Transcript Psy 5260 – Summer I 2009 Week Seven Lecture Notes

Medical Model of Mental Illness
 Pros and Cons
 Assumes biological etiology
 Potentially treatable with
psychotropic drugs
 There are no simple diagnostic tests for
mental disorders.
 Diagnosis is based on assessment of
behavioral symptoms.
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Anxiety Disorders
 Generalized Anxiety Disorder, Phobic Disorder,
Panic Disorder, Obsessive Compulsive Disorder,
Post-traumatic Stress Disorder
Psychotic Disorders
 Schizophrenia, Schizoaffective Disorder
Affective (Mood) Disorders
 Dysthymia, Major (Unipolar) Depression, Bipolar
Disorder
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Before 1950, “Malaria therapy”
Thiopental sodium – truth serum
Insulin shock therapy
Electroconvulsive therapy
Development of Phenothiazines in 1950s
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Historical Background
 “Accidental” discovery of promethazine and then
chlorpromazine by Henri Laborit, 1951
 Largactil marketed in Europe, 1953
 Thorazine marketed in U.S., 1955
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Other Names for Antipsychotic Drugs
 Neuroleptic
 Literally means “clasping the neuron”
 Refers to parkinsonian-like side effects of these drugs
 “Major” Tranquilizers
 Refers to sedating effects
 Misleading terminology , chemically and
pharmacologically distinct from “Minor” tranquilizers
(the benzodiazepines and barbiturates)
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Dramatic decline in numbers of people
institutionalized
Increase in outpatient treatment programs
Psychiatrists roles have changed
From hospitals to jails or on the streets
Number of patients in nonfederal hospitals, 1946-2002 (Figure from Ksir et al., 2007).
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Typical (Classical or Traditional)
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Atypical , 2nd generation
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Phenothiazines or similar to phenothiazines
e.g., chlorpromazine, haloperidol
e.g., clozapine, risperidone, olanzapine,
quetiapine,
Atypical, 3rd Generation
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e.g., aripiprazole, amisulpride, ziprasidone
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Routes of Administration/Absorption
 Oral administration common, although absorption is
erratic and unpredictable.
 In some cases (e.g., poor compliance with oral meds),
Depot injections (I.M.) may be given, once a month.
Distribution
 Rapid distribution throughout the body
 Easily cross blood brain barrier and placenta
 Considerable protein binding in blood
 Lower brain concentration compared to other body
tissues
 Absorbed in body fat and released slowly
Elimination
 Half-life: 24-48 hours
 Slow elimination due to protein binding and
accumulation in body fat
 Determining optimal dose, trial and error.
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Neuropharmacological Mechanisms
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Block DA, NE, ACh, and histamine receptors
CNS actions
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Limbic System: main therapeutic effects
Brain Stem: suppress behavioral arousal,
antiemetic effects
Basal Ganglia: akathesia, dystonia, parkinsonism,
and Tardive Dyskinesia
Hypothalamus-Pituitary: temperature regulation
impaired, breast enlargement, lactation,
impotence, infertility
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Side Effects/Toxicities
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Sedation due to antihistamine and antiadrenergic effects
Postural hypotension due to antiadrenergic effects
dry mouth, blurred vision, constipation, urinary retention
tachycardia due to anticholinergic effects
Extrapyramidal effects due to antidopaminergic effects in
basal ganglia
Impaired cognition due to anticholinergic effects
Despite many side effects, antipsychotics are not lethal;
high therapeutic index (100 to 1000)
Tolerance/Dependence
Tolerance develops to some of the side effects, but there is
NO evidence of tolerance to the therapeutic effects.
 These drugs do not produce physical dependence,
perhaps due to extremely slow elimination from the body.
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haloperidol (Haldol)
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molindone (Moban)
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Introduced in 1970s, structurally similar to 5-HT
Similar therapeutic and side effects to traditional antipsychotics
loxapine (Loxitane)
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Structurally distinct from phenothiazines
Similar pharmacological mechanisms and similar side effect
profile
Effective for treating acute psychosis due to rapid onset,
especially by injection
Despite structural similarity to clozapine, effects more similar to
traditional antipsychotics
pimozide (Orap)
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In U.S. primarily used in tx. of tics in Tourette’s Syndrome
Similar side effects to traditional neuroleptics, QT prolongation
potentially severe
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clozapine (Clozaril)
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Background
 Synthesized in 1959 and introduced into clinical practice
in Europe in early 1970s
 Fatalities due to agranulocytosis delayed introduction in
the U.S.
 1986, clinical trials in U.S.
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Pharmacokinetics
 p.o., absorbed well, peak plasma levels in 1-4 hours
 variable half-life 9-30 hours
 Blood monitoring especially important
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clozapine continued
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Pharmacodynamics
 High binding affinity for D4, 5-HT1C, 5-HT2, NEa1,
muscarinic and histamine receptors
 Low D2 affinity
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Side Effects/Toxicity
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Sedation in about 40% of patients
Weight gain for up to 80% of patients
Constipation in about 30% of patients
Agranulocytosis rare
Withdrawal symptoms may occur upon
discontinuation, alleviated by olanzapine
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risperidone (Risperdal)
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Introduced in 1993
Pharmacokinetics
 p.o., well absorbed
 Highly bound to plasma proteins
 Half-life about 3 hours, active metabolite with 22 hr.
half-life
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Pharmacodynamics
 Less effective than clozapine in relieving positive
symptoms, equally effective in relieving negative
symptoms
 Better safety profile than clozapine
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Side Effects
 Somnolence, agitation, anxiety, headache, nausea
 EPS at high doses (> 8 mg/day)
 Weight gain less than with clozapine or olanzapine
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olanzapine (Zyprexa)
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Introduced in 1996
 structurally/pharmacologically similar to clozapine, no
agranulocytosis
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Pharmacokinetics
 p.o., well absorbed, peak plasma levels 5-8 hours
 Half-life 27-38 hours
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Pharmacodynamics
 Superior or comparable to haloperidol
 Comparable efficacy to clozapine
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Side Effects
 Weight gain
 no agranulocytosis
 occasional EPS
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Other Uses of Olanzapine
 Bipolar disorder
 Pervasive Developmental Disorder
 Agitation and Aggression
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Other Atypicals
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sertindole (Serlect)
 1997
 D2/5-HT2 antagonist, no antihistaminic effects
 Prolonged QT interval, removed from market
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quetiapine (Seroquel)
 1998
 D2/5-HT2 antagonist, similar to clozapine
 Side effects: nausea, sedation, dizziness, weight gain no different from
placebo
 Other uses: bipolar, OCD
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ziprasidone (Geodon)
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D2/5-HT2 antagonist, 5-HT1A agonist
Relieves positive and negative symptoms, no weight gain
First atypical approved for IM use
Antidepressant activity, also effective in Bipolar disorder
Cardiac effects are a limiting factor, prolongs QT interval
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Aripiprazole
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Pharmacodynamics
 Considered a DA-5-HT system stabilizer
 5-HT2 antagonist, partial D2 and 5-HT1A agonist
No serious side effects
 Other recent uses
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 Bipolar disorder, conduct disorder in children
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Amisulpride
D2/D3 antagonist in limbic areas, not b.g.
 Low doses inc. DA release, high doses block
 First atypical that doesn’t block 5-HT receptors
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Potential Health Risks of Atypical
Antipsychotics
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Weight Gain
 hinders patient compliance
Diabetes/Hyperglycemia
 Electrocardiographic Abnormalities
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Subjective Effects
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In healthy subjects, classical neuroleptics produce
slow and confused thinking, difficulty concentrating,
clumsiness, sedation, some anxiety and irritability.
These effects probably responsible for poor
compliance among patients prescribed these drugs.
Atypical antipsychotics less of a problem.
Performance
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Few studies and reports are variable (deficits,
improvements, no effect)
Studies of acute effects on cognitive performance
indicate impairments are due to sedation and
tolerance to these effects occur within 14 days.
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Unconditioned Behavior
Suppression of spontaneous movement with high doses
causing immobility (which gave rise to the name
neuroleptic)
 Diminish frequency and intensity of aggressive behavior
in most species, possibly due to decreased motor
function.
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Conditioned Behavior
Decrease responding on schedules maintained by positive
reinforcement, although low doses may increase low
response rates (rate dependency similar to amphetamine)
 Decrease avoidance responding without affecting escape
behavior, similar to CNS depressants.
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Drug Discrimination
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Some antipsychotics not easily discriminated, large
doses and extended training required.
Generalization does not occur between Atypicals
(e.g., clozapine) and Typicals (chlorpromazine) or
between antipsychotics and other drug classes.
Self-administration
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Antipsychotics are NOT self-administered by
nonhumans.
They are never abused by humans.
In fact, compliance among patients is often a
problem.
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Symptoms
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extreme sadness/despair, diminished interest in
pleasure, diminished energy, loss of
appetite/weight loss, mental slowness,
concentration difficulties, restless agitation,
insomnia, recurrent suicidal thoughts
DSM-IV criteria list nine categories of symptoms
with five or more symptoms present during
same two week period
Prevalence in U.S.
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Approx 14 million (6.6 % of adults)
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50% receive medical treatment, which is
effective in only about 42% of those treated
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Pathophysiology of Depression
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A “reversible brain disease”
 Structural, neurochemical changes in hippocampus,
frontal cortex
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Once thought to be a consequence of
neurotransmitter deficiencies (e.g., NE, 5-HT)
More recent evidence suggests reductions in
neurotrophic hormones and reduced neuronal
plasticity are key factors in pathophysiology of
depression.
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First Generation (introduced in 1950s-1960s)
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MAO Inhibitors
Tricyclics
Second Generation, Atypical (1970s-1980s)
SSRIs (~ 1990s)
SNRIs
Dual-Action Antidepressants
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Combined SSRI + 5-HT2 antagonist or combined
SSRI/SNRI
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Examples of MAOIs
Iproniazid: first one introduced in 1950s, no longer on
the market
 phenelzine (Nardil)
 tranylcypromine (Parnate)
 moclobemide (Ludiomil): not available in U.S.
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Pharmacokinetics
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Short half-life, 2-4 hours
Neuropharmacological Actions
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Block degradation of monoamines by MAO
Indirect Agonist for all Monoamines
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Side Effects
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potentially fatal interactions with foods containing
tyramine or with adrenergic drugs; hypertensive
crisis.
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MAO-A vs. MAO-B
 Both in CNS: MAO-A mainly acts on NE and 5-HT;
MAO-B mainly acts on DA.
 MAO-A, in gastrointestinal tract; MAO-B, in liver and lungs
 Older MAOIs acted on both types, side effects such as
hypertensive crisis with tyramine rich foods.
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Recent advances
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Selective MAO-A inhibitor, moclobemide (not
available in U.S.)
Transdermal delivery of selegiline (Eldapril)
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Examples
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imipramine (Tofranil)
amitriptyline (Elavil)
desipramine (Norpramin)
Pharmacokinetics
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well absorbed with oral administration
long half-lives, ~ 24 hours
metabolized in liver
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Neuropharmacological Effects
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monoamine reuptake blockade
Indirect agonist for all monoamines
Side Effects
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Antihistaminergic effects: sedation
Anticholinergic effects: dry mouth, blurred vision,
urinary retention, increased heart rate, cognitive
impairments
overdose can be fatal due to cardiac toxicity,
concern with suicidal patients
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SSRIs
fluoxetine (Prozac)
 Sertraline (Zoloft)
 paroxetine (Paxil)
 Fluvoxamine (Luvox)
 citalopram (Celexa)
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SNRIs
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atomoxetine (Straterra)
 Commercially available in 2003 for ADHD
treatment
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reboxetine (Edronax, Vestra)
 Not currently available in U.S.
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nefazodone (Serzone)
 5-HT2 receptor antagonist and 5-HT/NE reuptake
blocker; chronic use down regulates NE/5-HT
receptors.
mirtazepine (Remeron)
 Tetracyclic and NaSSA
 5-HT2/5-HT3 receptor antagonist; also antihistamine
duloxetine (Cymbalta)
 5-HT/NE reuptake blocker
 also prescribed for chronic pain conditions, such as
diabetic neuropathy and fibromyalgia
venlafaxine (Effexor)
 5-HT/NE reuptake blocker
 also prescribed for general anxiety disorder
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Subjective Effects
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These drugs do not produce euphoric or pleasant
effects and may produce fatigue, apathy, weakness.
High doses may impair comprehension, cause
confusion and reduce concentration.
Performance
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Acute doses have detrimental effects on vigilance
tasks and can cause memory and psychomotor
impairments related to sedation.
With repeated use, these effects show tolerance.
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Unconditioned Behavior
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Antidepressants tend to increase locomotor
activity in rodents
Conditioned Behavior
Increase response rates in operant assays, both low and
high rates
 Decrease avoidance responding without affecting
escape behavior, similar to anxiolytic and antipsychotic
drugs.
 Do not increase, but tend to decrease punished
responding.
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Drug Discrimination
MAOIs and tricyclics are not discriminated, except at
extremely high doses
 SSRIS and SNRIs are discriminated at therapeutic
doses.
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Self-Administration
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None of the antidepressants are self-administered by
nonhumans.
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Reproduction
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Males, delayed or impaired ejaculation
Males and females, Reduced sex drive and
difficulties achieving orgasm.
Teratogenic effects with some antidepressants
 e.g., increased risk of miscarriage with fluoxetine and
TCAs.
 e.g., Lithium in early pregnancy can cause cardiac
malformations in fetus.
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Violence/Suicide
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Evidence for this largely from case studies.
Large scale studies actually show reduced incidence
of suicide and violence.
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Overdose
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SSRIs at high doses or combined with other
antidepressants or stimulants can cause Serotonin
Syndrome (excess serotonin transmission)
 Disorientation, agitation, fever, chills, diarrhea
 If untreated, can lead to respiratory, circulatory, and
kidney failure.

TCAS third most common cause of drug-related
fatalities
 Therapeutic index of TCAs only ~10-15.
 SSRIs considerably safer in this regard.
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Characteristic Symptoms
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recurrent episodes of mania and depression
widespread cognitive deficits
subtypes of varying severity (I, II, cyclothymia)
Prevalence
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up to 5% of population
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Treatment Issues
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long-term management is key
Ideal treatment is to:
 stabilize acute symptoms
 not induce alternate mood symptoms
 prevent future relapses
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Neuropathology of BD
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Initially conceptualized as a neurochemical imbalance
Recent evidence of neuronal injury
 Regional differences in neuronal density
 Evidence of neuronal pathology in hippocampus
 Cause or Effect?
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Mechanisms of Drug Action

Recent evidence indicates antimanic drugs (e.g.,
lithium, valproic acid) increase levels of cellularprotective proteins and appear to reduce brain
damage.
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History
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1940s, Lithium Chloride was used as salt substitute
 severe toxicity, deaths
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1949, John Cade’s studies in Guinea Pigs
 acceptance by medical community delayed
 Lithium Carbonate
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1970s, clinical research demonstrated clear evidence
for superior efficacy
Today’s “gold standard” in treating Bipolar
Disorder.
Problems with compliance, largely due to side
effects
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Pharmacokinetics
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Absorption
 Rapid by p.o. route
 Peak blood levels within 3 hours, complete
absorption within 8 hours
 Therapeutic efficacy directly correlated to blood
levels
 Crosses BBB slowly and incompletely
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Elimination
 excreted unchanged by kidneys
 18-24 hr. half-life
 When initiating once daily dosing, blood levels
accumulate slowly over 2 weeks until steady levels
reached.
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Determining Therapeutic Dose
 Close blood level monitoring required
 Recommended levels ~ 0.5-0.7 mEq/l
 Salt intake/excretion should be constant to avoid
adverse effects of Lithium
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Pharmacodynamics
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Lithium produces specific actions on mania, with
no psychotropic effects in normal individuals.
Mechanism of action not well understood
 second messenger signaling pathways
 e.g., modulation of intracellular protein kinase enzymes
 elevation of cellular protective protein, bcl-2
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Side Effects and Toxicities
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Multiple Organ Systems
 GI: nausea, vomiting, diarrhea, abdominal pain
 Kidneys: increased urine output, increased thirst and water
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intake
Thyroid: depressed function, becomes enlarged, weight
gain
Skin: rashes
CNS: tremor, lethargy, impaired concentration and
memory, dizziness, slurred speech, ataxia, muscle
weakness, nystagmus
Cardiovascular: cardiac arrhythmia
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Effects in Pregnancy
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Teratogenic potential, particularly heart
Generally not advised during pregnancy, especially
during first trimester.
If necessary tx. in a pregnant woman, discontinue
use several days before delivery.
Problems with Compliance
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Up to 50% of patients stop using AMA.
 recurrent manic episodes and greatly increased suicide
risk
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Noncompliance largely due to intolerance of side
effects, in particular weight gain and cognitive
effects.
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Carbamazepine (Tegretol)
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Studies in early 1990s indicated efficacy equivalent to
lithium, although more recent studies show lithium to
be superior.
Some patients resistant to both drugs respond to
combination of the two.
Adverse effects include GI upset, sedation, ataxia,
impaired vision, skin reactions, modest cognitive effects.
More serious risk: low white blood cell count, requires
blood monitoring
Drug interactions due to stimulation of CYP3A4 liver
enzymes
Teratogenic: neural tube defects in 1%
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Valproic Acid (Depakote)
 Introduced in 1994
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GABA agonist
 specific mechanisms of antimanic actions not yet
determined
 some evidence that gene expression modulated
Particularly effective in tx of acute mania, schizoaffective
disorder, rapid cycling bd
Positive response in 71% of lithium-resistant pts.
Increased efficacy in combination with Lithium
compared to either drug alone.
Side effects:
 GI upset, sedation, lethargy, tremor, hair loss,
cognitive impairments (in females, weight gain,
polycystic ovaries, increased androgens)
Potential toxicities:
 liver, pancreas, also teratogenic
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Gabapentin (Neurontin)
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Introduced in U.S. as anticonvulsant in 1993
Similar clinical efficacy to valproic acid, except
gabapentin superior analgesic, valproate superior
in tx of BD
GABA analogue, increases GABA levels in brain
Excellent pharmacokinetic profile: no binding to
plasma proteins, not metabolized, excreted
unchanged by kidneys, few pk drug interactions,
half-life 5-7 hours
Results of clinical studies suggest this agent is
most effective as adjunctive med. In pts. resistant
to other more effective mood stabilizers.
Side effects: dizziness, dry mouth, somnolence,
nausea, flatulence, reduced libido
Other Neuromodulators
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Pregabalin
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Lamotrigine
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antiepileptic, alcohol relapse prevention; key advantage weight loss
Tiagabine
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Improvement on carbamazepine
Topiramate
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effective tx of acute bipolar depression, poor tx of acute manic episodes
Inhibits glutamate release
Skin rashes possible serious side effect
Oxcarbazine
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under development for tx of GAD
limited efficacy, no controlled studies in tx of BD
Zonisamide
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Mid-2000 became available in U.S., prelim. studies show promise
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Olanzapine (Zyprexa)
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Quetiapine (Seroquel)
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Recent studies have shown equivalent efficacy to
lithium or valproic acid
mid-2000 FDA approved for short-term treatment of
acute mania
Recent studies show efficacy in treatment of Bipolar
Disorder
Others to be investigated
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ziprasidone
aripiprazole