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The Medications of Addiction and Psychiatric Medicine- 2012

The Medications of Addiction and Psychiatric Medicine- 2012 Merrill Norton Pharm.D.,D.Ph.,ICCDP -D Clinical Associate

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy Athens, Georgia mnorton@rx.uga.edu

Merrill%Norton%Pharm.D.,D.Ph.,ICCDP8D%

1%

   Epocrates    Monthly Prescribing Reference    Facts and Comparisons   
   Epocrates
   Monthly Prescribing
Reference
   Facts and Comparisons
   Stahl’s Essential
Psychopharmacology 3 rd
Edition
   Stahl’s The Prescriber’s
Guide 4 th Edition(2011)
   T-MAY Treatment of
Maladaptive Aggression
in Youth* (Just Released)
   Clinical Handbook of
Psychotropic Drugs
   Adults
   Children and
Adolescents
   19 th Edition (Adult)
   2 nd Edition (Children)
   Updated Yearly
   www.scribd.com/doc/
33609797/Prescribing-
Guidelines (Need
Facebook account)
2
Index to FDA's Drug Safety Initiative Communication with the Public Drug-Specific Information For patients,
Index to
FDA's Drug Safety Initiative
Communication with the Public
Drug-Specific Information For patients, consumers, and healthcare professionals.
Provides
links to safety sheets with the latest risk information about the drug, related press
announcements, and other fact sheets.
Consumer Education: What You Need to Know to Use Medicine Safely Information to help
patients and consumers work with health professionals to make the best medicine choices,
buy safely, and use medicine so it's as safe and effective as possible.
www.fda.gov/cder/drugSafety.htm
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   Addiction    ADHD    Major Depression    Bipolar Disorder 
   Addiction
   ADHD
   Major Depression
   Bipolar Disorder
   Psychotic disorders
   Anxiety Disorders/OCD
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Why Do People Abuse Prescription Drugs? These prescription drugs, like other drugs of abuse (cocaine,
Why Do People Abuse Prescription Drugs?
These prescription drugs,
like other drugs of abuse
(cocaine, heroin, marijuana)
raise brain dopamine levels
1100
AMPHETAMINE+
1000
900
800
700
600
500
400
300
200
Dopamine!
100
Neurotransmission !
0
frontal
0
1
2
3
4
5+hr
Time+After+Amphetamine
cortex
FOOD+
200
150
nucleus
accumbens
VTA/SN
100
Empty
50
Box Feeding
0
0
60
120
180
Time+(min)
Di Chiara et al.
BUT dopamine is also elevated
by natural re-enforcers
%+of+Basal+Release
%+of+Basal+Release
CNS Actions of Corticotropin Releasing Factor (CRF) Merrill Norton D.Ph.,NCAC II,CCS 8
CNS Actions of Corticotropin Releasing Factor
(CRF)
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Allostasis - Definition

“The ability to achieve stability through change”

“To obtain stability, an organism must vary all of the parameters of its internal milieu and match them appropriately to environmental demands.”

From:

Sterling P and Eyer J, Allostasis: a new paradigm to explain arousal pathology. In Fisher S and Reason J (eds),

Merrill Norton D.Ph.,NCAC II,CCS

Handbook of Life Stress, Cognition and Health, John Wiley, New York, 1988, pp. 629-647.

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Allostatic Change in Mood State associated with Transition to Drug Dependence Merrill Norton D.Ph.,NCAC II,CCS
Allostatic Change in Mood State associated
with Transition to Drug Dependence
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Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.
Stimulants (Ritalin, Adderall) Act like Cocaine Directly in the Dopamine Cells Distribution in the Human
Stimulants (Ritalin, Adderall) Act like Cocaine
Directly in the Dopamine Cells
Distribution in the Human Brain of Cocaine and Ritalin
Cocaine
Ritalin
Cocaine and Ritalin Act on the Same Sites in
Brain

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Pharmacokinetics in Human Brain [ 11 C]Cocaine! [ 11 C]Methylphenidate !
Pharmacokinetics in Human
Brain
[ 11 C]Cocaine!
[ 11 C]Methylphenidate
!
Relationship Between Drug Pharmacokinetics and the “High” [ 11 C]Cocaine [ 11 C]Methylphenidate 100 100
Relationship Between Drug
Pharmacokinetics and the “High”
[
11 C]Cocaine
[
11 C]Methylphenidate
100
100
80
80
60
60
40
40
20
20
"
High " !
"
High " !
0
0
0
10
20
30
40
50
60
70
80
0
10
20
30
40
50
60
70
80
Time (min)
% Peak
Rate of Drug Uptake Into the Brain iv cocaine iv Ritalin oral Ritalin 0.06 0.06
Rate of Drug Uptake Into the Brain
iv cocaine
iv Ritalin
oral Ritalin
0.06
0.06 0.0035
0.05
0.003
0.05
0.0025
0.04
0.04
0.002
0.03
0.03
Fast!!
! !
Fast!!
0.0015
Slow!!!
0.02
0.02
0.001
0.01
0.01
0.0005
0
0
0
0
20
40
60
80 100 120
0
20
40
60
80 100 120
0
20
40
60
80 100 120
Time (minutes)
Time (minutes)
Time (minutes)
Cocaine (iv) and Ritalin (iv) produce a “high” but
Ritalin (oral) does not.
The slow brain uptake of oral Ritalin permits effective
treatment without a “high.”
Uptake in Striatum (%/cc)
Uptake in Striatum (%/cc)
Uptake in Striatum (nCi/cc)

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11/27/12% Development of Alternative Medications with no Drug Abuse Potential Activation of CB2 Cannabinoid Receptors
Development of Alternative Medications with no Drug Abuse Potential Activation of CB2 Cannabinoid Receptors by
Development of Alternative Medications
with no Drug Abuse Potential
Activation of CB2 Cannabinoid
Receptors by AM1241Inhibits
Experimental Neuropathic Pain
Suboxone® Buprenorphine
monotherapy product
Subutex® Buprenorphine +
naloxone combination
product
(addition of opioid
antagonist)
Source: Ibrahim et al., PNAS, September 2, 2003.
Medications to Treat Those Addicted Effects of Buprenorphine Maintenance Dose on ! μ! -Opioid Receptor
Medications to Treat Those Addicted
Effects of Buprenorphine Maintenance Dose on !
μ! -Opioid Receptor Availability !
85 to 92%! 94 to 98%!
100!
90!
80!
70!
60!
27 to 47%!
50!
40!
30!
20!
10!
0!
2 mg!
16 mg!
32 mg!
Dose!
Source: Greenwald, MK et al, Neuropsychopharmacology 28, 2000-2009, 2003.!
% Receptor Occupancy !

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Brain Scan of ADHD- 1990

Brain Scan of ADHD- 1990

Brain Scan of ADHD- 1990
Dopamine in the Brain Scientific American Http//www.sciam.com/1998/0998issue/0998barkely.html#link1

Dopamine in the Brain

Scientific American
Scientific American

Http//www.sciam.com/1998/0998issue/0998barkely.html#link1

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The Neurobiology of ADHD Prefrontal Cortex LEFT BRAIN Dopamine Locus Coeruleus Substantia Nigra Norepinephrine
The Neurobiology of ADHD
Prefrontal
Cortex
LEFT BRAIN
Dopamine
Locus Coeruleus
Substantia Nigra
Norepinephrine
RIGHT
BRAIN
Corpus Callosum
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II,CCS
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   Stimulants remain the mainstay    Atomoxetine (SSRI) second line    Others-
   Stimulants remain the mainstay
   Atomoxetine (SSRI) second line
   Others-
Clonidine
Guanfacine
Bupropion
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ADHD Diagnosis Dextroamphetamine Methylphenidate or or Mixed Dexmethylphenidate amphetamine salts Dextroamphetamine
ADHD Diagnosis
Dextroamphetamine
Methylphenidate or
or Mixed
Dexmethylphenidate
amphetamine salts
Dextroamphetamine
Methylphenidate or
or Mixed
Dexmethylphenidate
amphetamine salts
Atomoxetine
Or
Bupropion
Tricyclic
Antidepressants
α 2 agonist

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   Atomoxetine (Strattera)- SNRI- second line- 2 cases of hepatic damage    Clonidine-
   Atomoxetine (Strattera)- SNRI- second
line- 2 cases of hepatic damage
   Clonidine- less robust, concern for
rebound HTN
   Bupropion (Wellbutrin)- Possible Utility in
adults, substance abuse, etc.
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   Amphetamines    Clonidine    Impriamine    Methylphenidate    Atomoxetine
   Amphetamines
   Clonidine
   Impriamine
   Methylphenidate
   Atomoxetine
   Guanfacine
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Dexmethylphenidate (Focalin XR) 5, 10, 15, 20mgs, isomer so theoretically half the methylphenidate dose Daytrana
Dexmethylphenidate (Focalin XR) 5, 10, 15,
20mgs, isomer so theoretically half the
methylphenidate dose
Daytrana Patch (Daytrana), 14 hr duration,
10, 15, 20, 30mgs
Lisdexamfetamine Dimesylate (Vyvanse)
lasts 12 hours, prodrug –need stomach to
activate, 20, 30, 40, 50, 60, 70mgs
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   Reduction of appetite    Insomnia    Anxiety    Irritability Merrill
   Reduction of appetite
   Insomnia
   Anxiety
   Irritability
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   HTN    Stroke    Sudden death    Heart attack 
   HTN
   Stroke
   Sudden death
   Heart attack
   Palpitations
   Arrhythmia
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Presynaptic 1.   Selectively blocks the NE reuptake transporter located on the presynaptic neuron Presynaptic
Presynaptic
1.   Selectively blocks the NE
reuptake transporter located
on the presynaptic neuron
Presynaptic
Neuron
Neuron
Dopamine
Dopamine
2.   Increases the concentration
of NE in the synaptic cleft
Norepinephrine (NE)
Norepinephrine (NE)
3.   Enhances the forward
transmission of NE
NE
Receptor
NE
Receptor
NE
Transporter
NE
Synaptic
Synaptic
Transporter
Cleft
Cleft
Postsynaptic
Postsynaptic
Neuron
Neuron
The precise mechanism by which atomoxetine produces its therapeutic effects in ADHD is unknown
*Based on preclinical data; Bymaster F, et al. Neuropsychopharmacology. 2002;27:699-711.
See Important Safety Information on slides 25–31, including Boxed Warning, and full
Prescribing Information for atomoxetine available during this presentation.
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presentation. Merrill Norton Pharm.D., D.Ph.,ICCDP-D 34    Modafinil (Sparlon, Provigil)    Armodafinil
presentation. Merrill Norton Pharm.D., D.Ph.,ICCDP-D 34    Modafinil (Sparlon, Provigil)    Armodafinil
   Modafinil (Sparlon, Provigil)    Armodafinil (Nuvigil)    Guanfacine( Intuniv) Merrill Norton
   Modafinil (Sparlon, Provigil)
   Armodafinil (Nuvigil)
   Guanfacine( Intuniv)
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Fournier JC, DeRubeis RJ, Hollon SD, et al.Antidepressant drug effects and depression severity: a patient-level
Fournier JC, DeRubeis RJ, Hollon SD, et al.Antidepressant
drug effects and depression severity: a patient-level meta-
analysis. JAMA. 2010;303:47-53.
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Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore
TJ, Johnson BT. Initial severity and antidepressant benefits:
a meta-analysis of data submitted to the Food and Drug
Administration. PLoS Med. 2008;5:e45.
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Rush AJ,Trivedi MH,Wisniewski SR, et al.Acute and longer-term outcomes in depressed outpatients requiring one or
Rush AJ,Trivedi MH,Wisniewski SR, et al.Acute and longer-term
outcomes in depressed outpatients requiring one or several
treatment steps: a STAR*D report. Am J Psychiatry.
2006;163:1905-1917.
National Institute of Mental Health. Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) Study.
www.nimh.nih.gov/trials/practical/stard/index.shtml.Accessed
December 28, 2010.
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Limbic System Prefrontal Cortex Raphe Nuclei Locus Ceruleus (NE Source) (5-HT source) Cooper JR, Bloom
Limbic System
Prefrontal
Cortex
Raphe Nuclei
Locus Ceruleus (NE
Source)
(5-HT source)
Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996.
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Functional domains of Serotonin and Norepinephrine 1-4 Serotonin (5-HT) Norepinephrine (NE) Depressed Mood Anxiety
Functional domains of Serotonin and Norepinephrine 1-4
Serotonin (5-HT)
Norepinephrine (NE)
Depressed Mood
Anxiety
Sex
Concentration
Appetite
Vague Aches and
pain
Irritability
Interest
Aggression
Motivation
Thought process
 Both serotonin and norepinephrine mediate a broad spectrum
of depressive symptoms
References:
1.  
Adapted from: Stahl SM. In: Essential Psychopharmacology: Neuroscientific Basis and
Practical Applications: 2 nd ed. Cambridge University Press 2000.
2.  
Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.
3.  
Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35.
4.  
Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.
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It’s not all in your head    Dysregulation of Serotonin (5HT) and Norepinephrine (NE)
It’s not all in your head
   Dysregulation of Serotonin (5HT)
and
Norepinephrine (NE) in the
brain are strongly associated with
depression
   Dysregulation of 5HT and NE in the
spinal cord may explain an
increased pain perception among
depressed patients 1-3
Descending Pathway
Descending
Pathway
Ascending
Pathway
   Imbalances of 5HT and NE may
explain the presence of both
emotional and physical symptoms
of depression.
Ascending
Pathway
Adapted from References:
1.  
Stahl SM. J. Clin Psych. 2002;63:203-220.
2.  
Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.
3.  
Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.

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When to begin medications Selection of Psychotherapy med’s Management Length of of Dose titration treatment
When to
begin
medications
Selection of
Psychotherapy
med’s
Management
Length of
of
Dose titration
treatment
Depression
D/C of
Side Effects
medications
Non-response
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 First line therapy   Generic Trade Initial Dose (mg/ day) Dosage Range (mg/day) Citalopram
 First line therapy
Generic
Trade
Initial Dose (mg/
day)
Dosage Range
(mg/day)
Citalopram
Celexa®
20
20-60
Escitalopram
Lexapro®
10
10-20
Fluoxetine
Prozac®
20
20-60
Fluvoxamine
Luvox®
50
50-300
Paroxetine
Paxil®
20
20-60
Sertraline
Zoloft®
50
50-200
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•  Newer Agents •  Less sexual dysfunctions in some cases •  No more affective than
•  Newer Agents
•  Less sexual dysfunctions in some cases
•  No more affective than TCAs or SSRIs
•  Alternative option for resistant depression
•  Indicated for major depression and generalized anxiety
disorder
Generic
Trade
Initial Dose (mg/
day)
Dosage Range
(mg/day)
Venlafaxine
Effexor
37.5-75
75-225
Duloxetine
Cymbalta
30
30-90
Desvenlafaxine
Pristiq
50
50
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Merrill Norton Pharm.D., D.Ph., ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy Athens,
Merrill Norton Pharm.D., D.Ph., ICCDP-D
Clinical Associate Professor
University of Georgia College of Pharmacy
Athens, Georgia
mnorton@rx.uga.edu
49
   Cymbalta (duloxetine)    Pristiq (desvenlafaxine)    Viibryd (vilazodone)    Abilify
   Cymbalta (duloxetine)
   Pristiq (desvenlafaxine)
   Viibryd (vilazodone)
   Abilify (aripiprazole)
   Symbyax (olanzapine/fluoxetine)
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Manufactured by Lilly Comes as a delayed-release capsule 20mg, 30mg & 60mg strengths Approved for
Manufactured by Lilly
Comes as a delayed-release capsule
20mg, 30mg & 60mg strengths
Approved for major depressive disorder, generalized
anxiety disorder, diabetic peripheral neuropathy,
fibromyalgia, & chronic musculoskeletal pain
Used off-label for urinary incontinence
*Generic Time Released Formulation approved
December 2011
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Manufactured by Wyeth Comes as an extended-release tablet 50mg & 100mg strengths Approved for major
Manufactured by Wyeth
Comes as an extended-release tablet
50mg & 100mg strengths
Approved for major depressive disorder
Used off-label for menopausal flushing
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Manufactured by Forest Labs Comes as an oral tablet 10mg, 20mg & 40mg strengths Approved
Manufactured by Forest Labs
Comes as an oral tablet
10mg, 20mg & 40mg strengths
Approved for major depressive disorder
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Viibryd™/)vilazodone)hydrochloride )

Pharmacology %

Vilazodone%is%a%novel%agent%that%combines%the% anHdepressant%acHvity%of%serotonin%reuptake% receptor%inhibiHon%with%parHal%agonist%acHvity% for%5HT 1A ,%a%common%iniHal%treatment%for% anxiety.%

However,%%the%net%effect%of%vilazodone%on% 5HT 1A% receptors%is%unknown.%

54%

Viibryd™%package%insert%

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Dosing Major depressive disorder: 10mg PO daily x 7d, then 20mg daily x 7d, then
Dosing
Major depressive disorder:
10mg PO daily x 7d, then
20mg daily x 7d, then
40mg daily
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Drug interactions Contraindicated for risk of serotonin syndrome: linezolid, methylene blue, tranylcypromine,
Drug interactions
Contraindicated for risk of serotonin syndrome:
linezolid, methylene blue, tranylcypromine,
isocarboxazid, selegiline, procarbazine,
rasagaline
Potential major interaction with warfarin,
NSAIDs, and aspirin
Potential major interaction with other SSRIs
Other major interactions exist
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Generic Trade Initial Dose (mg/ day) Dosage Range (mg/day) Amitriptyline Elavil® 25 100-300 Clomipramine
Generic
Trade
Initial Dose (mg/
day)
Dosage Range
(mg/day)
Amitriptyline
Elavil®
25
100-300
Clomipramine
Anafranil®
25
100-250
Doxepine
Sinequan®
25
100-300
Imipramine
Tofranil®
25
100-300
Desipramine
Norpramin®
25
100-300
Nortriptyline
Pamelor®
25
50-200
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   MOA: inhibition of MAO, the enzyme responsible for metabolizing norepinephrine, serotonin, dopamine 
   MOA: inhibition of MAO, the enzyme responsible for
metabolizing norepinephrine, serotonin, dopamine
   Used in patients who do not respond to other
antidepressants and/or to treat atypical depression
   Rarely used
◦   Dietary restrictions
◦   Side effect profile
◦   Dangerous drug interactions
   Commonly used agents:
◦   Phenelzine (Nardil®)
◦   Tranylcypromine (Parnate®)
◦   Selegiline (Emsam®)
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   High amounts of Tyramine ◦   Smoked, aged, or pickled meat or fish
   High amounts of Tyramine
◦   Smoked, aged, or pickled meat or fish
◦   Sauerkraut
◦   Aged chesses such as swiss and cheddar
◦   Fava beans
   Moderate amounts of Tyramine
◦   Beer, avocados, meat extracts, red wines
   Low amounts of Tyramine
◦   Caffeine-containing beverages, distilled spirits,
chocolate, soy sauce, cottage & cream cheese, yogurt &
sour cream
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1-2 weeks 2-4 weeks 6-8 weeks •  Sleep •  Sadness •  Full effects •  Appetite
1-2 weeks
2-4 weeks
6-8 weeks
• 
Sleep
•  Sadness
•  Full effects
• 
Appetite
•  Anhedonia
• 
Energy
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Depression%Guideline%Panel.%Depression%in%Primary%Care,%Vol.%2:%Treatment%of%Major%Depression.%Rockville,%Md:%US%Dept%of%Health%and%Human%
Services,%Public%Health%Service,%and%Agency%for%Health%Care%Policy%and%Research;%1993.%Clinical%PracHce%Guideline%No.%5.%
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 Uses: depression, extreme treatment resistant mania, psychosis, & seizures    Electrode Placement:
 Uses: depression, extreme treatment resistant mania, psychosis, & seizures
 Electrode Placement: Bilateral: increases confusion/memory loss.
Unilateral: decrease confusion/memory loss
 Treatment: ≥ 25 seconds in length minimum required for effect
 Number of treatments: 6-8 (12) in depression, more for mania (12-20)
and psychosis (20-40)
 Side Effects: post-ictal confusion/ memory loss, headache, slight muscle
soreness, nausea
 Medications
◦   Anticholinergic: atropine or glycopyrrolate MI/IV before tx prevents aspiration
and tachycardia
◦   Anesthesia: Methohexital IV. Pt is asleep when paralyzed
◦   Muscle relaxant: succinylcholine IV once anesthesia is complete prevents major
muscle contractions and resultant bone fractures
◦   Oxygen: prevents hypoxia
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   Uses: mild anxiety, the blues, mild to moderate depression ONLY    MOA:
Uses: mild anxiety, the blues, mild to
moderate depression ONLY
MOA: Serotonin reuptake inhibition, very
minor MAOI occurs
Side Effects: Mild and dose related: sedation,
GI distress, photosensitivity, HA, and fatigue
Dosing
◦   Depression: bottle says 900mg/day (300mg TID)
◦   Drug Interactions: CYP450-3A4
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   Data from initial clinical trials-    Twice as likely as placebo to
   Data from initial clinical trials-
   Twice as likely as placebo to have
“suicidal thoughts or behaviors”
   Possible explanations-
Improvement
Misdiagnosed?
Irritability
Withdrawal syndrome
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
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   A US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) has
  
A US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory
Committee (PDAC) has recommended approval of inhaled loxapine (Adasuve,
Alexza Pharmaceuticals), as the first inhaled antipsychotic for agitation associated with
schizophrenia and bipolar disorder (BD).
FDA Psychopharmacological Drugs Advisory Committee Dec. 12, 2011
  
Women who experience a psychiatric episode in the immediate postpartum period
appear to have an increased risk of developing bipolar affective disorder, according
to the results of a new study.
Trine Munk-Olsen, PhD;Thomas Munk Laursen,
PhD; Samantha Meltzer-Brody, MD, MPH; Preben Bo Mortensen, DrMedSc; Ian Jones, PhD Arch
Gen Psychiatry. Published online December 5, 2011. doi:10.1001/archgenpsychiatry.2011.157
  
Individuals with serious mental illness have a lifespan that is 15 to 20 years shorter
than that of the general population in 3 countries with high-quality healthcare, new
research shows.
Br J Psychiatry. 2011;199:453-458, 441-442.
  
Methodological issues like the inclusion of differing patient populations, differences
in who (patients, family members, caregivers) received psychotherapy, and varying
follow-up periods make it difficult to compare RCTs. Despite heterogeneous results,
the majority of the studies showed relevant positive results in terms of reduced
relapse rates, increased quality of life, better functioning or more favorable
symptomatic outcome. Curr Opin Psychiatry. 2011;24(6):549-555.
  
HHS Guidance Could Help States Improve Oversight of Psychotropic Prescriptions
in Foster Children GAO-12-270T, Dec 1, 2011
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   Virani,A. S., Bezchlibnyk-Butler, K. Z., & Jeffries, J. J. (Eds.) (2011). Clinical Handbook
  
Virani,A. S., Bezchlibnyk-Butler, K. Z., & Jeffries, J. J. (Eds.) (2011). Clinical
Handbook of Psychotropic Drugs (19th ed.). Seattle: Hogrefe & Huber.
ISBN: 978-0889373952.
  
Bezchlibnyk-Butler, K. Z., & Virani,A. S. (Eds.) (2007). Clinical Handbook of
Psychotropic Drugs for Children and Adolescents (2nd rev. ed.). Seattle:
Hogrefe and Huber. ISBN: 978-0-88937-309-9.
  
Schatzberg,A. F., & Nemeroff, C. B. (Eds.). (2009). The American Psychiatric
Publishing Textbook of Psychopharmacology (4th ed.).Washington DC:
American Psychiatric. ISBN: 978-1585623099.
   Hales, R. E., Shahrokh, N. C., Schatzberg,A. F., & Nemeroff, C. B. (2009).
Study Guide to Clinical Psychopharmacology:A Companion to The American
Psychiatric Textbook of Psychopharmacology, 4 th Edition. Washington DC:
American Psychiatric. ISBN: 978-1585623549
  
Stahl, S. M. (2008). Stahl’s Essential Psychopharmacology: Neuroscientific
Basis and Practical Applications (3rd ed). New York: Cambridge University
Press. ISBN: 978-0521673761.
  
Stahl, S.M.(2011) The Prescriber’s Guide (4 th ed). New York : Cambridge
University Press.
  
ISBN: 978-0521173643. (Optional Text)
67

Bipolar Disorder Bipolar I Bipolar II Characterized by the occurrence of manic episodes with or
Bipolar Disorder
Bipolar I
Bipolar II
Characterized by the occurrence
of manic episodes with or
without major depression
episode
Characterized by at least one
depressive episode with or
without a hypomanic episode
68
Affects 1% of the population First degree relative have increased rates of BPD-I, BPD-II, and
Affects 1% of the population
First degree relative have increased rates of
BPD-I, BPD-II, and MDD (4-24%)
Peak age of onset: adolescence through early 20s
Onset of first manic episode after age of 60 years is “red
flag” to consider substance use or general medical
condition
Season Variation
Depression more common in spring and autumn
Mania more common in summer
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Bipolar I Bipolar II Lifetime prevalence : 1% Lifetime prevalence: 0.5% Women and men are
Bipolar I
Bipolar II
Lifetime
prevalence : 1%
Lifetime prevalence:
0.5%
Women and men
are equally affected
Slightly more
common in women
Onset usually
before age 30
Onset usually
before age of 30
No ethnic
No ethnic
differences seen
differences seen
70
Genetic    1 st Degree Relative with Bipolar Disorder: 8 to 18 times more
Genetic
   1 st Degree Relative with Bipolar Disorder:
8 to 18 times more likely to develop the
illness
   Monozygotic twins: 75%
   Dizygotic twins: 5-25%
71
   Undiagnosed Bipolar Disorder -- Common and Concerning Angst J,Azorin JM, Bowden CL, et
  
Undiagnosed Bipolar Disorder -- Common and Concerning
Angst J,Azorin JM, Bowden CL, et al Arch Gen Psychiatry. 2011;68:791-798
  
Effects of Asenapine on Depressive Symptoms in Patients With Bipolar I
Disorder Experiencing Acute Manic or Mixed Episodes
Armin Szegedi; Jun Zhao;Arjen van Willigenburg; Kari R Nations; Mary Mackle; John
PanagidesEffects of Asenapine on Depressive Symptoms in Patients With Bipolar I Disorder
Experiencing Acute Manic or Mixed Episodes
  
Antipsychotic Polytherapy in Bipolar Disorder- Is it more or less
effective? Brooks JO; Goldberg JF; Ketter TA; Miklowitz DJ; Calabrese JR; Bowden CL;
Thase ME Safety and tolerability associated with second-generation antipsychotic polytherapy in
bipolar disorder: findings from the Systematic Treatment Enhancement Program for Bipolar
Disorder.J Clin Psychiatry. 2011; 72(2):240-7
  
Are Cholesterol Levels Linked to Bipolar Disorder?
  
One-year Risk of Psychiatric Hospitalization and Associated Treatment
Costs in Bipolar Disorder Treated with Atypical Antipsychotics
  
How Often Is Bipolar Disorder Disguised as Depression?
Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the
world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241-251.
  
Update on Antimanic Treatments:An Efficacy Comparison-
Yildiz A,Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of
randomized, controlled trials. Neuropsychopharmacology. 2011;36:375-389. 72

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MANIA ! MIXED EPISODE! HYPOMANIA ! NORMAL MOOD ! DEPRESSION ! Stahl S M, Essential
MANIA !
MIXED EPISODE!
HYPOMANIA !
NORMAL
MOOD !
DEPRESSION !
Stahl S M, Essential
Psychopharmacology (2000)!
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
73
Start Treatment Natural Course Treated Course Maintenance/ Acute Continuation Discontinuation Merrill Norton
Start Treatment
Natural Course
Treated Course
Maintenance/
Acute
Continuation
Discontinuation
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
74
EuthymicDepressed
First-line treatment of bipolar disorder   Lithium   Anticonvulsants (carbamazepine, valproic acid,
First-line treatment of bipolar disorder
  Lithium
  Anticonvulsants (carbamazepine,
valproic acid, divalproex)
  Olanzapine and other atypical
antipsychotics
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   Mood Stabilizers    Antidepressants    Antipsychotics    Anxiolytics   
   Mood Stabilizers
   Antidepressants
   Antipsychotics
   Anxiolytics
   Polypharmacy is the rule rather than
the exception!
76
   FDA approved age 13 and up    Mechanism- evidence of multiple neurotransmitter
   FDA approved age 13 and up
   Mechanism- evidence of multiple
neurotransmitter effects (dopamine,
serotonin, acetylcholine, NE, and GABA)
Common SE’s- thirst, GI, taste
   More troubling- tremor, acne
   Significant- renal, thyroid, ? Teratogenic
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
77
Gray Bcl-2 Matter GSK-3 β Manji HK, Moore GJ, Chen G, Biological Psychiatry 48: 740-755,
Gray
Bcl-2
Matter
GSK-3 β
Manji HK, Moore GJ, Chen G, Biological Psychiatry 48: 740-755, 2000
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   Valproate    Off label use- few rigorous studies    Mechanism likely
   Valproate
   Off label use- few rigorous studies
   Mechanism likely involves GABA, Protein
kinase C, possibly kindling
   Monitor levels
   Common SE’s- sedation, wt gain, GI
   Rare/Serious SE’s-Teratogenic (neural
tube), ?PCO, Hepatic damage, pancreatitis
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
79
   Carbamezepine- off label- literature limited    Autoinduction, leukopenia, rash, aplastic anemia,
   Carbamezepine- off label- literature
limited
   Autoinduction, leukopenia, rash, aplastic
anemia, thrombocytopenia- use more
infrequent
   Third Generation- Lamotrigine,
Topirimate- literature limited, some
promising info. Significant SE’s include
rash with Lamotrigine, weight loss with
Topirimate
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
80
   Typical AP’s (haloperidol, fluphenazine) less used-Atypicals more common-    Includes risperidone,
   Typical AP’s (haloperidol, fluphenazine)
less used-Atypicals more common-
   Includes risperidone, quetiapine,
olanzapine, ziprasidone-
   Mechanism- D2 blockade + 5HT2 effects
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   Na + channel blocker and reduces glutamate release    May be useful
Na + channel blocker and reduces
glutamate release
May be useful for refractory bipolar
disorders including rapid cycling
Slow titration due to the possibility of
rash, which can lead to the Stevens-
Johnson syndrome, which can be
fatal.
See page 415 in the Anticonvulsant Therapy lecture.
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
82
   Positives No blood tests Theoretically should be efficacious weight friendly    Negatives:
   Positives
No blood tests
Theoretically
should be
efficacious
weight friendly
   Negatives:
Higher rates of
SIADH reported
Twice a day dosing
Little data
Negative study
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
83
   Positives:    Negatives: Very weight friendly No blood tests Decreased cognitive dysfunction
   Positives:
   Negatives:
Very weight
friendly
No blood tests
Decreased
cognitive
dysfunction
Little data
Negative study
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Merrill Norton Pharm.D., D.Ph.,ICCDP-D 85
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
85
Merrill Norton Pharm.D., D.Ph., ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy Athens,
Merrill Norton Pharm.D., D.Ph., ICCDP-D
Clinical Associate Professor
University of Georgia College of Pharmacy
Athens, Georgia
mnorton@rx.uga.edu
86
   Asenapine (Saphris) Approved 2009    Iloperadine (Fanapt) Approved 2009    Lurasidone
   Asenapine (Saphris) Approved 2009
   Iloperadine (Fanapt) Approved 2009
   Lurasidone (Latuda) Approved 2010
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   Invega (paliperidone)    Invega Sustenna (paliperidone palmitate)    Saphris (asenapine maleate)
   Invega (paliperidone)
   Invega Sustenna (paliperidone palmitate)
   Saphris (asenapine maleate)
   Fanapt (iloperidone)
   Latuda (lurasidone)
   Symbyax (olanzapine/fluoxetine)
88
Manufactured by Janssen Comes as extended-release tablet 1.5mg, 3mg, 6mg & 9mg strengths Approved for
Manufactured by Janssen
Comes as extended-release tablet
1.5mg, 3mg, 6mg & 9mg strengths
Approved for schizoaffective disorder and
schizophrenia
89
Manufactured by Janssen Comes as extended-release intramuscular injection 39mg, 78mg, 117mg, 156mg & 234mg single-
Manufactured by Janssen
Comes as extended-release intramuscular
injection
39mg, 78mg, 117mg, 156mg & 234mg single-
syringe strengths
Approved for schizophrenia
90

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Manufactured by Merck Comes as sublingual tablet 5mg & 10mg strengths Approved for acute mixed
Manufactured by Merck
Comes as sublingual tablet
5mg & 10mg strengths
Approved for acute mixed or manic
episodes in bipolar I disorder & acute
treatment of schizophrenia
91
Manufactured by Novartis Comes as oral tablet 1mg, 2mg, 4mg, 6mg, 8mg, 10mg & 12mg
Manufactured by Novartis
Comes as oral tablet
1mg, 2mg, 4mg, 6mg, 8mg, 10mg & 12mg
strengths
Approved for schizophrenia
92
   Target Dose 12-24 mg per day in BID dosing (Tritrate slowly to avoid
   Target Dose 12-24 mg per day in BID
dosing (Tritrate slowly to avoid
orthostatic hypotension)
   ADE: Dizziness, Fatigue, Nasal
Congestion,Tachycardia
   Not First Line Agent Due to QTc-
Prolongation
93

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Manufactured by Sunovion Comes as oral tablet 40mg & 80mg strengths Approved for schizophrenia 94
Manufactured by Sunovion
Comes as oral tablet
40mg & 80mg strengths
Approved for schizophrenia
94
   Pregnancy Category B    Metabolized via P450 3A4 to two active and
   Pregnancy Category B
   Metabolized via P450 3A4 to two active
and two inactive metabolites
   Dosage: 40-80mg once daily with
Food( at least 350 calories)
Food increases absorption
   Dose should NOT exceed 40mg with
severe hepatic/renal impairment
95
   Atypicals are not necessarily interchangeable-each has a unique profile, and may differ considerably
   Atypicals are not necessarily
interchangeable-each has a unique profile,
and may differ considerably re side effects
   Research data exists for risperidone in
preschoolers
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Generic Trade Initial Dosage (mg/ day) Max Dose (mg/ day) Aripiprazole Abilify 20-30mg 30mg Olanzapine
Generic
Trade
Initial Dosage (mg/
day)
Max Dose (mg/
day)
Aripiprazole
Abilify
20-30mg
30mg
Olanzapine
Zyprexa
10-15mg
20mg
Quetiapine
Seroquel
50mg BID
800mg
Risperidone
Risperdal
2-3mg
6mg
Ziprasidone
Geodon
40mg BID
80mgBID
  Approved for treatment of bipolar mania or mixed mood episodes as
monotherapy or in combination with mood stabilizing drugs
  Useful in psychotic/aggressive pts
   Aripiprazole & Olanzepine approved for maintenance
97
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Merrill Norton Pharm.D., D.Ph.,ICCDP-D
98
   GABA is synthesized from glutamate    GABA neurons act to dampen neuronal

GABA is synthesized from glutamate GABA neurons act to dampen neuronal activity GABA receptors:

GABA A : Ionotropic control of a Cl - channel (IPSPs) GABA B : Metabotropic control of a K + channel (IPSPs) GABA C : Metabotropic control of a Cl - channel (IPSPs)

GABA C : Metabotropic control of a Cl - channel ( I P S P s

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   GABA A binding sites ◦   Benzodiazepine site (increases channel frequency): anxiolytic ◦

GABA A binding sites

Benzodiazepine site (increases channel frequency): anxiolytic Barbiturate site (increases channel duration) Steroid site (increases channel frequency) Picrotoxin site (inactivates the GABA A receptor)

GABA A receptors are comprised of subunits

α(6),β(4),γ (2)

Anxiolytic action of BZs requires α2 subunit Subunit configuration may change during chronic treatment (tolerance)

   Subunit configuration may change during chronic treatment (tolerance) Merrill Norton Pharm.D., D.Ph.,ICCDP-D 100

Merrill Norton Pharm.D., D.Ph.,ICCDP-D

100

   Short Acting-Midazolam(Versed),Triazolam(Halcion)    Immediate Acting-Alprazolam(Xanax),Estazolam
   Short Acting-Midazolam(Versed),Triazolam(Halcion)
   Immediate Acting-Alprazolam(Xanax),Estazolam
(Prosom),Halazepam(Paxipam),Lorazepam
(Ativan),Oxazepam(Serax),
Temazepam(Restoril)
   Long Acting-Chlordiazepoxide (Librium,Libritabs),
Clonazepam (Klonopin), Clorazepate (Tranxene),
Diazepam (Valium),Flurazepam (Dalmane),
Quazepam (Doral)
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101
   Earlier Identification and Aggressive Txmnt    Increase focus on primary and especially
   Earlier Identification and Aggressive Txmnt
   Increase focus on primary and especially
secondary Prevention
   Neurotransmitter and enzyme specific
treatment.
   More delineation of “Normal” behavior and it’s
relationship to our genes.
   More Exploration of Combined Therapy
   Remission not just response
Merrill Norton Pharm.D., D.Ph.,ICCDP-D
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