancet. September 2009)
Serotonin 5-HT3 receptors and N & V
• 5-HT3 in the CTZ (chemoreceptor trigger zone
of the brain stem) is responsible for vomiting
from chemo and post-anesthesia
• 5-HT3 in the duodenum is responsible for
nausea– “the organ of nausea”
• Anticipatory nausea and vomiting
Serotonin antagonists
for 5-HT3
• The “setrons” for chemotherapy, postanesthesiainduced, and migraine-induced nausea and
vomiting
• Granisetron (Kytril)
• Ondansetron (Zofran)*
• Dolasetron (Anzemet)
• Palonesetron (Aloxi)
• + decadron
• *approved for morning sickness in pregnancy
Irritable bowel syndrome
• Too much serotonin? Diarrhea-predominant
Rx: alosetron (Lotronex)—5-HT3 blocker
• Too little serotonin? Constipationpredominant
• RX. Lubiprostone (Amitiza)
Rx: tegaserod (Zelnorm)—a 5-HT4 partial
agonist was approved to increase motility of
GI tract (March 30 2007—d/c’d due to CV
events—can still get from drug company if
nothing else works)
St. John’s Wort…(the name?)
• “St. John’s wort is the most common herb
involved in drug interactions.”
•
(Bonakdar RA. Herb-drug interactions: what physicians need to know. Patient Care
2003; January: 58-69.)
Tatro DS, ed. Drug Interaction Facts: Herbal supplements and Food. St. Louis, MO. A.
Walters Kluwer Co; 2004; also available at www.factsandcomparisons.com
Digression: St. John’s Wort for
depression
• Does it work? Yes, it has been shown to be superior to
placebo.
• May boost serotonin, norepinephrine by mild MAO inhibition;
may also boost GABA and dopamine to varying degrees
• Also appears to decrease cytokines and hormones of the
stress response (IL-6 and cortisol) that may be responsible for
mild depression—INTERESTING EFFECT as it’s the ONLY drug
that has shown to reduce cortisol’s effects in the brain—
decrease stress? IMPROVE DEPRESSION AND MEMORY
• ??Effective for mild to moderate depression…not severe
• Do NOT use with other anti-depressants—especially SSRI’s
Serotonin syndrome
• Adverse drug reaction caused by an increase in serotonin
levels and stimulated central and peripheral postsynaptic
serotonin receptors
• Drugs associated with serotonin syndrome include SSRIs,
SNRIs (serotonin-norepinephrine reuptake inhibitors—
venlafaxine/Effexor, desvenlafaxine/Pristiq,
duloxetine/Cymbalta), MAO inhibitors, TCAs, opiates, OTC
cough meds, drugs of abuse, drugs for weight loss, and
herbal products (St. John’s wort)
• Also associated with medication withdrawal
• 60% of patients present within 6 hours of medication
initiation, overdose, or change in dosage; 74% present
within 24 hours (Evans)
A few notes on Pediatric depression
• The only FDA-approved medication for the treatment
of childhood depression (7+ age) is fluoxetine (Prozac)
starting dose 10 mg/day
• Do more kids commit suicide on anti-depressants? FDA
required warning labels on antidepressants in 2004
after a small but statistically significant increased risk
of suicidal thoughts and/or attempts in children and
adolescents taking antidepressants
• Studies did NOT show increased suicidal completion,
nor did they establish the base rate of suicide that
would have occurred without treatment
A few notes on Pediatric depression
• Studies since that ruling indicate that
antidepressants are efficacious in the
treatment of pediatric depression and the
risks of increased suicidality do NOT outweigh
the direct patient benefits of these
medications (Garzon DL, Nelson J, Figgemeir
M. Management of childhood depression. The
Clinical Advisor 2009 (October).
A few notes on Pediatric depression
• Mood improvement does not take place for a month or
more, while side effects tend to appear immediately. This
can worsen the sense of hopelessness and contribute to
the perception that the treatment is worse than the illness
• Meds increase energy level but the feeling of hopelessness
does not lift, and the patient finds the strength to carry out
a suicide plan
• The child who with major depression is actually showing
the first signs of bipolar illness and will swing toward mania
when treated with an antidepressant
• The number of new bipolar diagnoses in kids has jumped
4,000 percent between the years of 1994 and 2003. Dr.
Mark Olfson, Columbia University, NYC)
GABA (gamma-amino-butyric-acid)
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She is “inhibitory”…
NO, NO, NO
Simple amino acid
Similar in structure to the class of drugs
known as the BZ’s…benzodiazepines
• Valerian and the GABA-BZ receptor (“stink
weed”) and the Pied Piper
Benzodiazepines
• Benzodiazepines (anti-anxiety drugs)—first introduced in the
60s as “mother’s little helpers” (Librium w/ slogan—
“Whatever the diagnosis—Librium”)
• How do they work? GABA-BZ receptor; GABA is inhibitory and
“calms” the brain
• Cause sedation, reduce anxiety; muscle skeletal relaxation;
anticonvulsant effects
• Long-acting vs. short-acting
Anxiolytics/hypnotics
Benzodiazepines— “zepams” and “zolams”
*Diazepam—Valium (t1/2 20-100 h)
*Flurazepam—Dalmane (40-114)
*Quazepam—Doral (25-115)
Clonazepam—Clonapin (18-50 h)
Lorazepam—Ativan (10-20)
Oxazepam—Serax (5 -20)
Temazepam—Restoril (10-40)
Triazolam—Halcion (2.5)
*t ½ is your age in HOURS…
**chlordiazepoxide (Librium is also a BZ—wrong last name
tho’—half life as long as diazepam)
GABA-pentin (Neurontin, Fanatrex,
Gabarone)
• The “Swiss-Army Knife” of neurology
• Approved for use in 1994 as an anticonvulsant
• In 1996, research on other clinical uses began to appear in the
literature
• “off label” use for neuropathic pain in the late 1990s
• Approved for neuropathy and other chronic neuropathic patin
syndromes in 2002
• Major depressive disorder
• 2nd generation GABA agonist--pregabalin
1st approved for seizure disorders
• Glutamate is excitatory
• GABA is inhibitory
Seizures—anti-convulsants and GABA
• Gabapentin (Neurontin)
• Topiramate (Topamax)—increase inhibitory effects of GABA
and blocks excitatory effects of glutamate
• Tiagabine (Gabatril filmtabs)—inhibits GABA re-uptake
• Valproic acid—Depakote, Depakene, Depacon, Stavzor
A note on valproic acid
• Not only an anti-convulsant, but also a mood stabilizer—
PTSD, (bipolar patients)
• Survival benefit on the battlefield by preventing acetylation
in cells, causing certain “survival pathways” to be switched
on
• Pig research—drained 60 per cent of blood, subjected them
to injuries seen on battlefield; gave all of the pigs saline;
gave some of the pigs valproic acid, others a blood
transfusion and the rest untreated
• Only 25% of the pigs that received saline survived 4 hours,
the typical time it takes to get hospital treatment, while 86
percent of those injected with valproic acid lived
• Big fat no-no in pregnancy—birth defects; autism
More anti-convulsants
• Phenobarbital—enhances GABA-mediated chloride
influx through inhibitory neurotransmitter channels
• Phenytoin (Dilantin)—reduces sodium, potassium
and calcium currents across neuronal membranes
• Carbamazepine (Tegretal)—same as above (also used
with pain syndromes); Equetro is extended release
carbamazepine)
• Lamotrigine (Lamictal)—MOA? May stabilize neurons
and reduce glutamate release (also known as a mood
stabilizer)
Pain syndromes and Neurontin
• CRPS (complex regional pain syndrome)
• Peripheral neuropathy
• Pain and spasticity of MS (Botox and Baclofen
for spasticity too)
• Trigeminal neuralgia
• Migraines (Botox, face lift)
• PHN (postherpetic neuralgia)--shingles
• Myofacial pain
Other clinical uses of Neurontin
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Radiation myelopathy
RLS (restless leg syndrome)
ALS (Lou Gehrig’s disease)
Periodic leg movements
Fibromyalgia
Depression
Bipolar disease
Hot flashes
Inhibits “echo-like” effect in damaged nerves
Boosts GABA inhibition in the interneurons in spinal cord
Other anticonvulsants…
• Carbamazepine (Tegretol, Carbatrol, Epitol,
Equetro)—seizure disorders, bipolar disorder,
trigeminal neuralgia
also classified as a mood stabilizer
• Topiramate (Topamax, Topiragen)(2006)—seizure
disorders, migraine prevention (investigations are
ongoing for the treatment of alcoholism, obesity,
reducing binge eating, PTSD, OCD, smoking
cessation, neuropathic pain, cocaine dependence);
being studied in combination with phentermine to
forma a drug called Qnexa to Rx obesity
GABA and dopamine in chronic alcoholics
• Dopamine is like a toddler-run, run, run; gives you
energy
• GABA keeps dopamine in check
• Chronic alcoholics have decreased dopamine—no
energy
• ETOH takes the place of GABA
• When alcoholics don’t have access to booze,
dopamine “rebounds”
• Causes the DTs (delirium tremens)
Alcohol withdrawal syndrome
• The DTs (delirium tremens)
• Medical emergency with sx of hallucinations,
confusion, disorientation, generalized seizures and
pronounced autonomic activity
• Tachycardia, hypertension, hyperthermia, tachypnea
(rapid breathing), tremors
Alcohol, GABA, and dopamine
• Normally, GABA (Mom) inhibits dopamine (toddler—
energy)
• Chronic alcohol intake takes the place of GABA and
chronically keeps dopamine levels low (no energy)
• When alcohol is removed, it takes dopamine 3-5 days
(or less) to rebound—
• “Whoa!” where’s mom?
• There is NO mom as GABA has been chronically
depressed from alcohol
• Dopamine rebound results in the DTs with s & s of
catecholamine excess
How do you treat the DTs?
• The GABA-BZ (benzodiazepine) receptor—boosting
the GABA receptor with BZ’s during alcohol
withdrawal puts the brakes on dopamine rebound;
benzodiazepines “act” like GABA
• RX: “Mother’s little helpers”--Lorazepam (Ativan)—1
mg initial dose (range 2-4 mg); diazepam (Valium)—5
mg initial dose (10-20 mg range), chlordiazepoxide
(Librium)—25 mg is initial dose (50-100 mg range);
oxazepam (Serax)—15 mg is initial dose (10-30 mg
range)
Alternatives
• Short-acting BZs without active metabolites
(oxazepam/Serax) or lorazepam (Ativan) are
acceptable alternatives in the elderly or in patients
with advanced liver disease
• Non BZ anticonvulsants such as carbamazepine
(Tegretal), valproic acid (Depakote, Depakene),
gabapentin (Neurontin) and topiramate (Topamax)
have also been used in detoxification
Norepinephrine
• Gives you energy
• Boosts mood
• Lack of norepinephrine = anhedonia (the lack of interest in
day-to-day activities)
• Drugs that boost norepinephrine make you happy and give
you energy (amitriptyline/ Elavil; reboxitine (Edronax)
• Drugs that block norepinephrine have the opposite effect–
lipid-soluble beta blockers (propranolol, timolol, metoprolol,
carvedilol) and Prednisone (long-term) for example-anhedonia
• Helps control pain in the descending pain pathways
• Fight-flight response and aggression
Why Petey the pit bull?
• Higher levels of L-tyrosine, the precursor to
norepinephrine, the transmitter of aggression
• “fight/flight” system
• Nothing can terminate a pit bull attack
• Increased release of endorphins—may be addictive
at high doses which may explain why they will
continue to fight over and over again
Norepinephrine
• Initially large doses of Prednisone cause euphoria
due to the release of norepinephrine in large
amounts
• Eventually with continued use, norepinephrine can
be depleted
• “steroid psychosis”
• Predisone also boosts norepinephrine in your
appetite center
• Amitriptyline (Elavil) boosts N.E. in the appetite
center
• Mirtazepine (Remeron) does too.
Chronic stress and norepinephrine
• Long term elevations of cortisol (chronic stress), and
perhaps short term bursts (acute stress) can
permanently change the structure of the
hippocampus
• Cortisol is neurotoxic--direct toxicity to the neurons
of the hippocampus
• PTSD
Lithium (Eskalith CR, Eskalith, Lithobid)
• 1st used for gout in the 1800s as it was able to dissolve uric
acid crystals; because of prevalent theories linking excess
uric acid to a range of disorders, including depressive and
manic disorders; first used to treat mania in 1870s
• 1st used in 7-Up in 1929 as a medicinal ingredient of a
refreshment beverage; marketed specifically as a hangover
cure (Bib-Label Lithiated Lemon Lime Soda)
• Mood stabilizer
• decreases norepinephrine release, increases serotonin
synthesis
• Resets biological clock
• Boosts neurogenesis
Who put the dope in dopamine?
• What does dopamine do in the brain?
• Gives you a huge burst of energy, alertness, and
attentiveness (along with norepinephrine in the brain)
• Too much can cause anxiety, fidgety (think cocaine users)
• Excess? addiction, psychosis, hallucinations
(schizophrenics)
• Boosts sex drive
• Bombards the reward system which contributes to its
addiction potential. In other words—wowWEEE! That felt
good, let’s do it again, and again, and again
• Movement—get up and get moving; control of voluntary
movements and postural reflexes
So what can we become addicted to?
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Alcohol
Nicotine
Methamphetamine
Cocaine
Morphine
Hydrocodone
Oxycontin
Heroin
psilocybin (magic mushrooms); PCP;
peyote (mescaline);
LSD— “Lucy in the Sky with Diamonds”
Methadone
Sex
French fries
“FRENCH FRIES!!!” You shriek…
• Addictions to food activate the brain in the
same way that the brains of cocaine addicts
are affected when they think about their next
dose. The mere display of food significantly
increases metabolism in the areas associated
with addiction.
• Who throws on the brakes for Mickey D’s
FRIES?
Dopamine and the reward system
• A critical component of the reward system is dopamine
• All addictive drugs release it—and some increase dopamine
much more than any natural stimuli
• Stimulating dopamine is the common denominator of all
addictive drugs and behaviors—even tho’ each drug has its
own unique effects—the high of alcohol is different than the
high of cocaine, heroin or methamphetamine.
• Dopamine is critical for “wanting” something, not necessarily
“liking” it…
• With continued abuse of a substance, dopamine increases
not as a result of the behavior but in anticipation of the
behavior
Memory and the reward system
• The reward system also has the ability to
encode cues to help you repeat the
experience
• You remember the night you met the love of
your life—the room, the clothes, the smell,
the meal…and you look forward to repeating
this event (in fact, those initial few years are
drenched in dopamine…AND THEN???)
• Oxytocin is released…the hormone of
monogamy and comfort
Let’s get back to addiction
• Unfortunately, this “memory” becomes a
problem to the addict—cues that have no
particular importance to survival or pleasure—
such as a line of white powder, a cigarette, or a
bottle of brown liquid—activate the same reward
system
• With repeated use, the circuitry adapts to
dopamine, and normal pleasures, such as sex,
become less pleasurable compared to the drug.
• Addiction is one of the most powerful memories
we can have--relapses are common
• For example, nicotine cessation usually take 5 to
7 attempts
The addict’s brain has been reorganized or
“hijacked”
• Drug seeking responses are initiated according to
certain cues, therefore it’s critical to help the addict
avoid those cues
• Remove the addict from the environment where he
has become addicted (30 days is not enough)(airport
bars for example)
• Addict has to re-learn impulse control (30 days is not
enough)
• The addict needs to be retrained to inhibit impulses
toward drug use as they occur (30 days is not
enough)
Early exposure to drugs and alcohol…
• More and more evidence points to “when” you
start addictive behaviors increases your risk of
lifelong addictions
• Robert Downey, Sr. gave Jr. drugs and marijuana at
age 6—thinking it was “cute”…
• “I’m allergic to alcohol and drugs—I break out in
handcuffs. –Robert Downey, Jr.
By the way…
• the White House and drug “CZAR” still consider
marijuana as the “gateway” drug…(cheaper drug,
more accessible to young kids, feel that it’s not
dangerous, so they will try harder drugs?? Higher risk
in the first place?)
• Studies have shown that tobacco smoking is a better
predictor of concurrent illicit drug use than smoking
marijuana
• Even tho’ our problems with prescription drug abuse
and methamphetamine are escalating out of control,
we’re spending millions to find the one “pot” plant in
the basement of an 82-year-old grandmother
A note or two on marijuana
• At low to medium doses it reacts with
anandamide—(means “bliss” in Sanskrit)
• Other effects at low to medium doses—
decreased blood pressure, relaxation, reduced
coordination, sleepiness, disruptions in attention,
altered time and space, illusions and the
“munchies”
• Anti-motivational syndrome
• Pantoprazole (Protonix) use can test positive for
THC
Digression: The Teenage Brain
• Dopamine system of rewards is developing during
adolescence
• Dopamine is responsible for the “high”—wow, this
feels good…let’s do it again!
• Just how good? Sex and crystal meth (in a minute)
• Adolescents become addicted faster and with lower
doses of addictive agents including oxycontin, meth,
marijuana, alcohol, and nicotine
• hypersensitive to the value of experiences,
D3 receptors and addiction
• D3 receptors are the “addiction” receptors—
imaging studies have shown that the number
of D3 receptors in the brains of alcoholics are
decreased (is this the chicken or the egg?)
• Does it take more alcohol to stimulate fewer
receptors?
• If the level of receptors can be raised, will the
alcoholic decrease their alcohol intake? The
answer is yes, at least in rats.
Other transmitters involved in addiction
• Glutamate
• Serotonin
• Endorphins— “endogenous morphines”— “runner’s
high”…(Candace Pert and the discovery of morphine
receptors/Bill Moyers and Healing and the Mind)…
“Why Bill…you would be surprised…”
Boosting dopamine in the treatment of Parkinson’s
disease can boost addictive potential
• Parkinson’s disease results from a deficiency of
dopamine in the striatal area of the brain; treating
PD involves either boosting or replacing dopamine
• Dopamine boosters such as pramipexole (Mirapex)
and ropinirole (Requip) primarily stimulate
dopaminergic receptors (D1) and the release of
dopamine from any remaining dopamine containing
neurons
• Side effects—hallucinations (D2), gambling
addictions, food addictions, sexual addiction
(become sexual pests)(D3)
Addiction and dopamine agonists
• Pramipexole (Mirapex) is the biggest offender; 1.5% of the
patients on Mirapex become pathologic gamblers, alcoholics,
gluttons, and sexual pests
• Develops within first month and up to 30 months; usually
dramatically clears within one month of stopping drugs
• These are the same drugs used as 1st line Rx—RLS (restless
leg syndrome) and can lead to addictive behaviors
“Well, I started ‘cause I heard that crystal meth
was great for sex…” How great might that be?
• Well, harken back to your last orgasm…hmmmm…
• The POO (plain’ ol’ orgasm) releases 10,000 molecules
of dopamine as the molehill moves…
• The methamphetamine induced orgasm releases
70,000 molecules and the earth moves, mountains
move, volcanos erupt and of course, you want to do it
again…and again…
• The addiction potential is enormous—only 10% of the
people who try alcohol will ever become alcoholics
whereas, close to 95% of those who try
methamphetamine over an entire weekend will
become addicted to the drug
Meth effects: Depletion of dopamine producing
cells over the year; rapid aging
• Potent vasoconstrictor—hypertension,
strokes, acute coronary syndromes
Speaking of methods of ingestion
• Swallowing pills or ETOH—produces a slow rise in the
brain concentration (depending on how fast you
drink of course, and the amount, and gender, etc.)—
pills must be digested, absorbed, and
metabolized/detoxified by the liver; marijuana
brownies
• Smoking a substance—much quicker route to the
brain—7 to 9 seconds
• IV drug use—to the brain in 2 seconds; numerous
veins used; dorsal vein of the penis; infections (HIV,
HCV, staphylococcus, endocarditis, GABHS)
It’s not just youngsters on drugs…
• Estimated 1.7 million baby boomers addicted to
drugs
• By 2020 the number will increase to 4.4 million
• First generation to have a high incidence of using
recreational drugs
• Long-term risks of pot?
• LSD and mescaline? Flashbacks?
• Cocaine? Chronic heart disease? Acute MIs?
• Heroin? Hypertension, HIV, liver and pulmonary
diseases (67% of heroin users smoke)
Speaking of methods of ingestion…
• Mucous membranes (as in Witche’s brew-“deadly” nightshade plant”, henbane
(scopolamine for “twilight sleep”, mandrake and
on occasion, hemlock—teenagers and alcoholsoaked tampons; champagne enemas; rubbing
cocaine on the gums; snorting cocaine and meth
(insufflation)
• Anesthesiologists have the highest rate of
addiction of all MDs
• Nicotine via the rectum for other reasons in the
old days—nicotine receptors in the bowel trigger
bowel movements—surgeons and cigars
Dopamine receptors
• D1 receptors (boosting D1 initiates movement and
reduces prolactin secretion) and D2 receptors
(psychosis/hallucinations)
• Bromocriptine (Parlodel) boosts D1 receptors in the
hypothalamus/pituitary to inhibit the release of
prolactin –was commonly given to lactating moms in
the old days to dry up breast milk production; the
problem was the movement disorder that it
triggered
D2 receptors
• D2 receptors are the key targets in dopamine blocking
agents, but blocking the D1 receptor can cause disabling
side effects…Parkinsonism, or hyperkinesia and
galactorrhea
• The “old” antipsychotics (such as
chloropromazine/Thorazine (1952) *and
haloperidol/Haldol, Mellaril (thioridazine), fluphenazine
(Prolixin), Trilafon (perphenazine), thiothixene
(Navane),trifluoperazine Stelazine)—reduced
hallucinations and psychosis, but induced a “statue-like,
zombie” state and the patients were shooting breast milk
across the room!
• *Serendipitous observation that this drug improved
symptoms when give as a pre-anesthetic agent
The newer “atypical” antipsychotics
• Thought to improve negative symptoms, hence the
term “atypical”—but no difference between old
and new w/ neg sx
• Efficacy is the same—SIDE EFFECTS are different
• Block 5-HT2C serotonin receptors (helps to
decrease hallucinations and psychosis) but are also
specific for D2 receptors
• Need to block at least 65% of D2 receptors for
antipsychotic efficacy; greater than 70% blockade
increases S.E.
The newer “atypical antipsychotics”
• Blocking 5-HT2c serotonin receptor increases
weight gain; increased susceptibility to insulin
resistance and type 2 diabetes
• P.S. Schizophrenics have ALWAYS had a higher
risk of insulin resistance and diabetes
LOOONG before these drugs were used…these
drugs just help to unmask it
“Atypical” antipsychotics—mixed
D2/5-HT2A antagonists
• Clozapine (Clozaril)(’90)—best of the bunch as far as
reducing symptoms and improving negative
symptoms. “It’s rare to see dramatic responses in
schizophrenia, but those patients who have the
diagnosis and yet who present as completely
healthy—in terms of the way they dress, talk and so
on—those are the people who are likely to be on
clozapine—Dr. Dost Ongur, Clinical Director, McLean
Hospital, Harvard Medical School; interviewed in The
Carlat Psychiatry Report, December 2009)
“atypical antipsychotics”
•
•
•
•
•
olanzapine (Zyprexa)(’96),
risperidone (Risperdal)(’93),
quetiapine (Seroquel)(’97),
ziprasidone (Geoden)(‘01),
olanzapine + fluoxetine = Symbyax (approved
for depressive episodes associated with
bipolar disorder);
• paliperidone ER (Invega)
“atypical antipsychotics”
• aripiprazole (Abilify)(’02)
• Dopamine system stabilizer (partial agonist at D2
and 5-HT1A/ full antagonist at 5-HT2A)
• Iloperidone (Fanapt)—less effective than
risperidone (Risperdal) and haloperidol (Haldol)
• Asenapine (Saphris)—sublingual for acute
mania—mouth numbness
•
Atypical antipsychotics
• Weight gain= Clozapine (Clozaril)(biggest offender)
and #2 is Olanzapine (Zyprexa); 10 weeks/10 pounds
• Agranulocytosis w/ Clozapine—1st 3 months;
1/10,000
• Risperidone w/ intermediate wt gain, ziprasidone
(Geodon) with least weight gain
Clozapine>olanzapine>risperidone/paliperidone>que
-tiapine>ziprasidone/aripiprazole
Atypical antipsychotics
• As the risperidone
(≥6mg)/paliperidone/ziprsidone dose
increases, so do the extrapyramidal system
(EPS) side EPS effects
• But not quetiapine (Seroquel) or clozapine
(Clozaril)
Antipsychotic use in the elderly and
mortality rates
• There is a large increased mortality in patients
with AD who are prescribed antipsychotic meds
• Evidence of modest short-term benefits of
antipsychotic Rx for neuropsychiatric sx, however,
at 2 years survival was 46% in the antipsychotic
group and 71% in the placebo group; at 3 years
the survival was 30% in the antipsychotic group
and 59% placebo
• Overall, the risk of death was 42% lower in the
placebo group than the antipsychotic group
Tardive dyskinesia
• Metoclopramide (Reglan) is the most common
cause of drug-induced movement disorders
(FDA 2/26/09)
• High risk groups? Elderly females (over 65) for
longer than 3 months
• Involuntary, repetitive movements of
extremities, tongue protrusion, grimacing,
puckering/pursing of lips, impaired movement
of fingers)
118
The “older” antipsychotic drugs
• Did you also know that schizophrenics, in
general, are at risk for extrapyramidal
symptoms, even WITHOUT drug therapy?
• Tardive dyskinesia was described in the late
19th century, over 50 years before the
discovery of the first antipsychotic med;
approximately 40% of schizophrenics will
develop TD in the absence of treatment
(Fenton)
119
Temperature regulation and dopamine
• Patients on neuroleptic drugs (central
dopamine blockers) tend to have lower basal
temperatures (always complaining of “feeling
cold”)
• Schizophrenics may be wrapped in a blanket in
the summer
• Lower basal temperatures—need to reconsider what is “febrile” in a patient on
neuroleptic drugs
Dopamine and the GI tract
•
•
•
•
•
Dopamine inhibits GI peristalsis
Acetylcholine boosts GI peristalsis
Balance between the two is 50:50
Patient with gastroparesis?
Block dopamine with metoclopramide (Reglan)
allows unopposed acetylcholine and peristalsis
• Problem: Reglan is lipid-soluble and crosses BBB;
blocks dopamine in the basal ganglia and can cause a
drug-induced Parkinsonism and other movement
disorders
Dopamine—too much? Too little?
• Too little can cause depression (chronic
alcoholism)
• Too little can cause too little movement (think
Parkinson’s disease or parkinsonism from
drugs—like metoclopramide/Reglan)
• Too much can cause too much movement—
chorea/athetosis (Huntington’s
chorea)(Tourette’s syndrome)(Tardive
dyskinesia)
Too much dopamine
•
•
•
•
Huntington’s chorea
Crack cocaine
Carbon monoxide poisoning
Tourette’s syndrome
123
Movement disorders…
• The basal ganglia—
• Paired nuclei at the base of
the brain
• 50:50 balance between
acetylcholine and dopamine
• Gamma-amino butyric acid
(GABA) keeps dopamine in
check
Caudate nucleus
Globus pallidus
Substantia nigra
Subthalamic nucleus
124
The BASAL GANGLIA…
• Control of movement, initiation and cessation
of movement
• Postural reflexes—the righting reflex
• Dopamine levels decrease with aging
gradually—we all slow down
• Dopamine reserves, in particular, decrease
with advancing age, and medications that may
affect dopamine pathways are likely to trigger
extrapyramidal effects (Timiras )
125
Clinical symptoms
• Anosmia (loss of smell)(may predate
Parkinson’s disease by a decade)
• As can REM sleep behavior disorder—in which
dreams are accompanied by excessive
movement (portends neurodegenerative
disorders – including Parkinson’s disease,
Lewy body dementia, or multiple system
atrophy--that manifest up to 25 years later)
(Boeve B, Neurology , August 10, 2010.
126
Parkinson’s disease
•
•
•
•
•
•
Resting tremor (70%)—unilateral or bilateral
Rigidity (vs. spasticity of stroke patients)
Loss of voluntary movements (spontaneous)
Bradykinesia (check gait)
Postural instability (sternal push)
Progression to dementia is common (40-60%)
Parkinson’s disease
• By the time signs and symptoms of PD emerge,
approximately 50% of the dopaminergic neurons in the
substantia nigra have degenerated, and more than 6080% of dopamine has been lost.
• Treatment is to replace dopamine
• The clinical benefit of levodopa/carbidopa varies with
the duration of chronic levodopa treatment
• Initially, symptom control is very good and most
patients retain the benefits even if a dose is missed
• However, wearing off motor fluctuations can begin as
early as several months after initiation of treatment
• Dopamine agonists—not as potent;
bromocriptine (Parlodel), pergolide (Permax),
pramipexole (Mirapex), ropinirole (Requip)
• Side effects: gambling addiction, sexual pests
• Used for restless legs syndrome as well
Glutamate
• The excitatory neurotransmitter
• Has been determined to play a major
pathological role in the neurodegenerative
disease ALS (amyotrophic lateral sclerosis) or Lou
Gehrig’s disease
• May play a major role in schizophrenia along with
GABA—diffusing into the tissues surrounding the
synapse may kill neurons; glial cells are
responsible for clearing out glutamate and GABA;
glial cells may not be functioning normally
• Plays a role in migraines?
Possible new treatment, not yet FDA approved:
Memantine (Namenda) for migraines
• Females have a lower threshold for a phenomenon
called cortical spreading depression (CSD)—bursts of
intense electrical activity across the cortex resulting
in migraines
• Memantine (Namenda) blocks CSD
• Clinical trial reported in the September 2007 issue of
the Journal of Headache Pain found the more than
50% of the patients reported that their headaches
were half as frequent and of much less severity
(Charles A, Brennan K, et al.)
• Use with Alzheimer’s drugs such as Aricept
The flu, pregnant women, and
schizophrenia
• Mom’s – GET THE FLU SHOT
• Higher risk of schizophrenia in fetus’ exposed
to the flu at critical periods of development
• Cortical thinning and enlarged ventricles
How long do drugs stay in the body?
• Blood and urine tests are most reliable; hair samples are not
• THC (the substance in marijuana responsible for the high) is detected in
the blood for 4 to 8 hours in frequent users and 3 to 4 hours in nonfrequent users
• 9-carboxy THC (product of metabolism of THC) is detectable in urine and
blood for much longer periods of time
• Frequent users? 2 weeks up to 3 months in heavy users
• Infrequent users? Up to 10 days
• Can passive smoke cause + blood tests? For a day or so with heavy smoke
exposure in an enclosed room; most tests have intentionally high
standards to avoid false + results due to incidental ingestion
Cocaine metabolites in urine for up to 3 days…some drugs can have a false +
as can some diseases
Bibliography
• Alati R, et al. “In Utero Alcohol Exposure and Prediction of
Alcohol Disorders in Early Adulthood: A Birth Cohort Study,
Archives of General Psychiatry (September 2006); 63 (9);
1009-16.
• Bailey BN et al. Prenatal exposure to binge drinking and
cognitive and behavioral outcomes at age 7 years. Am J Obstet
Gynecol 2004 Sep;191:1037-43.
• Enoch M, Goldman D. Problem drinking and alcoholism:
Diagnosis and Treatment. American Family Physician 2002;
65(3).
• Matsuo M, et al. Restless legs syndrome: association with
streptococcal or mycoplasma infection. Pediatric Neurology
2004; 31(2).
Bibliography
• Angier N. Woman: An Intimate Geography. 1999 Anchor Books.
• FDA February 26, 2009. Metoclopramide and Tardive Dyskinesia
• Fenton WS. Prevalence of spontaneous dyskinesia in schizophrenia. J
Clin Psychiatry 2000;61(Suppl 4):10-14.
• Mann J. Murder, Magic and Medicine. 2000. Oxford University Press.
• Medical Letter. Drugs for Tobacco Dependence. September 2008.
• Nicolaou KC, Montagnon T. Molecules that Changed the World. Wiley.
• Pert, C. Molecules of Emotion.1997. Touchstone, New York, NY.
• Porter R, Madness: A brief history. 2002. Oxford University Press.
• Restak R. Receptors.. 1994. Bantam Books.
Bibliography
• Tarascon Pocket Pharmacopoeia, 2010 Deluxe
Pocket Edition.
• Trenkwalder, C, et al. The restless legs
syndrome. The Lancet Neurology 2005; 4(8).
• Waldman SA and Terzic A. Pharmacology and
Therapeutics. 2009. Saunders.
• Winkelman JW, et al. Restless Legs syndrome:
nonpharmacologica and pharmacologic
treatments. Geriatrics 2007 (October);62(10):1316.
Bibliography
• Glial cells, GABA, and Glutamate. The Carlat
Psychiatry Report, December 2009.
• Berner LK, Kriston L. St John’s wort for major
depression. Cochrane Database of Systematic
Reviews 2008, Issue 4. Art. No.:CD000448.
DOI:10.1002/14651858.
Bibliography
• Pool Robert. Why do people die that way? NewScientist 2009
Feb 28; 37-39.
• Szalavita M, Volpicelli J. Paradoxical Profile: Alcohol’s risks and
benefits. Cerebrum: The Dana Forum on Brain Science 2005
(Winter); vol.7(1):39-52.
• Tonsad S. et al. Effect of maintenance therapy with varenicline
on smoking cessation; A randomized controlled trial. JAMA
2006;296:64.
• Trenkwalder, C, et al. The restless legs syndrome. The Lancet
Neurology 2005; 4(8).
• Porter R, Madness: A brief history. 2002. Oxford University
Press.