Psychopharmacologypresentation

Psychopharmacology
Principles, Neuroanatomy,
mechanism of action

Pharmaockinetics vs. Pharmacodynamics

Pharmacokinetics
• Absorption- How drugs pass into the bloodstream- e.g.
Orally a drug must be soluble and stable in stomach
fluid (not destroyed by gastric acids) enter the intestine
and then bloodstream-Liquids more quickly absorbed
than tablets) vs. Inhalation –Lung tissues have large
surface areas with rapid absorption into pulmonary
capillaries > aorta. I.V.- advantages vs. disadvantages
• Distribution Once in the bloodstream distribution
throughout body Most of drug found in remote
areas(from receptors) at any one time Cell membrane
fat/protein-small lipid soluble molecules
Capillary pores 90-150 angstroms –larger than most
drug molecules but not red blood cells or plasma (liquid
component of blood, in which blood cells are
suspended) allows passage

Blood Brain Barrier
• BBB- tightly joined capillaries covered with a glial
sheath-passage depends on 1) size of molecule 2) lipid
solubility (e.g. penicillin does not cross BBB –treats
infections outside brain-Placental “barrier”

Pharmacokinetics (continued)
• Metabolism-Major route of drug elimination from
the body is renal excretion of drug metabolites
produced by the hepatic (enzymatic)
biodegradation of the drug. Lipid soluble
psychoactive drugs must be broken down to less
active molecules
• Elimination Drug travels to liver, metabolized to by-
products, returned to bloodstream, travel to kidney
and excreted

Examples of drug-drug interactions
• CYP450 family (CYP1,CYP2,CYP3 involved in most
drug metabolisms-broad action with nonspecific
enzymes working on different drugs
• Tegretol INCREASES production of CYP3A3/4-
reduces blood levels and therapeutic efficacy of
various SSRIs
• SSRIs inhibit CYP-1A2 and CYP-2C INCREASING
toxicity of some antidepressants, some
antiasthmatics and some heart medications
(possibly fatal interactions)
• SSRIs inhibit CYP-2DC blocking metabolism of
codeine to morphine thereby blocking analgesic
effect

Half-Life
• Half-Life- -How long a drug remains in the body. For
each half-life the blood level falls by 50% therefore a
varying amt of drug metabolized with each half-life(e.g.
4 half-lives clears 94% of drug -see table) A different
absolute amount of drug is metabolized within each
half-life; the time interval remains constant

Drug Tolerance
• Drug Tolerance- State of progressively decreasing
responsiveness to a drug, requiring a larger dose of
the drug to achieve the effect originally obtained by
a smaller dose- 1) Metabolic Tolerance Drug
metabolized by C P450 enzymes 2) Cellular-
adaptive/Pharmacodynamic Tolerance number of
receptors in/decreased (up/down regulation or
sensitivity in/decreased) 3) Behavioral conditioning
processes- drug tolerance enhanced by
environmental cues

Physical Dependence
• Physical or Physiological Dependence – drug needed to
avoid withdrawal symptoms Not just seen in ‘addictive
drugs’ Alcohol nervousness Anxiety excited Emotional
volatility, Depression Fatigue Difficulty with thinking clearly
Bad dreams SSRI withdrawal syx Disequilibria GI Flulike syx
(chills fatigue) Sensory (paresthesia) Sleep
• Physiological dependence is characterized by occurrence of
withdrawal symptoms when drug is not taken (Symptoms
range from sleep disturbance-convulsions
• Tolerance-refers to inducing drug metabolizing enzymes in
liver and adaptation of brain cells to presence of drug
• Psychological dependence –refers to positive reinforcement
value of drug

Alcohol
• Alcohol belongs to a class of drugs called sedative-
hypnotics which depress functioning of the brain
resulting in relaxation, disinhibition, drowsiness and
sleep as doses increase
• Such agents are often taken to ease anxiety and
tension and behaviorally induced state of anxiolysis
(relief from anxiety)
• Increasing doses provoke sedation, sleep,
unconsciousness, coma and eventually death from
respiratory and cardiac depression
• Among the drugs in the category of sedative-
hypnotics are alcohol, barbiturates and
benzodiazepines

Sedative - Hypnotics
• Barbituates have been largely replaced by the
benzodiazepines for the treatment of anxiety and
other disorders due to greater safety; however
benzodiazepines are not devoid of potential to
cause significant problems including dependency
and abuse
• The terms sedative, tranquilizer, anxiolytic and
hypnotic can be applied to any CNS depressant,
including alcohol which diminish environmental,
reduce response to sensory stimulation, depress
cognitive functioning, decrease spontaneity and
reduce physical activity

Sedative - Hypnotics
• At higher doses drugs in this class induce lethargy,
clouding of consciousness with amnesia and
unconsciousness.
• The effects of any CNS depressant potentiate the
effects of any other CNS depressant (e.g. alcohol
exaggerates the effects of benzodiazepines).
• Such additive effects may be unpredictable and
dangerous if not fatal. All CNS sedative hypnotics
carry the risk of physiological and psychological
dependence and tolerance

Alcohol (continued)
• Main difference from other depressants is that
ethanol (alcohol) is used primarily for recreational
rather than medical purposes. Ethyl alcohol is rarely
drunk in its pure form (12-14% wines, 3-5% beers
40-50% “hard liquor
• Alcohol is soluble in both water and fat and it
diffuses easily across all biological membranes. In a
person with an empty stomach ~ 20% of a single
dose of alcohol is absorbed directly from the
stomach, usually rapidly while 80% is absorbed
from the upper intestine (limiting factor is the time
it takes to empty the stomach)

Alcohol (continued)
• Women absorb more alcohol than men making them
more impaired from the same amount of alcohol due
to lower amount of drug metabolizing enzyme –about
50% less gastric metabolism vs. men- gastric enzymes
metabolize 15% of ingested alcohol (also women have
more body fat with less vascularization limiting amount
that can be diluted
• After absorption alcohol is evenly distributed
throughout all body fluids and tissues and freely
crosses the BBB as well as across the placenta and
easily enters the brain of a developing fetus-Fetal blood
alcohol levels are essentially the same as the drinking
mother

Alcohol -Metabolism and Excretion
• ~95% of alcohol ingested is enzymatically
metabolized by alcohol dehydrogenase with the
other 5% excreted unchanged through the lungs.
Most of metabolism of alcohol occurs in liver with a
smaller proportion metabolized by a gastric alcohol
dehydrogenase in the lining of the stomach (same
enzyme found in liver)
• The metabolism of alcohol by this stomach enzyme
is part of a ‘first pass metabolism” in which
enzymes reduce the amount of alcohol reaching
the blood

• Rapid gastric emptying (drinking on an empty
stomach) reduces the time alcohol is susceptible to
first pass metabolism and results in increased blood
levels and result in increased alcohol blood levels.
Drinking on a full stomach retains alcohol in the
stomach, increasing its exposure to alcohol
dehydrogenase
• If person ingests more alcohol in any given hour than
is metabolized, his or her blood concentrations
increase
• With long term use alcohol can induce drug
metabolizing enzymes in the liver increasing the liver’s
rate of metabolizing alcohol and inducing tolerance

• Mechanism of alcohol still not completely
understood. Believed that alcohol acts through a
general depressant action on nerve cells and
synapses (alcohol crosses all biological membranes)
resulting in a non specific depression of neuronal
function.
• While accounting for its generalized depressant
behavioral effect this does not explain the evidence
that alcohol may disturb synaptic of various and
specific neurotransmitters, especially major
excitatory (Glutamate) and inhibitory (GABA)
systems

Brain Areas affected in Alcohol
• vas and O’Brien (2008) focused on the initial release of the
neurotransmitter dopamine from cells in the brain region called the
ventral tegmental area (VTA) that is induced by addictive drugs. The
VTA is one of the components of a system of interconnected brain
regions called the mesolimbic dopamine system. In this system,
neurons whose cell bodies are located in the VTA, extend long “arms”
(i.e., axons) to various other brain regions, most prominently the
nucleus accumbens (NAc) and the prefrontal cortex

Brain Areas affected in Alcohol
• When activated, these neurons release dopamine that acts on other
neurons in the NAc and prefrontal cortex. For many years, researchers
thought that this dopamine release mediates positive reinforcing properties
of alcohol drugs s or other stimuli. More recently, it has been proposed that
the dopamine release, particularly in the NAc, signals the importance (i.e.,
salience) (Iversen and Iversen 2007) of the stimulus to the individual. In
either case, dopamine release in the mesolimbic system (e.g., NAc) likely is
critical for the drive to ingest alcohol and other drugs. For example, Kalivas
and O’Brien (2008) postulate that the released dopamine promotes
neuroplasticity in the mesolimbic system through the activation of certain
signaling pathways that ultimately alter gene expression. Such changes in
gene expression may be associated with the transition from social drug use
to relapsing drug use.

Alcohol- Receptors-Glutamate
• Glutamate receptors- With chronic alcohol intake
and persistent glutaminergic suppression, there is a
compensatory regulation of NMDA receptors.
Therefore on removal of ethanol’s inhibitory effect
(as in alcohol withdrawal) excess receptors result in
withdrawal signs including seizures
• The drug acomprosate (a structural analogue of
glutamate) is used as an anticraving drug to
maintain abstinence in alcohol dependent persons

Alcohol’s effect at the synapseActions of the brain’s glutamate system. Glutamate (green circles) exerts its effects by acting on
various types of receptors, including the N-methyl-D-aspartate receptors (NMDARs) and α-
amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors (AMPARs), both of which are ion
channels, and metabotropic glutamate receptors (mGluRs), which are coupled to G-proteins. G-
proteins, in turn, indirectly activate protein kinase C (PKC) and activate or inhibit adenyl cyclase
(AC), depending on the mGluR and G-protein involved. In the absence of alcohol, glutamate
leads to the activation of the postsynaptic neuron and the generation of a new nerve signal.
Actions of the brain’s glutamate system. In the presence of alcohol (ethanol, purple circles), the
activity of the N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-
methylisoxazole-4-proprionic acid receptors (AMPARs), is inhibited, reducing cation entry into
the cell. As a result, the activity of the neuron is reduced and no or fewer nerve signals are
generated

Alcohol- Receptors-GABA
• Ethanol activates GABA mediated increases in
chloride flow resulting in neuronal inhibition
(including sedation, muscle relaxation and motor
and cognitive inhibition).
• Therefore the use of alcohol to self-medicate one’s
panic or anxiety disorder probably contributes to
co-morbid syndromes
• Ethanol binds to a different subunit of the GABAA
receptor than do other GABA agonists. A chronic
adaptive effect seems to involve changes in
intracellular mRNA suggesting that alcohol can
affect gene expression. As a result of GABAergic
action, other transmitter systems are affected

Alcohol- Receptors-GABA
Certain steroid hormone metabolites that have activity as modulators of
GABAA receptors but lack conventional hormonal effects—including allopregnanolone
and allotetrahydrodeoxycorticosterone—are synthesized within the brain, predominantly
in principle (excitatory) neurons, and also in peripheral tissues
GABAA receptor modulatory neurosteroids confer seizure protection in diverse
animal models
Catamenial epilepsy is characterized by an increase in seizures during particular
phases of the menstrual cycle
Progesterone reduces seizure susceptibility partly through conversion to
neurosteroids such as allopregnanolone, which enhances GABAA receptor function
and thereby inhibits neuronal excitability. In animal models, withdrawal from
chronic progesterone and, consequently, of allopregnanolone levels in brain, has
been shown to increase seizure susceptibility

Alcohol Opioid receptors
• Alcohol dependent individuals and their
offspring may have a deficit in brain opioid
activity. Ethanol may induce opioid release
which in turn triggers dopamine release in the
brain reward system
• Naltraxone (ReVia, Trexan) blocks opioid
release and may reduce alcohol craving and is
approved for treatment of alcohol
dependency

Alcohol- Serotonin Receptors
• 5-HT2 and 5-HT3 receptors are located on dopaminergic
neurons in the nucleus accumbens (Nacc) Antagonistic
drugs that block these receptors (sertraline-Zoloft) appear
to reduce alcohol drinking in alcoholics of lower risk and/or
severity
• Alcohol administration elevates 5-HT levels in the nucleus
accumbens, ventral tegmental area (VTA), amygdala, and
hippocampus, an effect that is more pronounced in alcohol-
preferring rats. Reduced activity of the 5-HT system might
contribute to depression during withdrawal and increase
vulnerability to relapse (Kirby et al. 2011).

Alcohol Serotonin Receptors
Alterations in serotonin 1B receptor (5HT1BR) function might contribute to alcohol dependence
by influencing not only serotonin (5HT) input to the ventral striatum via the receptors’ role as
5HT terminal autoreceptors,1 but also dopaminergic input to the striatum via the role of these
receptors as heteroreceptors2 on GABA terminals within the ventral tegmental area, and
glutamatergic activity within the ventral striatum via heteroreceptors on corticofugal
projections

Alcohol Cannabinoid Receptors
• Recent research also indicates the involvement of
cannabinoid receptors. Chronic ingestion of ethanol
stimulate the formation of endogenous
neurotransmitter anandamide which activates
cannabinoid receptors.
• Continued ethanol ingestion eventually leads to
down regulation of these cannabinioid receptors.
This down regulation then disinhibits the nucleus
accumbens (endogenous reward system) Removal
of ethanol by cessation of drinking leads to
hyperactive endocannabinoid reaction which
appears to result in craving for alcohol

Alcohol Cannabinoid Receptors
• Mice genetically bred to lack these cannabinoid
receptors do not voluntarily consume alcohol and also
lack alcohol induced dopamine-mediated reward
responses in the nucleus accumbens.
• Similarly administration of drugs that block
cannabinoid receptors (antagonists) prevents relapse to
alcohol ingestion.
• Therefore it now appears that ethanol and cannabinoid
agonists activate the same reward system. Down
regulation of cannabinoid receptors may be involved in
development of tolerance and dependence on ethanol
and an active response from cannabinoid receptors
after alcohol detoxification may lead to alcohol craving
and eventual compulsion to relapse

Pharmacological Effects Alcohol
• Respiration transiently stimulated at low doses but at
higher doses becomes progressively depressed and at
very high blood concentration and is the cause of death
While alcohol is an anticonvulsant, withdrawal from
alcohol accompanied by prolonged period of
hyperexcitability increases likelihood of seizures.
• Alcohol abuse one of most common causes of adult-
onset-seizures. Seizures occur in !10% of adults during
alcohol withdrawal and can be life threatening.
Peripheral (skin) dilation. Low doses of alcohol daily
may reduce risk of coronary artery disease (Mukamal et
al. 2003a) and possibly ischemic strokes (strokes due to
loss of oxygen to specific brain areas possibly through
mechanism of increased HDL cholesterol and decrease
in platelet aggregation (like aspirin) While alcohol
induces behavioral disinhibition it interferes with sexual
performance

Psychological Effects Alcohol
• At low doses the setting and mental expectations
highly relevant. In one setting someone may be
relaxed and euphoric and in another setting
withdrawn and violent,. At low doses a person may
still function although with less coordination and
memory concentration and insight progressively
dulled. At higher doses these factors of setting and
mental expectations become progressively less
important
• Alcohol is implicated in more than half of all
homicides and assaults. About 40% of violent
offenders in jail were drinking at the time of the
offense for which they were incarcerated

Alcohol Proposed mechanism of action-
Aggression
• Proposed mechanism mediating aggressive
and criminal behavior
• 1) Through GABA system alcohol reduces the
anxiety about consequences of aggression
• 2) Through dopaminergic activation impuse
control is reduced
• 3) Through glutamate depression cognitive
functioning is impaired

Alcohol Effects
• Cognitive and attentional deficits cause a focus on
the present, reduce fear and anxiety and impair
problem solving. Alcohol use seems to increase
concerns of power and dominance. Frontal lobe
‘executive function’ particularly vulnerable to
alcohol abuse
• Alcohol has little nutritional value and if nutrition
from other sources is neglected, consumption
slowly leads to vitamin deficiencies and nutritional
diseases (alcohol abuse may be most common
cause of vitamin and trace element deficiencies in
adults

Alcohol Tolerance and Dependance
• Three types of tolerance
• Metabolic Tolerance-Liver increases amount of drug
metabolizing enzyme. This type of tolerance accounts
for ~25% of alcohol tolerance
• Tissue or functional tolerance-Neurons in brain adapt
to amount of drug present. Those with this type of
tloerance ujsually display blood alcohol levels about
twice those of a nontolerant individual at a similar level
of behavioral adaptation. Despite behavioral
adaptation, impairments in cognitive function are
similar at similar blood levels in both tolerant and
nontolerant persons(even if the tolerant person may
appear less intoxicated)
• Associative contingent or homeostatic tolerance-
Various environmental manipulations can counter the
effects of ethanol

Alcohol Withdrawal• Blocking seizures during withdrawal is a major goal of
detoxification and involves 1) benzodiazepines and 2)
ACDs A kindling model of alcohol withdrawal seizures
suggest that repeated wtihdrawals may led to an
increase in frequency of seizures. Multiple
detoxifications may lead to more obsessive thoughts
about alcohol and drinking urges and may lead to a
‘kindling’ of such behaviors, thoughts and compulsions
and may persist despite drug treatment
• In addition to withdrawal seizures and cravings, alcohol
withdrawal may consist of periods of tremulousness
with hallucination, psychomotor agitation, confusion,
sleep disorders
• Detoxification is accompanied byu a normalization of
low responsiveness of dopamine receptors which
occurs in alcohol abuse (Markianos et al. 2000)

Alcohol Side Effects and Toxicity
• Reversible drug induced dementia (clouded
sensorium) :Liver damage most serious long term
physiological consequence. Ethanol produces active
oxidants during metabolism by hepatocytes
resulting in oxidative stress on liver cells
• Cirrhosis 7th leading cause of death in United
States. Irreversible destruction of nerve cells may
lead to permanent dementia-Korsakoff’s syndrome.
Pancreatitis and chronic gastritis (and possibly
cancer may be due to increased free radicals

Alcohol Teratogenic Effects
• Rate of FAS~3-5/1,000 births. CNS dysfunction,
microcephaly, retarded growth rate, facial
anomalies (short nose, wide set eyes, small
cheekbones) congenital heart defects, malformed
eyes and ears.
• Alcohol Related Neurodevelopmental Disorder
(ARND) and FAS causal mechanisms unclear

Treatment History and Perspective
• Alcoholics Anonymous founded in 1935 based on a
moral model of alcoholism in a spiritual and behaviroal
framework to recovering from alcohol compulsion.
• Regardless of any genetic behavioral or medical cause of
alcoholism, it is clear that the age of onset of drinking
markedly affects long term outcomes eith heavy uses at
early ages have the poorest outcomes
• Often alcohol may be consumed as an attempt at self
medication with 30-50% of alcoholics meeting criteria
for major depression, 33% comorbid anxiety disorder
and many have personality disorders and many
addicted ot other drugs (Goodwin and Gabrielli, 1997)
38% have an impulse control problem (Lejoyeux et al. 1999)

Pharmacotherapies - Alcohol
• Goals of pharmacotherapy
• 1) Reversal of the acute effects of alcohol. No
current agent can reverse acute pharmacological
effects of alcohol- Caffeine a behavioral stimulant,
can only increase but cannot reverse motor
cognitive and other induced dysfunctions of alcohol
2) Treatment and prevention of withdrawal
symptoms
• 3) maintenance of abstinence and prevention of
relapse with agents that decrease craving or make it
unpleasant to drink alcohol
• 4) Treatment of coexisting psychiatric disorders

• If taking alcohol reduces glutamate activity and
increases GABA activity in the brain then alcohol
withdrawal results in the opposite effect or reduced
GABA and increased Glutamate which may explain
uncontrolled excitation and damage to cognitive
function and a major goal of alcohol withdrawal or
detoxification is to prevent this excitation
• Strategies for treatment- Benzos as first line therapy
Other medications (beta blockers or clonidine,
α2adrenergic agonist which block sympathetic
functioning) and adjunctive use of antipsychotics
(to alleviate hallucinations and delirium

• Alcohol sensitizing drugs- Disulfam (discovered by
accident Antabuse) produce adverse affects if person
drinks alcohol by allowing acetyldehyde to accumulate
resulting in headache, nausea, vomiting and chest pain
(Calcium carbimide may have fewer effects) Both
interfere with the normal metabolism of alcohol by
preventing the breakdown of the metabolic byproduct
acetaldehyde
• In the liver, the enzyme alcohol dehydrogenase oxidizes
ethanol into acetaldehyde, which is then further
oxidized into harmless acetic acid by acetaldehyde
dehydrogenase
• Controlled trials disappointing and person can simply
not take the medication

• Opioid Antagonists
• Naltrexone (ReVia, Trexan) believed mechanism
of action blocks opioid system-may reduce
craving by reducing positive reinforcement
associated with alcohol use. More recent studies
indicate it is not effective in preventing relapse.
Effective if used with drinkers of 20 years or less
and who have a strong support system (Fuller &
Gordis 2001)
• Injectable long-lasting depot-slow release
formula that provides continuous protection for
a month at a time

• Acomprosate (Campral) used as anticraving and
specifically designed to maintain abstinence in
ethanol dependent individuals after detoxification
Chemical structure similar to GABA While its
mechanism of action is not fully understood it is
believed that it exerts both a GABA agonistic action
at GABA receptors and an inhibitory action at NMDA
receptors. Because it is poorly absorbed orally it is
usually given in high doses (~2grams/day) It is
thought to be comparable to naltrexone with efficacy
enhanced when added to CBT rehabilitation focused
programs
• Side effects include diarrrhea, allergic reactions, irregular
heartbeats and low or high blood pressure, while less serious
side effects include headaches, insmnia and impotence.
Acomprosate should not be taken by people with kidney
problems or allergies to the drug

• Dopaminergic drugs
• Buproprion-Wellbutrin DA/NE reuptake inhibitor
• Antidepressant useful in treating comorbid
disorders of alcoholism and depression and since it
is a dopaminergic drug it is believed to operate on
the DA reward system. Also used in treating
smoking cessation, ADHD, Obesity, some anxiety
disorders (not panic) Not likely to cause sexual
dysfunction

Main ascending mesolimbic and nigrostriatal dopaminergic pathways. Abbreviations: ACC:
anterior cingulate cortex; HC: hippocampal complex; NAcc: nucleus accumbens; PFC: prefrontal
cortex; VTA: ventral tegmental area

• Serotonergic Medication
• Recent experimental data, both in animals and the clinic
suggest that drugs selectively interacting with the 5-HT
system may reduce alcohol intake. Althohj the precise
mechanisms underlying these drug effects are unknown,
it seems that there are at least two pharmacological
strategies available. First enhancement of 5-HT neuronal
activity using compounds that release 5-HT, block 5-HT
reuptake or act as selective 5-HT receptor agonists
(BuSpar 5-HT1A agonist). A second approach involves
selective 5-HT3 receptor antagonists (Zofran)
• BuSpar 5-HT1A agonist improves co morbid anxiety but less
effective in reducing alcohol consumption
• Cannabinoid Mechanisms
• Rimonabant CB1 antagonist (also used to treat obesity)
may moderate consumption of alcohol by reducing
craving (drug taken off market 2009)

Psychostimulants
• Generally these drugs act to augment the action of
several neurotransmitters, most importantly
dopamine
• Cocaine amphetamines and some other drugs
increase DA activity in the nucleus accumbens
• The nucleus accumbens (NAcc), also known as the
accumbens nucleus or as the nucleus accumbens septi
(Latin for nucleus leaning against the septum) or as
part of the pleasure center, is a collection of neurons
and forms the main part of the ventral striatum. It is
thought to play an important role in reward, pleasure,
laughter, addiction, aggression, fear, and the placebo
effect

Psychostimulants
• Output- neurons of the nucleus accumbens send axon
projections to the ventral globus pallidus, know as the
ventral pallidum (VP) the VP in turn projects to the
medial dorsal nucleus of the dorsal thalamus which
projects to the prefrontal cortex as well as the striatum.
Otter efferents from the nucleus accumbens include
connections with the substantial nigra and the pontine
reticular formation
• The NAcc is often described as one part of a cortico-straito-thalamo-cortical
loop

Psychostimulants
• Dopaminergic input from the VTA is thought to
modulate the activity of neurons with the NAcc
These terminals are also the site of action of highly-
addictive drugs such as cocaine and amphetamine,
which cause a manifold increase in DA levels in the
NAcc
• In addition to cocaine and amphetamine, almost
every recreational drug has been shown to increase
DA levels ihn the NAcc
• Another major source of ijnput comes from the CA1
and ventral subiculum of the hippocampus to the
dorsal medial area of the NAcc

Psychostimulants - Cocaine
• In low doses cocaine and other psychostimulants
evoke an alerting arousing or activating response
somewhat similar to a nromal reaction to stress or
an emergency, increasing BP HR and dilatingh
pupils. Blood flow shifts from skin and internal
organs to muscle and levels of glucose and oxygen
rise in the blood
• “Positive” effects include elevation of mood
(euphoria) increased alertness, reduced fatigue
and appetite and increased energy. Negative
effects include anxiety insomnia and irritability- As
doses increase these become more intense

• Cocaine is absorbed from all sites of application and
therefore can be snorted, smoked, taken orally or
intravenously. Snorted intranasally, cocaine poorly
crosses the mucosal membranes as it is a powerful
vasoconstrictor limiting its own absorption so that
only 20-30% of the snorted drug is absorbed into
the blood slowly, prolonging the euphoric effect.
• Vaporized and smoked molecules pass quickly onto
lung surfaces with rapid and more complete
absorption. Onset of effects is within seconds,
peaks at 5 minutes and persists for ~ 30 minutes

• IV injection bypasses barriers and goes immediately
to the blood stream. The 30-60 second delay of
action simply reflects the time it takes the drug to
travel from the site of injection to the pulmonary
circulation and into the brain
• Metabolism and Excretion- While rapidly removed
from the plasma, cocaine is more slowly removed
from the brain and can be detected (its metabolite)
up to 2 weeks in chronic users (long term users
might accumulate the drug in body tissues

Interaction Cocaine & Alcohol
• In individuals using both cocaine and ethanol, a unique
from of the metabolite of cocaine (benzoylecgonine) is
produced by the liver enzymes that metabolize the two
drugs which is as pharmacologically active as cocaine in
blocking the presynaptic dopamine reuptake transporter
(benzoylecgonine is normally an inactive metabolite but
the dual usage creates the metabolite cocaethylene)
potentiating the euphoric effect of cocaine and increasing
the risk of dual dependency and the severity of
withdrawal in chronic users
• Cocaethylene metabolite is more toxic than cocaine
and exacerbates cocaine's’ toxicity and has a longer
half-life than cocaine in the body (About 85-90% of
cocaine users are also alcohol dependent (Julien)

Cocaine-Mechanism of Action
• Cocaine has three prominent actions that
account for its physiological and psychological
effects
• 1) It is a potent vasoconstrictor (which accounts
for cardiovascular toxicities
• 2) It is a potent local anesthetic
• 3) It is a powerful psychostimulant with strong
reinforcing qualities

Cocaine Action at Receptor Sites
• Cocaine blocks reuptake of DA,NE and 5-HT with most
of the focus placed on the dopamine receptors believed
to be related to the reinforcing properties of cocaine.
Increased levels of DA in the nucleus accumbens and
other aspects of the DA reward system appear to be
responsible for the euphoric addictive effect of cocaine.
• Dopamine is primarily an inhibitory neurotransmitter.
Dopamine, cocaine and cocaethylene all decrease the
discharge rate of neurons in the VTA (ventral
tegmentum) and nucleus accumbens. Cocaine
markedly potentiates the dopamine induced decrease
in firing (discharge) potentiating its inhibitory action
(on post synaptic receptors)
• Cocaine competes with dopamine for the presynaptic
receptor, blocking it and prolonging the effect of
dopamine in the synapse

Cocaine Serotonergic Actions
• Augmentation of DA transmission remains the hypothesized
basis for the euphoric/reinforcing properties of cocaine but in
mice lacking the DA transporter, DA would not be expected to
be reinforcing but it was (Rocha 1998) therefore the serotonin
system may provide an addition component of reinforcement.
• Further in knock out mice lacking the 5-HT1B receptor
cocaine’s effects were greater and these mice were even more
motivated to self-administer cocaine. Thus the 5-HT1B
receptor may normally antagonize the reinforcing properties
of cocaine.
• It is possible that individuals with altered serotonin receptor
function may have greater susceptibility to cocaine. In mice
studied without either DA or 5-HT transporters Sora et al.
(2001) concluded that cocaine may work on both sites and
either one may modulate cocaine reward properties in the
absence of the other

Cocaine Pharmacological and Psychological Effects
• Psychological effects at low doses include immediate
euphoria, enhanced self-consciousness, boastfulness
which last for about 3o minutes. This is followed by
milder euphoria mixed with anxiety lasting about 60-90
minutes.
• Thoughts typically race and speech becomes rapid and
pressured possibly argumentative and sometimes
tangential and incoherent. Appetite and sleep are
suppressed but later rebound. Awareness and motor
activity are increased but later followed by depression.
• Cocaine promotes desire to take more cocaine even
instead of food. People graduate quickly to higher
doses so that low dose effects are difficulty to maintain.
Sexual dysfunction is common in heavy users as they
lose interest in interpersonal and sexual interactions

Cocaine Effects
• Extinction training (withdrawal) demonstrates that
cocaine withdrawal induces increases in AMPA
receptors in the nucleus accumbens (Sutton et al.
2003) This study concluded that extinction induced
plasticity in AMPA receptors may facilitate control over
cocaine seeking by restoring glutaminergic function in
the nucleus accumbens
• Effects of long term high use may result in markedly
altered perception of reality and the person may
become aggressive, paranoid or homicidal in response
to imagine persecution consisting of toxic paranoid
psychosis

Chronic Cocaine Use
• Chronic cocaine users demonstrate virtually every
psychiatric syndrome including affective disorders,
schizophrenia like syndromes and personality
disorders.
• Similar to alcoholics and heroin addicts, cocaine
addicts show a personality profile on testing with
reckless, rebellious behaviors and low tolerance for
frustration and a craving for excitement.
• Opiates and alcohol are often used to enhance the
effects of cocaine or to self medicate for unwanted
side effects such as calming jitters, dulling
perceptions and reducing paranoia

Cocaine and Pregnancy
• Because of its vasoconstrictive effects cocaine decreases blood
flow to the uterus and placenta reducing oxygen delivery to the
fetus. Such blood flow disruptions may include placental
detachment or insufficiency, premature birth, LBW, IUG,
microcephaly, abnormal sleep patterns, tremors, poor feeding ,
irritability, seizures and increased risk of SIDS and other alterations
in nervous system development.
• Virtually any body organ of the neonate can be adversely affected
if blood flow to the organ is restricted during development. The
mechanism of cocaine induced congenital anomalies may be
related to placental vasoconstriction and fetal hypoxia with HIE
causing congenital anomalies.
• Cocaine easily crosses the placental barrier and fetal
concentrations can equal those in the mother. Vasoconstriction in
either the mother of the fetus can increase blood pressure in the
fetus and lead to intracerebral hemorrhage, thickening of heart
muscle and various structural and vascular abnormalities

Cocaine Pharmacological Treatment
• Several obstacle complicate treatment including the
intense reinforcing action of cocaine and its strong
tendency to induce relapse. Also most addicts have
comorbid disorders and other drug dependencies.
Several areas of potential pharmacological
intervention can be identified
• 1) Aversive agents similar to disulfiram for alcohol
dependence. This area has not been fruitful and no
such agents have been identified. Also there is no
clearly defined agent that works through
substitution as methadone can substitute for heroin
or benzodiazepines can substitute for alcohol

• 2) Dopaminergic agents used to assist in withdrawal
and restore the hypodopaminergic functioning of
limbic system areas. Prolonged cocaine use is
associated with a down regulation of dopamine
receptors leading to a hypofunctional dopaminergic
system which likely persist for weeks or months
after drug abstinence. Methylphenidate (Ritalin-
Enhances release of DA and NE) and Buprorion (Wellbutrin-
NE reuptake inhibitor) are two dopaminergic drugs
which might assist in withdrawal and reverse a
hypodominergic state. Even though some positive
results can be demonstrated they are not clinically
robust

• 3) Anticraving agents studies focus on ACD
neuromodulators and cannabinoid receptors
Gabapentin neuromodulator has been reported to be
effective in treatment of cocaine dependence.
Vigabatrin exhibits anticraving effects against alcohol,
heroin, nicotine and cocaine (inhibits GABA
transamninase, increasing GABA activity and
attenuates drug induced increases in extracellular
nucleus accumbens dopamine and behaviors
associated with dopamine increase. Side effect in
some visual field damage possibly due to atrophy of
the optic nerve. Cannabinoid antagonists (blockers of
anandamide receptors endogenous fatty acid
cannabinoid) can be effected anticraving agents

• 4) Agents for comorbid disorders- Majority of people who abuse
cocaine have a history of depression and a positive family
history of affective illness. Buproprion has a similar action to
cocaine (blocking presynaptic dopamine transporter) but may
not be effective as an antidepressant for this population. Some
studies have reported favorable effects for TCAs (desipramine,
imimpramine) in improving mood and prolong abstinence in
patients withdrawing from cocaine and suffering from
depression. SSRIs may also be effective in this population but is
contested
• Levin et al., (1998) state that 35% of cocaine abusers seeking
treatment have a history of childhood ADHD and ~ 15% of adult
users may have ADHD In patients with comorbid cocaine
dependence and adult ADHD when placed on long acting
methylphenidate (Ritalin SR) with relapse prevention therapy,
both the ADHD and cocaine dependency were reduced
• Psychosocial interventions appear to offer promise, ranging
from 12 step recovery programs to group and individual
counseling with CBT or behavioral approaches

Amphetamines
• From 1935 to the end of WWII many conditions were treated
with amphetamines including schizophrenia , morphine
addiction,. Tobacco smoking, head injury, radiation sickness
etc. Large scale use began in the 1940’s by students and truck
drivers to maintain wakefulness and increase alertness.
During WWII amphetamines were used to fight fatigue and
enhance the performance of soldiers and others in the armed
services. Amphetamines continued to be used as appetite
suppressants despite the fact that the anorectic effect persist
only for the first two weeks and then diminishes.
• In the 1960’s they were used as diet pills. Today use is
generally restricted to the clinical treatment of ADHD
Consequently current interest in amphetamines involves two
areas 1) Therapeutic use in the treatment of ADHD and
narcolepsy 2) Compulsive use and dependency with the
derivative methamphetamine in its various forms and routes
of administration

Amphetamines
• Amphetamines are sympathomimetic agents as they
mimic the action of adrenaline, a transmitter in our
sympathetic nervous system. Amphetamines produce
other symptoms in the CNS including vasoconstriction,
hypertension, tachycardia and other signs of a normal
alerting response.
• Other signs include tremor, restlessness, increased
motor activity, agitation , insomnia and loss of appetite
which follow the presynaptic release of DA and NE (and
to a lesser extent direct stimulation of catecholamine
receptors. Representative amphetamines include
Adderall. Dextroamphetamine (Dexedrine) and
methamphetamine (Methadrine) as used for ADHD

Amphetamines-Mechanism of Action
• Amphetamines exert their effects (physiological and
psychological) through the release of newly synthesized NE
and DA from presynaptic storage sites in nerve terminals.
High doses show stereotypical behaviors (repetitive
meaningless acts) appear to involve the dopaminergic
systems in the caudate nucleus and putamen of the Basal
Ganglia. Aggressive behaviors are more complex to
understand. Aggression in adults may be due to
psychostimulant toxicity.
• However in children (and perhaps adults) with ADHD, low
doses may have a calming effect. Although cocaine has a
different mechanism of action, along with amphetamines, the
net effect is of increasing the amount of dopamine available
(cocaine abusers may not distinguish between the subjective
effects of similar amount of cocaine and dextroamphetamine
when they are delivered intravenously

Amphetamines and Dopamine
• Amphetamine increases the concentration of dopamine in the
synaptic cleft in 3 ways:
• (1) It can bind to the pre-synaptic membrane of dopaminergic
neurons and induce the release of dopamine from the nerve
terminal;
• (2) amphetamine can interact with dopamine containing synaptic
vesicles, releasing free dopamine into the nerve terminal; and
• (3) amphetamine can bind to the dopamine re-uptake transporter,
causing it to act in reverse and transport free dopamine out of the
nerve terminal.
• Amphetamine can also cause an increased release of
noradrenaline into the synaptic cleft."

Amphetamines-Pharmacological Effect
• At low doses all amphetamines increase BP, relax
bronchial muscle and increase heart rate and produce
other responses following the body’s general alerting
response
• As a powerful CNS psychomotor stimulant increases
alertness,, euphoria, excitement, wakefulness, a
reduced sense of fatigue, loss of appetite and
increased motor and speech activity as well as a sense
of power
• The release of DA increases the amount of dopamine
available to the postsynaptic receptor similar to
cocaine –both drugs have the net effect of increasing
the amount of DA available even if it is through
different mechanisms-explains why difficult for
cocaine abuser to distinguish between drugs when
delivered by IV

Amphetamines-Pharmacological Effect
• At moderate doses additional signs are noted such as
increased respiration, slight tremors, restlessness, insomnia
and agitation (even at low to moderate doses of 20-50mgs
some individuals can have a toxic reaction
• Chronic users of high doses show a differs set of effects
including stereotypical behaviors (repeated purposeless acts)
sudden outbursts of aggression, violence, paranoid delusion
and sever anorexia.
• Continued use may include psychosis and abnormal mental
conditions skin sores, infections due to neglected health.
Most high does users show a progressive deterioration in
their social personal and occupational functioning. Toxic
doses vary widely from low doses of 20-30mgs although
some users have tolerated doses of 400-500mgs or more

Amphetamines-Dependence and tolerance
• Physical dependence is readily induced in both
laboratory animals and humans. Tolerance rapidly
develops and can necessitate higher and higher doses
starting a vicious circle of drug use and withdrawal.
Tolerance to the euphoriant effects develops and
periods of prolonged binge drug use begin.
• Tolerance combined with the memory of drug induced
highs leads to further use, social withdrawal and a
focus on procuring the drug. In withdrawal paranoid
symptoms may persist but do not develop as a result of
withdrawal.
• Sudden discontinuation of amphetamines may result in
depression and suicidal ideation. Use of
antidepressants may be considered as well as some
antipsychotic medications to treat the paranoia

Methamphetamine
• Methamphetamine is more potent than
dextroamphetamine and was initially a lecit drug used
to treat ADHD however it is rarely used legitimately
now and illicit use dominates.
• Methamphetamine is easily synthesized from readily
obtainable chemicals and can be used orally, injected
intravenously, snorted or (based form vaporized)
smoked.
• ICE is to methamphetamine as crack is to cocaine: the
free-base concentrated smokable form of the parent
compound but unlike crack, methamphetamine has an
extremely long half-life (~12 hours) resulting in an
intense persistent drug action

Methamphetamine
• After distribution to the brain, about 60% of the
methamphetamine is slowly metabolized in the
liber (and excreted through the kidney along
with about 40% metabolized drug) Repeated
high doses are associated with violent behavior
and paranoid psychoses with long lasting
decreases of DA and 5-HT in the brain and also
unlike cocai9ne, smoked methamphetamine
(“ice”) can induce a psychosis that persists for
days or weeks

Reinforcement Addiction in the brain
Neuroanatomy and pharmacology of
addiction and reward systems

Reinforcement Addiction in the brain
• Drug addiction appears to rewire the nucleus
accumbens Repeated use of cocaine increases
release of DA in nucleus accumbens and
greater drug seeking behavior while nucleus
accumbens responses less normal to other
incentives including sex. Drugs may interfere
with frontal lobe connection which normally
facilitates Nacc responding to reinforcing
experiences

Drug Addiction as a model of other disorders- Obesity
• Eating tasty foods activates similar brain areas as do certain
drugs. Drug addicts who cannot get drugs sometimes
overeat as a substitute and food deprived people or
animals become more likely to use drugs. A cycle of food
deprivation followed by overeating strong stimulates brain
reinforcement areas similar to drug deprivation followed by
drug use (Hoebgel et al. 1999)
• Rats were food deprived for 12 hours a day and then
offered a very sweet syrupy solution of 25% glucose. Over
several weeks the rats drank more and more each day and
increased greatly how much they drank the first hour they
wee allowed access to the solution. This increase released
DA and opioid similar to many drugs When deprived of the
liquid they shoed withdrawal symptoms (head shaking,
teeth chattering) which could be relieved by injecting
morphine (i.e. sugar addiction In this model bulimia with its
cycles may constitute an addiction

• (A) Illustration depicting the structures of the brain involved
in addiction and obesity. The nucleus accumbens is thought
to be important in identifying stimulants by assessing reward
and saliency (which is the feature of a thing that makes it
stand out from all others). The orbitofrontal cortex is involved
in decision-making and determining the expected rewards
and punishments of an action. The amygdala and
hippocampus are involved in forming memories of the
stimulus/reward relationship, whilst inhibitory control and
emotional regulation are provided by the prefrontal cortex
and the anterior cingulate gyrus. Addictive drugs and food,
particularly in obese individuals, are believed to cause
neurons from the ventral tegmental area to release the
neurotransmitter dopamine in the nucleus accumbens. These
regions regulate activity in the frontal cortical regions. This
pathway is referred to as the mesolimbic reward pathway
(arrows marked in red).

B,C) Schematics showing the reward pathways in the non-addicted and addicted brain. In a
person suffering from addiction, the reward pathway is disrupted such that the prefrontal
cortex and cingulate gyrus are no longer controlling factors and compulsive behaviour is driven
by the enhanced activation of the reward and saliency and memory and conditioning regions of
the brain. As such, when an individual is exposed to the reinforcing stimulant-drug or food-the
system goes into overdrive. Figure adapted from Baler RD , Volkow ND (2006) Drug addiction:
the neurobiology of disrupted selfcontrol. Trends Mol Med 12: 559–566

Overview of brain areas and
neurotransmitter systems in Addiction
• Many areas exist in the brain for which rats will work to
deliver stimulation mostly which result in increased release of
dopamine in nucleus accumbens (Olds and Milner 1958 Wise
1996) If prolonged, rapid brain stimulation depletes the
dopamine supply and brain stimulation becomes less
reinforcing.
• Other types of reinforcing experiences also stimulate DA
release in NAcc including sexual excitement, gambling and
habitual video game playing (and most abused drugs).
However DA is not the only neurotransmitter involved in
reinforcement and the NAcc is more than simple pleasure
and appears to involve craving (wanting) not necessarily
liking something (Berridge and Robinson, 1998) and addiction
involves cravings even when the drug itself no longer
produces pleasure

neurotransmitter systems
• Stimulant drugs increase excitement, alertness and
activity by increasing release of DA from
presynaptic terminal Instead of DA being
transported back into the cell by the DA transmitter
on the presynaptic cell Amphetamine reverses the
transporter causing the cell to release DA instead of
reabsorbing it (amphetamines also increase release
of other neurotransmitters; NE, 5-HT etc)

neurotransmitter systems
• Cocaine blocks reuptake of DA, NE and 5-HT
but ultimate effect (like amphetamines)
increases these transmitters at synapse.
Excess DA gets removed from the synapse
(washes away) faster than it can be replaced
by presynaptic cell so that DA is depleted and
a few hours after taking amphtetamine or
cocaine a user crashes

Stimulants and effects
• Rats with a genetic deficiency in DA receptors
(which are more impulsive) are more likely to self
administer cocaine lever pressing ( Dalley et al.
2007) In human twin studies the twin abusing
stimulant drugs showed attentional problems that
remained for a year after quitting the drug (Toomey
et al. 2003) By altering blood flow cocaine also
increases the risk of stroke and epilepsy

Stimulants and effects (continued)
• Methylphenidate is a stimulant for ADHD and like
cocaine blocks DA reuptake but methylphenidate (in
pill form) causes a gradual increase in the drugs
concentration and does not produce a sudden
‘rush’ of excitement or cravings or addiction.
• However if injected or taken in larger amounts
methylphenidate resembles cocaine in its addictive
qualities (While methylphenidate treatment may
not lead to later drug abuse it may show other side
effects after prolonged use (increased fearfulness
Balanos, et al. 2003)

Stimulants and effects (continued)
• MDMA methylenedioxymethamphtetamine –ecstasy is
a stimulant at low doses releasing DA. At higher doses
(as in recreational use) it increases 5-HT release
producing alterations in perception and cognition
usually decreasing anxiety/depression. After effects
wear off lethargy and depression are common- Large
injections of MDMA appear to damage 5-HT neurons
due to 1) increased body temperature and high
temperature impairs neurons and 2) excessive 5-HT
release results in cell’s mitochondria oxidizing the
excess molecules (loss of electrons) with one of the
breakdown products being hydrogen peroxide H2 O2.

MDMA continued
• While Hydrogen peroxide is naturally produced in
organisms as a by-product of oxidative metabolism
and the brain tolerates some amounts high doses of
MDMA flood the neurons with H2 O2 , damaging
the mitochondria and impairing or killing the
neuron The oxidizing capacity (ability to add
electrons) of hydrogen peroxide is so strong that it
is considered a highly reactive oxygen species (ROS)

Nicotine
• Nicotine receptors abundant on neurons that
release DA in the NAcc (Levin & Rose 1995)
similar to cocaine Stimulation of nicotinic
receptor correlates with exposure to novel
environments and novel stimuli Repeated
exposure to nicotine in rat studies appears to
result in less responsiveness in NAcc cells
involved in reinforcement (i.e. Nicotine and
many events become less reinforcing with
repetition)

Efficacy and Effectiveness of Antidepressants: Current
Status of Research -H. Edmund Pigott et al. Psychother Psychosom 2010;79:267–279
• Real-World Effectiveness of Antidepressants
• Analyzes STAR * D (Sequenced Treatment Alternatives to Relieve Depression),
the largest antidepressant effectiveness trial ever conducted.
• In conformity with this goal of enrolling more representative MDD patients,
the NIMH-funded STAR * D study :
enrolled 4,041 real patients seeking care versus persons responding to
advertisements for depressed subjects;
included patients with comorbid medical and psychiatric conditions as well as
those whose current MDD episode was 1-2 years;
included patients currently undergoing antidepressant treatment provided that
there was not a history of nonresponse or intolerance to either step-1 or step-
2protocol antidepressants;
• used ‘ remission ’ versus ‘ response ’ as the primary criterion of successful
treatment which is a higher clinical standard than used in prior effectiveness studies;
• provided 12 months of continuing care while monitoring the durability of
treatment effects versus only reporting acute-care improvement.

Real-World Effectiveness of Antidepressants
• STAR*D represents a 7-year effort by literally hundreds of
people and thousands of patients
• This highly representative clinical sample of depressed
outpatients has revealed that major depression is often
chronic, severe, and associated with substantial general
medical and psychiatric comorbidity. Longer times than
expected were needed to reach response or remission. In
fact, one-third of those who ultimately responded did so after
6 weeks (and half of those who ultimately remitted did so
after 6 weeks) . These results suggest that stopping a
vigorously dosed treatment for patients who report little
benefit by 6 weeks is ill-advised
• Those who fared better in the prior step and who evidenced
minimal intolerance preferred augmentation, while those
with little benefit or substantial intolerance with the prior
treatment preferred to switch. Whether augmentation is best
even if the initial treatment is minimally effective could not
be evaluated in the STAR*D design

• As for specific medications at the second step, results suggest
that either a within-class switch (e.g., citalopram to sertraline)
or an out-of-class switch (e.g., citalopram to bupropion-SR) is
effective, as was a switch to a dual-action agent (e.g.,
venlafaxine-XR). While bupropion-SR and buspirone were not
different as augmentation options in the second-step treatment
according to 17-item Hamilton Rating Scale for Depression
scores, secondary measures (e.g., tolerability, symptom change
from baseline to exit in the 16-item, clinician-rated Quick
Inventory of Depressive Symptomatology) recommended
bupropion-SR over buspirone.
• Thus, substantial pharmacologic differences between the
second-step medications did not translate into substantial
clinical differences in efficacy STAR*D: What Have We
Learned? John Rush Am J Psychiatry 2007;164:201-204

• Meta-analyses of FDA trials suggest that antidepressants are only
marginally efficacious compared to placebos and document
profound publication bias that inflates their apparent efficacy.
These meta-analyses also document a second form of bias in which
researchers fail to report the negative results for the prespecified
primary outcome measure submitted to the FDA, while highlighting
in published studies positive results from a secondary or even a
new measure as though it was their primary measure of interest.
The STAR * D analysis found that the effectiveness of
antidepressant therapies was probably even lower than the
modest one reported by the study authors with an apparent
progressively increasing dropout rate across each study phase.
• Conclusions: The reviewed findings argue for a reappraisal of the
current recommended standard of care of depression.
• Despite the pervasive belief regarding the effectiveness of
antidepressants and cognitive therapy (CT) among physicians and
society at large, STAR * D shows that antidepressants and CT fail to
result in sustained positive effects for the majority of people who
receive them.

• The cognitive therapy findings at the second step were
both encouraging and disappointing. There was no
difference between cognitive therapy as a switch or as
augmentation strategy versus medication as a switch or
augmentation strategy . Yet cognitive therapy may well
be treating a group that is not particularly medication
responsive .
• However, far fewer patients than expected elected
randomization that included cognitive therapy—
perhaps because of the need for additional
copayments, the fact that some patients were already
seeing a therapist, or the need to visit yet another
provider at another site. Thus, future work to enhance
the delivery and convenience of obtaining cognitive
therapy is needed

• STAR*D results also raise important research design and
treatment issues. Why not include more broadly
representative patients in placebo-controlled efficacy trials
that are used to develop treatments? Presently,
symptomatic volunteers who are not fully representative of
actual patients commonly populate these early efficacy
trials. Unlike self-declared patients seen in practice settings,
these subjects often have minimal medical or psychiatric
comorbid conditions, nor are they chronically ill. Thus,
efficacy trial findings may not generalize to actual practice. If
we could protect patient safety and ensure internal validity
in such efficacy trials, results would be more directly
applicable to our patients, who are less likely to improve
spontaneously than symptomatic volunteers. Such patients
would reduce placebo response rates and thereby reduce
the likelihood of failed trials

• The gap between what we do in practice and what we
know is very large. We insist that remission is our goal,
yet we do not routinely carefully measure symptoms in
practice to determine if remission occurs. Yet we know
that “better but not remitted” consistently leads to a
worse prognosis than full remission. We often
underdose or poorly titrate medication. Finally, we
often combine treatments in practice, yet very few
trials have assessed either safety or efficacy of these
efforts. Analogous to treating hypertension, diabetes,
or many other medical conditions, our patients deserve
every chance to reach remission. “Less hypertensive” is
not the goal of treatment of hypertension. Nor should
“less depressed” be the goal for our depressed patients

• in light of the meager results of STAR * D, it is worth
reconsidering the term ‘treatment-resistant depression’ when
referring to patients who do not respond favorably to drug
treatment. Should we not direct our attention to what is
wrong with our treatment rather than classifying some
patients as having an exotic form of depression because they
fail to respond? Our understanding is hampered by using
language that wrongly implies that there is an exceptional
subgroup of patients who are refractory to an otherwise
effective treatment. The inescapable conclusion from STAR *
D results is that we need to explore more seriously other
forms of treatment (and combinations thereof) that may be
more effective. This effort will require developing new service
delivery models to ensure that as such treatments are
identified, they are widely implemented

"Real World" Atypical Antipsychotic
Prescribing Practices in Public Child and
Adolescent Inpatient Settings Elizabeth Pappadopulos, et al. Schizophrenia Bulletin, Vol. 28, No. 1,
2002
• The widespread use of atypical antipsychotics for youth treated
in inpatient settings has been the focus of increasing attention,
concern, and controversy. Atypical antipsychotic medications
have supplanted traditional neuroleptics as first line treatments
for schizophrenia and other psychotic disorders in adult
populations. A similar trend has also been observed in the
treatment of child and adolescent psychiatric patients, although
data on the safety and efficacy of atypical agents in youth are
scarce
• Among child and adolescent inpatients, atypical antipsychotics
are mainly prescribed for aggression rather than for psychosis.
Current debates revolve around whether these agents are
appropriately monitored and managed. In an effort to address
these concerns, a survey was developed and administered to
physicians at four facilities and to a group of 43 expert clinicians
and researchers.

Adolescent Inpatient Settings
• Taken together, these studies show that as many as 98
percent of children and adolescents in psychiatric hospitals
are treated with psychotropic medications during their
inpatient stay and approximately 45 percent to 85 percent of
these patients receive multiple medications simultaneously.
Antipsychotics are the most commonly prescribed agents
across most inpatient settings for the treatment of aggression
• While overall rates of psychotropic prescribing (ranging from
68% to 79% of patients) did not differ across inpatient units,
preferences for particular classes of medications varied by
facility. In addition, a higher percentage of patients were
given antipsychotics in the county-university hospital (74%)
than in the State hospital (57%) or the private hospital (35%).
While these trends may be due to differences in the patient
populations treated at each facility, Kaplan and Busner note
that the use of antipsychotics for nonpsychotic disorders was
statistically equivalent across settings.

• Atypical antipsychotics represent a major advance in the
treatment of schizophrenia and psychosis among adults
because of their superior efficacy and side effect profile in
comparison to conventional antipsychotics. However, because
these benefits have not been reliably established in children
(Sikich 2001), antipsychotic prescribing practices for child and
adolescent psychiatric inpatients have largely developed from
clinical experience rather than from scientific evidence.
• A recent literature review shows that published data on
treatments for aggression are primarily from open studies and
case reports. Much of the research conducted involves
aggressive youth with compromised intelligence and are not
easily applied to the general population of youngsters with
aggressive behavior problems.

• Concerns about side effects, such as weight gain, elevated
prolactin levels, and abnormal electrocardiograms, especially
in children, have yet to be resolved by research. In the face of
limited data from clinical trials, intensive study is needed on
factors that influence physicians' antipsychotic prescribing
preferences and that result in unnecessary treatment
variability.
• Taken together, the audit of patient charts reveals much-
needed real-world information about the administration of
antipsychotics and other psychotropic medications in this set
of public inpatient facilities for children and adolescents. The
children and adolescents treated in these settings represent a
particularly severe and comorbid patient population. Despite
the fact that inpatient youth diagnosed with psychosis
accounted for only a fraction (20%) of the population,
antipsychotics were commonly prescribed in this sample and
were often used in combination with other agents.

"Real World" Atypical Antipsychotic prescribing practices
Antipsychotics are administered to children and adolescents in public
inpatient settings in high proportions for complex comorbid
conditions involving aggression. Ironically, this real-world patient
population is excluded from clinical research, leaving clinicians to
rely on clinical experience rather than empirical evidence,data reveal
that there are great disparities in the use of antipsychotics across
facilities, and this may be due in part to the lack of available data to
guide these practices.
Several findings regarding the administration of psychotropic
medications surprised us and raised important areas of concern. The
number and proportion of medications on admission were very
similar to medication regimens at discharge. One would expect that
after an average stay of more than 3 months, more adjustments
would be made to the medication regimen. The rationales for this
lack of change in treatment regimen are situation makes it difficult
to determine whether and how changes in medication might affect

Prescription practices
• The administration of two or more psychotropic medications
(polypharmacy) is also an area of concern. In our chart review, because
the number of medications given to patients tended not to change over
the course of treatment, it is possible that polypharmacy in these facilities
represents treatment inertia. In other words, physicians at these facilities
tend to sustain, rather than initiate, the use of polypharmacy. Patients'
charts did not provide enough information regarding rationale for
physicians' medication strategies, and given that cases are often seen by a
number of physicians, there is little evidence of continuity in medication
use. For example, one study found that nearly half of patients given
risperidone in a State hospital were taken off their medication within 15
days after discharge by their outpatient physician
• A clear rationale for medication strategy was often missing from
medication progress notes. This is particularly important given the great
concern over antipsychotics' side effects, a concern that was repeatedly
raised during focus groups. In these ways, physicians' actual practices did
not match experts‘ agreed-upon best practices. Many current practices

Prescription practices
• Physicians unanimously support the use of atypical antipsychotics
over conventional antipsychotics, and yet conventional agents are
administered in high proportions as prn/stat medications, thus
indicating that they are still widely used in this capacity.
• During focus groups, physicians reported that decisions to use
antipsychotic medications for youth with aggressive and disruptive
behavior problems were influenced by several factors. Physicians
feel social pressure to use antipsychotic medications when staff
report patient behavior that is particularly disruptive or considered
dangerous. Such pressures become even more pronounced when
there are limited staff resources available to provide intensive
observation, seclusion, or restraint.
• In some facilities insurance companies may limit the amount of
time that a patient can spend in an inpatient unit. Because
antipsychotics are quick acting, physicians may therefore prescribe
these medications to appease insurance companies. Physicians also
considered the use of antipsychotics to be more humane than the
repeated use of are pressured to minimize the use of physical and
chemical restraints on inpatient settings, standing doses of atypical
antipsychotics have become the treatment of choice for aggressive
and disruptive inpatient youth.

Theories of how the retrograde gaseous neurotransmitter nitric oxide could be involved in Long-
Term Potentiation (LTP) of a glutamatergic hippocampal synapse. The excitatory
neurotransmitter glutamate first activates AMPA and metabotropic glutamate receptors which
leads to recruitment of NMDA receptor activity. Calcium ion entry, via NMDA receptor channels,
into the postsynaptic site activates nitric oxide synthase (NOS). The nitric oxide gas (NO)
produced diffuses to the presynaptic site where it is absorbed by the haem group of an NO-
sensitive guanylate kinase enzyme which triggers the production of cyclic GMP which increases
neurotransmitter glutamate release. Key: mGluR, metabotropic glutamate receptors; IP, inositol
triphosphate second messenger; PDE, phosphodiesterase, which inactivates cyclic GMP.
Adapted from Fig 2 in Holscher (1997).
Read more: http://www.answers.com/topic/neurotransmitters-and-
neuromodulators#ixzz2MuP0yxjY

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