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Transcript
Objectives
To discuss some underlying
neurobiological correlates of
psychiatric conditions
including the connection with
the biogenic amines and
faster neurotransmitter
systems
To review the some basic
psychopharmacologic
principles
To review drug interactions and
serious adverse drug
reactions
Geriatrics, Royal Ottawa Mental Health Centre
T. Lau, MD, FRCPC, MSc., Assistant
Professor, UNIVERSITY OF OTTAWA
“We have to ask ourselves whether medicine is to
remain a humanitarian and respected profession or
a new but depersonalized science in the service of
prolonging life rather than diminishing human
suffering”
Elisabeth Kubler-Ross
(Swiss-American psychiatrist and author )
1.
2.
3.
4.
5.
To help prepare for the LMCC
exam Part 1.
To review the biogenic amine
neurotransmitter systems
To review the pharmacologic
management of depression,
bipolar disorder and schizophrenia
To discuss each of the medication
classes and representative
examples.
To review drug interactions and
serious adverse drug reactions
1. Names and classes of medications
2. Pathways and actions of biogenic amine neurotransmitters
3. Mechanism of action of the common medications (eg SSRI’s,
TCA’s, Antipsychotics etc.)
4. Generally be aware of the different pharmacological options
for the three most common psychiatric conditions
5. Principles on how to start medications and follow their
management over time.
6. Be aware of some significant adverse side effects




SECTION 1. Intro
 History of Psychopharmacology
 Neurons & Neurotransmitters
SECTION 2. Specific Disorders and Algorithms
 Depression and Anxiety
 Bipolar Disorder
 Schizophrenia
SECTION 3. Specific Medications
 Antidepressants
 Mood stabilizers
 Antipsychotics
SECTION 4. Drug Interactions
1. History of Psychopharmacology
2. Some Principles of Pharmacology
3. Neurons & Neurotransmitters
Psychopharmacology
Noradrenergic and
Atypical
specific serotonergic
Antipsychotic
antidepressant
Mono-amine oxidase
inhibitor
AAP
MAOI
NaSSA
AP
1950
1960
1970
1980
TCA
SSRI
Non-selective
tricyclic AD
Selective serotonin
re-uptake inhibitor
1990
200I
SNRI
Serotonin
noradrenaline
re-uptake
inhibitors
•Antidepressants
•TCAs (tertiary, secondary)
•MAOIs/RIMAs
•SSRIs
•SNRIs
•SARI
•DRI

 “major tranquilizers”
 Typical (1st generation)
 Atypical (2nd generation)

Sedative/hypnotics
 “minor tranquilizers”
 Benzos
 barbiturates
•Mood stabilizers
•Lithium
•Anticonvulsants
•Atypical APs
Antipsychotics

Cognitive Enhancers
 AchEI
 NMDA receptor
antagonists
Pinson and Gray Psychiatric Services 2003

Pharmacology
 is the study of how drugs interact with
living organisms to produce a change in
function.
 Pharmacokinetics describes the effect of
the body on the drug (e.g. half-life and
volume of distribution).
 Pharmacodynamics describes the drug's
effect on the body (desired or toxic).

Psychopharmacology
 is the study of how substances that
crosses the blood-brain barrier affect
behavior, mood or cognition.
Downstream signal
transduction
1. Different receptors for
same ligand
2. Different effects at
dendritic soma and axon
3. Different effects pre and
post synaptically
4. Receptor desensitization
and localization- changes
over TIME.
5. Different pathways and
function

If, in a disease state, there is too little, the
treatment goal is to raise it.
 Eg. Depression with serotonergic/noradrenergic
underactivity, antidepressants increase

If, in the disease state, there is too much, the
treatment goal is to block it
 Eg. Psychosis with overactivity of the mesolimbic
pathways, antipsychotics decrease, (dopamine
antagonists)

Monoamines
 Catecholamines:
 Dopamine, Norepinephrine
 Indolamines: Serotonin,
 Histamine
 Acetylcholine





Amino acids:
 glutamate, GABA, glycine
Steroid hormones
 estrogen, androgen, corticosteroids
Gases: nitric oxide
Feedback: cannabinoids
Peptides and proteins:
 opioids, endorphins, GH, CCK, PRL,
angiotensin II, oxytocin,
calcitonin,
insulin, glucagon.

“Top down”






Sleeping pills
Sedatives
Anti-convulsants
Mood stabilizers
Alcohol
“Bottom up”
 Antidepressants
 Antipsychotics
NA, DA and 5HT Synthesis
Noradrenaline Deficiency Sydrome
• Deficiency syndrome
– Impaired attention
– Problems
concentrating
– Deficiencies in
working memory
– Slowness of
information
processing
– Depressed mood
– Psychomotor
retardation
– Fatigue
Noradrenaline Deficiency Sydrome
• Deficiency Syndrome
•
Sleep problems,
•
anxiety,
•
obsessions,
•
irritability,
•
impulse control problems,
•
appetite disturbance
4 pathways in the
brain
1. Mesocortical
2. Mesolimbic
(pleasure pathway)
3. Tuberoinfundibular
4. Substantia Nigra

Dopamine deficiency
 Depressed.
 Anhedonia, no motivation,
procrastination and the inability to feel
pleasure. Difficulty getting up in the
morning. Problems concentrating
 Hypersomnia
 Parkinson’s
 Prone to form addictions,
 a need for caffeine or other stimulants,
and gaining weight.

Dopamine Excess
 Psychosis
 Aggression
 Hypervigilance
•
•
Differential Diagnosis
1. Mood disorders
2. Anxiety
3. Psychosis
Treatment Algorithms
1. Depression
2. Bipolar Disorder
3. Schizophrenia
Differential Diagnosis of Mood
disorders
• Major depressive disorder
• Dysthymic disorder
• Depressive disorder NOS
• (PMDD, Minor depressive disorder,
RBDD, postpsychotic depressive
disorder of schizophrenia, etc.)
• Bipolar I disorder
• (including mixed episodes)
•
•
•
•
Bipolar II disorder
Cyclothymia
Mood disorder due to a GMC
Substance induced mood
disorder
Differential Diagnosis of Anxiety
•
•
•
•
•
•
•
•
•
•
•
Social phobia
Specific phobia
Generalized Anxiety Disorder
Post Traumatic Stress Disorder
OCD
Panic with and without agoraphobia
Separation anxiety disorder
Associated w depression / psychosis
Somatoform / Dissociative disorders
Personality disorder
Substance and general medical exclusion
Differential Diagnosis of Psychosis
• Mood D/O
• Depression or Mania with psychosis
• SCZ
• Schizophrenia, Schizoaffective,
Schizophreniform
• Brief Psychotic Episode
• Delusional disorder
• Dissociative D/O
• Delirium
• Personality Disorder
• Substance and General Medical
Exclusion
Initiate treatment with
SSRI, SNRI, NRI, other
Partial or no response after 4-6
wks of tx at adequate dosages
R/A Diagnosis. Optimize dose
Switch to new
antidepressant from
a different class
Consider psychotherapy at
any point particularly with
early childhood trauma
Inadequate response
2nd
Augment
1st Lithium
atypical antipsychotic
3rd Lamotrigine
4th Thyroid T3
Combine 2
antidepressants from
different classes
Consider ECT at any time particularly when
Very severe depression
Not eating or drinking
Catatonia
Psychosis
Suicide Risk
Med Intolerance / Pregnancy
Determine Phase of illness
MANIA
Lithium
Epival
Typical and Atypical
Antipsychotics
ECT
MIXED
AAP
CMZP
DEPRESSION
1) Lithium (for Cade’s
disease)
2) Mood Stabilizer (Li, VPA,
AAP) plus Antidepressant
3) Lamotrigine
4) Seroquel Monotherapy
5) ECT
EUTHYMIA
Lithium
AAP
?Lamictal
Consider ECT at any time particularly when
Very severe depression
or uncontrolled mania
Not eating or drinking
Catatonia
Psychosis
Suicide Risk
Med Intolerance / Pregnancy
APA Schizophrenia Guidelines 2004. Schizophrenia Tx Algorithm
Schizophrenia Tx
Algorithm

Antidepressants









SSRI’s
SNRI’s
SARI’s
NaSSA’s
NDRI
TCA’s
MAOI
RIMA’s
Novel Agents

Mood stabilizers
 Lithium
 Epival
 Lamotrigine

Antipsychotics





Clozapine
Olanzapine
Risperidone
Quetiapine
Ziprasidone
1. SSRIs (Fluoxetine, Fluvoxamine, Paroxetine,
Sertraline, Citalopram, Escitalopram)
2. SNRIs (Venlafaxine, Des-Venlafaxine,
Duloxetine)
3. SARIs (Trazodone)
4. TCAs (Clomipramine, Amitriptyline, etc)
5. MAOIs (Nardil, Parnate)
6. RIMAs (Moclobemide)
7. Dopamine agonist (Mirapex)
5HT reuptake inhibition
Increased availability of 5HT in synapse (and somatodendritic areas)
Increased activity of 5HT 1A autoreceptors acutely
and decreased firing rate (negative feedback loop)
Desensitization of presynaptic 5HT1A autoreceptors
Return of normal firing rate with ongoing decreased
reuptake.
Increased 5HT release and
neurotransmission
NE reuptake inhibition
Increased availability of NE in synapse (and somatodendritic areas)
Increased activity of alpha2 autoreceptors acutely
and decreased firing rate (negative feedback loop)
Desensitization of presynaptic alpha 2autoreceptors
Return of normal firing rate with ongoing decreased
reuptake.
Increased NE release and neurotransmission
Downregulation of beta adrenergic receptors
Sensitization of alpha 1 adrenergic receptors

Prozac (Fluoxetine)
[Bech BJP 2000, Beasley JCP 2000]
 Longest t ½, ~15 days, active metabolite, elderly watch for SIADH, EPS. Inhibitor of
2D6. Norfluoxetine 6 week washout. Can be problematic b/o of this.

Paxil (Paroxetine)
[Wagstaff CNS drugs 2002]
 Shortest half life, some anticholinergic ASE, no metabolites, high risk of
discontinuation syndrome. Substrate and inhibitor of 2D6 leading to non-linear
pharmacokinetics

Luvox (Fluvoxamine)
[Edwards BJP 1994]
 Interacts with coumadin. Least protein bound, no metabolites, no chiral center,
weakest potency, sedating. Inhibitor of 1A2 and 3A/4

Zoloft (Sertraline)
[Perry CNS Drugs 1997, DeVane
Clin Pharmaco 2002]
 Needs to be taken w food, DA activity: EPS and active metabolite, few drug
interactions, can cause diarrhea and heartburn. Dose dependent variable
neurotransmitter effects.

Celexa (Citalopram)
[Keller JCP 2000, de Lima EBMH
2001]
 Most selective. Few drug interactions. Doesn’t effect INR (coumadin).

Cipralex


[Burke JCP 2002]
escitalopram
S-enantiomer of Celexa. More of a dose dependent response curve due to differential binding at
the allosteric and active drug site

Pharmacodynamics
 Blocks 5 HT reuptake
 5HT 1A antidepressant anxiolytic
 5HT 1B food intake/temp
regulation
 5HT 1C sensory
 5HT 1D anti migraine
 5HT 2A sleep disruption/sexual
ASE, suicide R-changes, EPS,
 5HT 3 nausea

Indications:
 MDD, dysthymia, OCD, PD, SP,
PTSD, GAD, BN, Pain d/o, migraine,
FM, selective mutism,
autism/Tourette’s













T
H
E
N
E
W
A
G
E
S
Tremors
H/A’s 20-30%
Euphoria 8% MDD, 50% BAD
Nervousness (agitation, dizziness,
restlessness)
Endocrine (SIADH, galactorrhea)
weight gain
anorgasmia and other sex problems
20-50%)
GI upset, GI bleed (age>85, prev GI bleed)
Excretions
Sleep disturbance (REM suppression
except luvox, inc awakenings, nocturnal
myoclonus), sedation
75% tolerate SSRI’s w no ASE’s
25% ASE disappear by day 14 (most w/I 3-4d).
~10% do not develop tolerance
5HT syndrome, discontinuation syndrome
GASH:
•GI (upset, N/D/C,
bleed 1:8000)
•Activation / Anxiety,
•Sexual dysfxn / Sleep
disturbance / Sedation
/ Seizure 0.2%,
•Head ache


In the elderly, >85 or previous GI
bleed increased risk of GI bleed
[Dalton CNS Drugs 2006].
Retrospective data base reviews
limited by confounders including
NSAID use.
Increased risk of fracture in those
over 50 OR=2.1, falls OR 2.2
[Richards AIM 2007]


Pharmacology of 1, 2 or all 3
monoamines, depending on the dose
(Harvey AGP 2000)
At low doses 5HT

 May be safer if combined with
coumadin
 Mirtazapine or Nefazadone may block
some 5HT effects
 (same ASE’s: nausea, agitation, sexual
dysfxn, insomnia)

At medium to high both 5HT and NE
Reuptake blockade
 Watch for HTN, severe insomnia,
agitation, nausea, H/A, EPS

At very high doses all three
 May be useful in melancholic, severely
depressed inpatients and those refractory
to other antidepressants


Steady state [ ] ~3d, t ½ ~5hrs, ~11h for
active metabolite (ODV ~56% of any
given dose), unless XR.
Metabolized by 2D6, weak inhibitor of
2D6
Few drug interactions

ASE’s (E vs placebo) [ISDNSSH]:
 Insomnia(18vs10%), somnolence 1723 vs. 8-9%), dizziness (19vs 8%),
anxiety (XR better), dry mouth (22 vs
11%, 12 vs. 6% XR), nausea (31-37 vs.
11-12%), h/a (24% comparable to
placebo), sweating (<75: 5-6%
=placebo, 225: 12.4%, 375 19.3%),
sexual dysfxn (12-16 vs <1%),
sustained HTN (<75: 1%=placebo, 225:
2.2, 375: 4.5%), withdrawal effects
common




Desvenlafaxine (Pristiq) AKA, Odesmethylvenlafaxine,
Desvenlafaxine is a synthetic form
of the major active metabolite of
venlafaxine (Effexor)
It is being targeted as the first nonhormonal based treatment for
menopause.
Theoretically useful for slow 2D6
metabolizers


The most commonly observed
ASE (incidence >= 5% and at least
twice the rate of placebo in the 50
or 100 mg dose groups) were
nausea, dizziness, insomnia,
hyperhidrosis, constipation,
somnolence, decreased appetite,
priapism, night terrors, anxiety,
and delayed ejaculation.
Nausea was consistently the
most common complaint (3050% vs placebo 9-11%) and the
most common reason for
discontinuation.







Dual “balanced” 5HT and NE
reuptake inhibitor (still 2:1 in vivo)
Higher potent affinity for 5HT and
NE transporters than Effexor
T1/2= 10-15 hours
SE consistent with NE potentiation
(BP, HR)
Cases of hepatitis/jaundice (LFTs up
20x)
Moderately potent 2D6 inhibitor
Dosing 20-60 mg daily with food

Raskin J et al. Pain Med. 2005;6:346-356.

Trazadone




T ½ is 7-8 hrs
Trazadone is a potent 5HT 2A/C antagonist, at higher doses weak SSRI
Metabolized by CYP 3A4, 2D6, 1A2
Active m-CPP metabolite is a 5HT2C agonist with anxiogenic propertiesfound in low levels
 S/Es: dizziness, postural hypotension, priapism
 Hypnotic (inc. slow wave sleep / dec. REM sleep)
 May be arrhythmogenic in cardiac patients
 Arrhythmias identified include isolated PVC's, ventricular couplets, and in 2 patients short
episodes (3 to 4 beats) of ventricular tachycardia
 Dosing: sleep 12.5-150 mg/day, antidepressant 150-600 mg/day



Sedation may be higher at
lower doses
More than one mechanism of
action
Consider for depression with
 Anxiety, Agitation
 Insomnia, SSRI induced sexual
dysfxn, nausea, GI distress
 Panic, Weight loss
 Severe depression

May be useful in tx resistance
as an augmentation agent


Low likelihood of drug interactions
• Adverse clinical effects of drowsiness
(23% versus 14%), excessive sedation
(19% versus 5%), dry mouth (25%
versus 16%), increased appetite (11%
versus 2%) and weight increase (10%
versus 1%).
• [SWD]
Pharmacology
 Blocks alpha 2 auto and 5HT-alpha 2
heteroreceptors
 Blocks 5HT2 (anxiety, sleep)
 Blocks 5HT3 (nausea)
 Blocks H1

Start 15mg qhs increase to 30-45 mg/d


unicyclic aminoketone
Indications:
 MDD, BAD depression, smoking cessation, ADHD, SAD, cocaine abuse.

Mechanism of action
 Through noradrenergic mechanisms, actually has poor affinity for
Dopamine reuptake pump, probably through a GABA interneuron with 5
HT involved.

Therapeutic profile






Retarded depression, hypersomnia (NA depression)
Nonresponder /can’t tolerate 5HT agents
No sexual dysfxn/wt gain. Safe in elderly with cardiovascular disease
Cognitive slowing/pseudodementia
50% response in stimulant responders in ADHD
Negative effects (seizures) reported in eating disorder patients



H
E
L
H/A*,
excitement*, anxiety
lowers seizure threshold

 seizures 0.1% < 300 mg/d, 0.4% > 400 mg/d







P
I
N
G
A
C
T
p450 interactions
insomnia*, irritability*
nausea*
GI distress
agitation, amphetamine like
effects, allergic reactions
constipation, cardiac palpitations
tremor, tinnitus



Recommended dose 150-300
mg/d single SR dose. Start at
100 and titrate upwards to
clinical effect. T1/2 = 1014h/SR 21h, Time to peak
plasma [ ] =2-3h, Steady
state levels b/o 3 metabolites
= ~10 days.
Inhibitor of 2D6, substrate of
2B6, has three active
metabolites
NDRI (low NA, high DA, also
some 5HT, alpha 2, M1)
Labs may give false positive
urine amphetamines
Relatively
5HT>NE
More other
receptors ASEs

Tertiary Amines
 Imipramine, Amitriptyline,
Doxepin, Clomipramine

Secondary Amines
CYP 1A2
CH3
 Desipramine, Nortriptyline,
Protriptyline

Tetracyclics
 Amoxapine
 Maprotiline
NE>5HT
Fewer side
effects
CYP 2D6

Anticholinergic
 Dry mouth, blurred vision, urinary retention, confusion

Orthostatic Hypotension
 Alpha 1 adrenergic blockade, transient

Cardiac Conduction Changes
 Quinidine like type 1a antiarrhythmic effect
 Depressed ST and blunted T wave. Prolongation of PR, QT, QRS
 Tertiary amines and hydroxylated metabolites worse

Endocrine
 Weight gain, elevation in blood sugars, SIADH

CNS
 Sedation, myoclonic twitches, tremors, seizures (worse with maprotiline)

Allergy
 Photosensitivy, jaundice

Psychiatric
 Switch to mania in 50% of Bipolar vs. 1-7% Unipolar

Sexual Dysfunction
 Related to anticholinergic, alpha 1 blockade, 5HT reuptake inhibition and
altered dopamine







MAO – oxidative deamination
of amines 5HT, NE, DA
Discovered accidently in tx of
TB (IPZ)
MAOIs structurally similar to
catecholamines
MAOIs block monoamine
oxidase inhibitor permanently
and irreversibly
Suggested to be more
effective in MDD with atypical
features
Divided into 2 groups
 Hydrazine (Phenelzine-Nardil)
and Non-Hydrazine
(Tranylcypromine-Parnate)
 Nardil-more sedating
 Parnate-amphetamine like
qualities, can be activating
Common ASEs





Orthostatic hypotension
Weight gain
Sexual dysfunction
Ankle edema
Other Side Effects
 Insomnia with daytime sedation ‘Nardil
Nod’
 Myoclonus, tremor and akathisia,
parathesias
 Dry mouth and urinary retention

Rare but serious
 Hypertensive crisis (tyramine cheese
reaction-displaces NE in vesicles).
Guidelines is <6 mg
 Blood dyscrasias
 Hepatotocity
 Teratogenecity





Selective and reversible inhibitor of monamine
oxidase subtype A (RIMA)
Efficacy shown in depression and social phobia
D0sage: initiate at 300 mg divided. Maximum dose
600 mg/day. Looses its selectivity above 900 mg/day
Few side ffects. Can be useful in patients who cannot
tolerate the GI ASE of SSRIs/SNRIs
Pharmacokinetics: Short t1/2 of 1-2 hours. 1-2 day
washout.





No cheese reaction at 600 mg/day [150 mg
tyramine=3kg cheese raises SBP by 30mmHg]. Dietary
restrictions not necessary <600 mg/day.
Inhibition of MAO-A returns to normal within 1 day of
cessation
Metabolized by flavin-containing mono oxygenase and
CYP 2C19
Fatalities reported with combination with SSRIs Lancet
1993. Do not combine with MAOIs, DM, Ephedrine,
meperidine
Serotonin Syndrome and HTN




Metaanalysis of Moclobemide with SSRIs in
MDD. Papakostas and Fava
Can J. Psych Oct 2006
Main Finding n=1207 (risk ratio 1.08; 95%
confidence interval, 0.92 to 1.26; P = 0.314)
Limitations
 The absence of comparative studies involving
citalopram and escitalopram precludes
generalization to all SSRIs.
 Based on 12 RCT Comparison trials with no placebo.
The lack of placebo comparison groups means that
no conclusion can be made about the assay
sensitivity of these trials.
 There were no outcome data for the subset of
patients with atypical depression
Lithium
Epival
Lamotragine
Carbamazepine
Gabapentin
(more used for anxiety or neuropathic pain)




Simplest solid element
Natural salt discovered in 1817
First described by John Cade
(1949) to have antimanic
properties
Pharmacokinetics
 100% absorbed, 0% protein
bound
 T ½=24-36 hrs
 No metabolites
 100% renal excretion with renal
excretion interactions

Pharmacology
 Increases release of 5HT
 Blocks release of NE and
DA
 Blocks receptor mediated
actions of several hormones
on adenylate cyclase (eg.
ADH and TSH)
 Possible stabilization of
catecholamine and
acetylcholine receptors
 Alters distribution s of other
ions, Mg 2+, Ca 2+, K+, Na+

Responders
 Classic euphoric mania, infrequent episodes with full interepisode
recovery, FHx of Li response& BAD, PHx of Li response,

Non-responders
 Severe, dysphoric, mixed, psychotic mania, rapid cycling, adolescent, >3
episodes, substance abuse, 2o mania

Dosing
 Adult- 600-1500 mg/d (0.5-1.2). Geriatric- 150-600 mg/d (0.3-0.8)
 Once pt is stabilized switch to once daily dosing. Check plasma levels 5
days after start then twice weekly for the 1st two weeks then weekly for
the next 2 weeks, then if stable @ clinical discretion (at least every 6
months). Also check lytes, BUN, Cr, regularly, and TSH (periodically after 3
months and every 6-12 months afterwards)















T
H
E
M
A
G
I
Levels
 Increased by NSAIDS, thiazide diuretics, ACEI,
tetracycline, anticonvulsants
 Also consider decreased clearance with aging,
renal disease, dehydration, low salt diet
 Decreased by osmotic diuretics (eg. mannitol),
carbonic anhydrase inhibitors, caffeine,
theophylline, high salt diet
 Pregnancy (increased plasma volume but also
GFR).
Tremor
Hypothyroid
CG changes
uscle weakness
lopecia
I upset
ncreased WBC
(transient)
C
ardiac arrhythmias  ASE’s
W
eight gain
 Poly’s (60%), N, abdo pain, V, D, vertigo, muscle
A
cne
weakness, fine tremor M>F 54 vs. 26%, wt gain
N
eurological
F>M (47 vs 18%), hypothyroidism (5-15% F>M
D
rinks/ diabetes
(recent study 37 vs. 9% F>M, predictor=wt gain).
insipidus
 Toxicity: usually starts w GI then tremor, then
GPWITH
thirst and inc u/o, then drowsiness, ataxia, tinnitis,
(GI, Polys, wt gain, incr
blurred vision.
WBC, tremor,
hypothyroid)


Potentiation of GABA
Interactions
 Inhibits metabolism of benzos, carbamazepine (Inc levels of CBZ-E metabolite).
CBZ by induction dec VPA levels
 Increases plasma levels of prozac, TCA’s, Lamotragine.
 May worsen tremor w Li, VPA can increase levels of Li (Li can decrease levels of
VPA)
 VPA displaces protein bound-ASA



Begin at 250mg BID or TID to reduce ASEs. Dosage range 750-3000 mg/d.
Poor correlation of clinical effect w plasma levels (350-800 umol/L). Check
levels after 3days, then weekly for the first 2 weeks and then with clinical
discretion
Labs: CBC, INR, PTT, monthly for 6 months then q 6 months. LFT’s monthly
for 3 months then q 3-6 months. Could also check Lipase.

T
U
R
N
S
O

B





tremor (10-29%)
unsteadiness
rashes
nausea (20%) / GI upset
sedation (31%)
oligomenorrhea / PCO
(menstral irreg in 45%)
blood dyscrasia

(thrombocytopenia, anemia)







A
L
D
&
F
A
T
alopecia
LFT elevation (up to 44%)
dysarthria




fat (59% mean wt gain 8-21 kg
F>M), (also overestimates serum
FFA)
ammonia levels can rise
teratogen (5-15%)



Common ASE: N, V,
indigestion, usually
transient and rarely require
d/c. 11% discontinuation
rate in trials.
Common:
[WITH GST]
Wt gain,
Irregular menses,
Teratogen,
Hair loss,
GI, Sedation (cognitive
dulling,), Tremor

Indications
 May be effective in bipolar depression, may also cause a switch.
 Not effective in treating mania

Pharmacology
 Works thru voltage sensitive Na channels unlike others no GABA effects.
 No clear clinical response correlation with levels

Clinical
 Start 25-50 mg/d and titrate gradually every 2 weeks up to 250 mg BID.
Therapeutic range appears to be 50-200 but some additional benefit seen
occasionally by inc dose to 500 mg/d.
 Starting low and going slow may decrease risk of rash
 Lamotrigine decreases levels of Epival
 Epival increases Lamotrigine’s T ½
 Use doses below 150 mg/d (half the dose)
 CBZ decreases t ½ (double the dose)
 Safe in combination w Li
R rash (10-25%-cf 5% PCB, 2-3% require drug d/c). SJS
and TEN higher in epileptic patients. Serious
rash=0.3% adults/1% in children. With slow titration
risk was reduced to 0.01% comparable to other
anticonvulsants.
A activation (3-8%), ataxia
S spaced out (cognitive slowing), sedation, sleep
disturbance
H H/A, hypersensitivity reactions, Nausea,





Similar to GABA in structure
Some evidence for efficacy in neuropathic pain, RLS
Evidence for efficacy in social phobia
Maybe an effective anxiolytic
Pharmacokinetics
 Not metabolized, safe in od, few ASE
 Fatigue at higher doses, inc appetite, ataxia, wt gain, hypomania,
if stop to quickly can see sx
 Can be inc rapidly, well tolerated, but watch for renal failure,
ataxia and delirium: 900-1800 mg/d.
 Case reports of TD


Evidence for efficacy in RLS
New related med pregabalin has shown efficacy in GAD


Similar in structure to tricyclics
Multiple ASE (lots of receptors, induction of hepatic
metabolism eg. 3A/4 OCP), autoinducer (half life shortens 3-5
weeks later)
 ASEs:



Active metabolite 10,11 epoxide CPZ (VPA blocks further
breakdown),
Poor correlation between blood level and clinical effect
Regular B/W: transient leukopenia (agranulocytosis 1/10-25
000, fatality 1/22 million), contraindicated w Clozaril
•Typicals
•Haldol
•Chlorpromazine
•Atypicals
•Risperidone
•Paliperidone
•Olanzapine
•Quetiapine
•Ziprasidone
TYPICAL ANTIPSYCHOTICS
• Phenothiazine antipsychotics
• Chlorpromazine, Fluphenazine,
Mesoridazine, Perphenazine,
Prochlorperazine, Promazine,
Thioridazine, Trifluoperazine
•
Thioxanthene
• Thiothixene [Navane]
•
Dibenzodiazepines
• Loxapine (Loxitane) Clozapine (Clozaril)
•
Butyrophenones
• Droperidol (Inapsine) Haloperidol (Haldol)
•
Indolone
• Molindone (Moban)
•
Diphenylbutylpiperidine
• Pimozide (Orap)
ATYPICALS
• Amisulpride,
Aripiprazole,
Clozapine,
Olanzapine,
Quetiapine,
Risperidone/Paliperid
one}, Sertindole,
Sulpiride,
Ziprasidone, Zotepine
High potency group
D2 blocking action is
strong.
More Extrapyramidal
symptoms
Few side effects on
circulatory system.
Phenothiazines
fluphenazine
perphenazine
Butyrophenones
haloperidol
Low potency group
Fewer Extrapyramidal
symptoms
More side effects on
autonomic nerves and
circulatory system.
Sedative action is strong.
Phenothiazines
chlorpromazine
thioridazine

Response
 70% Positive Sx in SCZ
 BPRS, PANSS

Remission
 <10%

NNT’s with CI’s.

Risperidone
 Used in Schizophrenia, psychotic disorders, dementia (BPSD),
mood disorders (mania and depression augmentation) [latter 2 at
lower doses <2 mg/day]
 Higher rates of EPS compared to other SGA. Prolactin elevation.

Paliperidone
 Used in Schizophrenia, mania. Has anti alpha 1 and 2 adrenergic
effects (more cardiac concerns). Extended release, hydroxylated
risperidone.

Olanzapine
 Used in Schizophrenia, psychotic disorders, mood disorders
(mania, depression, maintenance Bipolar). Causes weight gain
and metabolic syndrome. Can also cause glycemic changes.

Quetiapine
 Very sedating. Used in Schizophrenia, psychotic disorders,
mania and for bipolar depression (BOLDER 1&2) and possibly
unipolar depression. Sedating and can cause orthostatic
hypotension.

Ziprazodone
 Has 5HT 1a properties; therefore may help with depression

Clozapine
 Many side effects including risk of agranulocytosis which leads to
regular and frequent blood tests. Difficult to use in the elderly
because of anticholinergic/antiadrenergic ASEs. Associated with
weight gain and metabolic syndrome.

Indications
 SCZ, Mania, BPSD, Depression augmentation.

Efficacy
 Acute (3 PCT’s)
 N= 160, 6 wk DB, flex dose < 10 mg (avg. 7.8), vs. Haldol
< 20 mg. Risp > PCB BPRS. SANS, CGI.
 N=1356, fixed doses (1,4,8,12,16 mg/d) vs Haldol 10
mg/d or PCB. Dosed Risp > 1mg > PCB (optimal
response 4-8 mg), PANSS, BPRS.
 N=513, 4 doses (2,6,10 or 16 mg/d) w Haldol 20 mg/d or
PCB. Risp > PCB PANSS, BPRS, CGI although 2 mg not
always reached stat sig.
 Efficacy in once daily dosing also established.

RESHAPE







R Restless legs, Rhinitis
E EPS,
S Somnolence
H H/A
A appetite / agitation
P PRL
E edema, peripheral




Some patients tolerate it better than risperidone
Hyper PRL with low E2 may accelerate
osteoporosis
Like Risperidone, may cause more motor ASE
than other SGAs
Trilayer tablet

Aripiprazole
 (Abilify, Abilify Discmelt) is an atypical antipsychotic used
for schizophrenia, bipolar disorder, and augmentation for
clinical depression.


Pharmacology
 Partial agonism at D2R
 Partial agonism of 5HT1A
 Blockade of 5HT2A
 Alpha 1 blockade (ASE)
Drug interactions
 Metabolized by 2D6 and 3A4. Ketaconazole may increase
dose.

Dosing:
 15-30 mg/day
 For some less may be more: those not acutely psychotic 2.510 mg/d to avoid akathisia and activation.
 For some more may be more: some may benefit from doses
above 30 mg/day.
 Due to its long life may take longer to reach steady state.

Clinical Pearls:
 Weight gain not as common and is less sedating

ASEs:
 dizziness, insomnia, akathisia, activation, N/V

Indications
 Treatment resistant psychosis, mania,
depression
 Landmark study Kane et al (AGP 1988) of tx
resistant patients. Markedly lower rates of EPS
 CATIE confirmed superiority (although it was an
open phase of the study)

Baseline B/W:
 CBC w diff, lytes, BUN, Cr, TSH, ECG, LFT’s,
CXR. Consider HIV, Tb testing. Check CBC
qweekly for 26 weeks then biweekly afterwards
 Contraindicated w CBZ b/o transient
leukopenia.
W weight gain
A agranulocytosis(<0.5, 0.7 %) cytopenia(<1.5, 3 %).
~90% in first 26 weeks. Higher risk in those >50
Guidelines: CBC weekly x 26 weeks then every two weeks or 4 weeks after D/C. Evaluate twice
weekly and CBC if WBC (2.0-3.5), ANC (1.5-2.0), single fall WBC or sum of falls >3.0 reaching a level <
4.0, a single fall or sum of falls of ANC > 1.5 reaching a level of <2.5, or flu like symptoms. If below
WBC 2.0, ANC 1.5, Clozapine should be discontinued and patient followed closely. Cultures and
reverse isolation if WBC <1, ANC<0.5
T tachycardia (up to 25%)
C2 constipation (14%), cardiac other (ECG changes, pericarditis, myocarditis)
H hypotension (dizziness 19%) / H/As (7%)
E EPS (rare, including NMS)
S4 Sedation (39%), Seizures (<300mg 1-2% like other APs, 600900 mg 5%), Sialorrhea (31%), Sugars (diabetes 33%),
Sedation and hypersalivation sometimes mistaken for Parkinsonism

Indications
 SCZ, BAD-mania, acute agitation, ?Dementia (BPSD)
 Superior effects on cognition in SCZ
 ?Superior effects on mood

Efficacy in SCZ
 Acute
 2 x 6 wk PCT n=335, n=431, fixed doses, 10, 15 > PCB on
BPRS, CGI. OLZP 15mg > Haldol 15 mg SANS.
 6 wk PCT 2 fixed doses 1 and 10 mg. 10 mg > PCB
PANSS, BPRS, CGI.
 6 wk (n=1996) comparison dose range study OLZP 5-20
(13.2 avg) mg, Haldol 5-20 (11.8 avg) mg, OLZP> BPRS
(+neg cluster), PANSS neg, CGI. Also OLZP>H on
MADRS but not validated in SCZ.
 Continuation
 3 DBC-extension/main trials. > PCB in the one trial,
comparable or > than active comparators in 3 other
studies.
SAD COST


Somnolence
Appetite / Wt gain
 (acute mean 2.8, chronic mean 5.4 kg,
?level @39 wks, may not be dose
dependent)





Diabetes, DKA, dry mouth
Constipation
Orthostatic hypotension
Seizures
Transaminase (ALT) / TG elevation

Efficacy
 Acute 3 x 6 wk PCTs
 N=361, 5 fixed doses (75, 150, 200, 600, 750 mg),
4 highest doses > PCB BPRS, CGI
 N=286, high/low titration up 750 mg/ up to 250
mg), only high dose BPRS, CGI, SANS > PCB.
 N=618 2 fixed doses 450 vs 50 mg. 450 mg > PCB
on BPRS, CGI, SANS.
 One study showed no improvement in SANS
sim to Haldol.
 Comparison studies
 QUEST (Quetiapine
experience safety tolerability)
 Mixed population

SOLD




Somnolence
Orthostatic hypotension
Liver transaminase elevations
Dizziness / Dry mouth / Dyspepsia


Ziprasidone (Geodon, Zeldox)
Indications:
 schizophrenia, and acute agitation IM in schizophrenic patients, mania
and mixed states associated with bipolar disorder.

Pharmacology:
 Has high affinity for dopamine, serotonin, and alpha-adrenergic
receptors and a moderate affinity for histamine receptors, as an
antagonist. Has perhaps the most selective affinity for 5-HT2A
receptors relative to D2 and 5-HT2C receptors of any neuroleptic.
 5HT 1A agonism
 Antagonism at histaminic and alpha adrenergic receptors likely
explains some of the side effects of ziprasidone, such as sedation and
orthostatic hypotension.

Clinical Pearls:
 Increases QTC
 Should be taken with food to increase absorption
 Less weight gain (maybe even weight loss), risk of
diabetes, dyslipidemia
 Efficacy maybe underestimated because it is usually
underdosed (<120 mg/day)
 More activating that some of the other SGAs
 Has an IM form
Starting a medication
Adverse Side Effects
Serotonin Syndrome
Mechanisms Underlying Drug Levels
Drug Interactions

FIRST (check diagnosis,
comorbidity, medical causes)

S

T

E

P
S

Safety (including drug-drug
interactions)
Tolerability (acute and long term
potential ASE’s)
Efficacy (response rate, relapse
prevention, for your particular
patient’s characteristics)
Payment/cost
Simplicity (dosing, blood work)
Preskorn JCP 1997

Cardiovascular
 [mainly antidepressants and antipsychotics]
 Arrhythmias (tachycardia, QTC prolongation), HTN, Hypotension,
rarely myocarditis

Hematological
 [mainly anticonvulsants and clozapine]
 Blood dyscrasia (anemia, agranulocytosis, thrombocytopenia)

GI
 Dyspepsia, nausea, constipation or diarrhea, rarely: liver or pancreatic
inflammation

Neurological
 Dizziness, ataxia, blurred vision, dyskinesias, tremor
 Receptor mediated effects

Drugs bind to more
receptors than they ideally
should
Psychomotor activation
Psychosis
Sedation/Drowsiness
Weight gain
Blurred vision
Dry mouth
Constipation
Sinus tachycardia
Urinary retention
Memory dysfunction
DA reuptake
`
inhibition
5HT2
Stimulation
Sexual dysfunction
Activating
side effects
Insomnia
Nausea
Ach block
Antidepressant
5-HT reuptake
inhibition
Priapism
Alpha2 block
Postural hypotension
Dizziness
Reflex tachycardia
GI disturbances
Activating effects
NE reuptake
inhibition
Dry mouth
Urinary retention
Activating effects
Tremor
Adapted from Richelson E. Current Psychiatric Therapy. 1993;232-239
Anticholinergics
Red as a beet
Dry as a bone
Hot as a hare
Mad as a hatter
Blind as a bat
Bowel and
Bladder loose their tone
And the heart goes off
alone
Vasodilation
Dry mucous mbs, anhydrosis
Hyperthermia
Delirium, hallucinations, agitation, cognitive
impairment
Blurred vision, worsens glaucoma, photophobia
Constipation
Urinary retention,
Tachycardia
Also delayed or retrograde ejaculation
Memory impaired in Elderly
Tune et al. Am J Psychiatry 1992;149:1393-4.
Miller et al. Am J Psychiatry 1988; 145: 342-5








 PATHOPHYSIOLOGY
1960—tryptophan and MAOIs
 Stimulation of 5-HT
1984—Libby Zion: meperidine,
 receptors in brain, GI tract and
phenelzine and cocaine
vessels
15% incidence in patients overdosing
 Drugs may stimulate receptors
SSRIs
directly
Toxic exposure surveillance system 2002
 Tryptophan
in the US
 Sumatriptan (Imitrek)
7,349 patients reported in 2002
 Buspirone (Buspar)
93 deaths
 or block reuptake and
0.4 cases/1,000 patients—months on
metabolism
SSRIs
 SSRIs
Oates JA (1960), Neurology 10:1076 Meperidine
1078; Asch DA (1988), N Engl J Med
318(12):771-775
 MAOIs

SSRIs
 Sertraline (Zoloft), fluoxetine (Prozac), fluvoxamine
(Luvox), paroxetine (Paxil), citalopram

Other antidepressants
 Trazodone, nefazodone, buspirone, clomipramine
(Anafranil), venlafaxine (Effexor)

MAOI
 Phenelzine, isocarboxazid (Marplan)

AEDs
 Valproate (Depacon)

Analgesics
 Meperidine, fentanyl (Duragestic), tramadol (Ultram),
pentazocine (Talwin)

Antiemetics
 Ondansetron (Zofran), metoclopramide (Reglan)
Boyer NEJM 2005
Boyer NEJM 2005

Migraine
 Sumatriptan

ABx
 Liezolide (Zyvox), ritonavir (Norvir)

Abused drugs
 MDMA, LSD

Dietary supplements
 Trypotphan, St. John’s Wort, ginseng


Lithium, dextromethorphan
REPORTED AGENTS INVOLVED
 Sertraline, fluoxetine (Prozac, Sarafem), fluvoxamine, paroxetine,
citalopram, trazodone, netazodone, buspirone, clomipramine, venlafaxine,
phenelzine, moclobemide (Manerix), isocarboxazid, divalproex (Depakote),
meperidine, fentanyl (Duracesic, Sublimaze), tramadol, pentazocine,
ondansetron, granistron (Kytril), metoclopramide, sumatriptan, sibutramine
(Meridia), dexfenfluramine (Redux), fenfluramine (Pondimin), linezolid,
ritonavir, tranylcypromine (Parnate), imipramine, mirtazapine (Remeron)

SEVERE SS combos
 Phenelzine and
meperidine
 Phenelzine and SSRIs
 Paroxetine and buspirone
 Linezolide and
citalopram
 Tramadol and
venlafaxine and
mirtazapine


Serotonin Syndrome
 Agitation/restlessness (most
common)
 Confusion
 Hyperthermia
 Tachycardia, HTN
 Autonomic instability
 Diaphoresis
 Hyperreflexia
 Myoclonus
 Ataxia
 Incoordination

Serious complications
 Sz, DIC, respiratory failure, inc
temp, death
NMS











Fever, rigidity, neuroleptic use +
Altered mental status
Seizures, coma, catatonia
Mutism
Dyphagia
Leukocytosis
Elevated CPK
Myoglobinuria
Decreased renal fxn
Dec TIBC (?epiphen)
Risk factors
 Underlying medical illness, young, M,
recent dose inc, low TIBC, dehydration,
Lithium,

Tx
 D/C neuroleptic, supportive
management, consider DA agonists,
ECT. If rechallenge >2/52
Same: autonomic instability (fever, tachy)
Different: SS- hyper reflexia, myoclonus, ataxia, incoordination, mydriasis active bowel sounds.
NMS- rigidity, dysphagia, dysarthria, incontinence, sialorrhea, SOB, EPS, markedly increased CK,
increased WBC/myoglobin, neuroleptic use






Flu like symptoms, vertigo, dizziness and nausea, jolt
like bursts several times throughout the day
Differs from SSRI S/E
Occur within 1-3 days after abrupt discontinuation of
the SSRI- subsiding within two to several days after
the last dose
Most frequently cited with paroxetine and
venlafaxine
Term not to be confused with withdrawal seen in
addiction
Rx: taper the SSRI slowly or start another SSRI

anticholinergic effects

 peripheral, central


 parkinsonism, dystonia,
akathisia, catatonia, NMS
 Movement disorders. TD
 NMS
sedation, falls / #’s
CVS
 QTC and conduction defects /
repolarization delays

 Highest w Thioridazine, Ziprasadone,
Haldol (intermediate). K rectifier pump.
QTC>480 ms. F>M. Elderly [>75] QTC
>430 ms RR of death 2.4 Nilsson
Eurospace 2006

 orthostatic hypotension,
tachycardia
EPS
Sexual dysfxn
 CPZ, thioridazine, risperidone
Seizures
 Higher w low potency agents

Miscellaneous
 Photosensitivity, Cholestatic
jaundice,




Weight gain
 Variable (highest w Clozapine, OLZP)
Diabetes / Metabolic changes
 Atypicals > Typicals 9% when controlled for age.
Highest w Clozapine, OLZP.
Hyperprolactinemia
CVA’s/TIA’s and mortality when studied with AD

Modifiable Risk Factors Affected by
Psychotropics





Overweight/obesity
Insulin resistance
Diabetes/hyperglycemia
Dyslipidemia
Newcomer JW (2005), CNS Drugs 19(Supp 1):1-93

Nemeroff CB (1997), J Clin Psychiatry 58 Suppl 10:45-49; Kinon BJ et al. (2001), J Clin Psychiatry
62(2):92-100; Brecher M et al. (2004), American College of Neuropsychopharmacology. Poster 114;
Brecher M et al. (2004), Neuropsychopharmacology 29(suppl 1):S109; Package insert Geodon
(2005); Package insert Risperdal (2003); Package insert Abilify (2005)

Absorption
 Transporters, ATP dependent transporters, intestinal mobility, food, other
drugs (acid-base, competition for active transport, drug-drug binding)

Distribution
 Genes that encode proteins that bind drugs in the blood decreasing their
bioavailability. Lipophilic tissues absorb drugs and slowly releases them as
blood levels decrease

Metabolism





(some drugs may be pro-drugs)
Phase I- CYP (liver and intestine)
Phase II- UGT (liver)
Others enzymes- Thiopurine s-methyltransferase (TPMT) and Vitamin K
oxide receptor complex (VKORC1), etc.
Elimination
 Kidney function, P-glycoprotein i.e. efflux transporters (Intestinal
enterocytes)





Age—>65 have 3 fold
increase risk
Polypharmacy
Lack of awareness of
cytochrome (CYP) 450
system is a problem.
Most clinically
significant interactions
have been mediated
through P 450
Brown CS (2000), US
Pharmacist.

P450 Enzyme System
 Located in liver, kidney, intestine, lungs, brain
 Individual enzymes metabolizing >95% of all
drugs:
 Subtypes:1A2, 2B6, 2C9, 2C19, 2D6, 3A4
Relative Importance of Cytochrome p450 in Drug
Metabolism - adapted from Shimada T J
Pharmacol Exp Ther 1994

Drug interactions occur
during phase
1metabolism
 (oxidation, hydroxylation,
methylation)

Phase 2 metabolism
prepares the compound
for
 elimination by making it
water soluble (e.g.,
glucuronidation)

www.fda.gov./cder/drug/drugreactio
ns/default.htm.


7% of Caucasian population
have polymorphisms of CYP2D6
isoform
20-30% Asians CYP2C19
 Poor metabolizers (PM)
 Extensive metabolizers (EM)
 Ultra-rapid metabolism (URM)
Relative Importance of Cytochrome p450 in Drug
Metabolism - adapted from Shimada T J
Pharmacol Exp Ther 1994
Relative Importance of Cytochrome p450 in Drug Metabolism adapted from Shimada T J Pharmacol Exp Ther 1994

3A ¾ (50%)

SUBSTRATES
 B benzos
 E effexor
 S sertraline
 T tertiary amine,
trazadone
 C clozaril
 L luvox
 O OCP
 N Nefazadone
 E Erythromycin
INHIBITORS
 N nefazadone,
norfluoxetine
 F fluoxetine
 L luvox





R retrovirals
A antifungals
G grapefruit
E erythromycin
• 2D6 (20-25%)
•
SUBSTRATES
•
•
•
•
•
•
•
•
•
E effexor
A AP’s,
antiarrhythmics
T trazadone
C clozaril, codeine
R risperidone
O olanzapine
P prozac, paxil
S secondary
amines
INHIBITORS
•
•
•
P2 paxil, prozac
B buproprion
S sertraline
• 1A2 (10-15%)
•
•
SUBSTRATES
• C clozaril, coumadin,
caffeine
• H haldol
• A acetaminophen
• T tertiary amines,
theophyline
INHIBITORS
• L luvox
•
•
•
E erythromycin
C cipro, cimetidine
G grapefruit juice
Drugs Withdrawn For Excessive
Adverse Drug Reactions






Terfenadine (Seldane)—February 1998
Mibefradil (Posicor)—June 1998
Astemazole (Hismanol)—July 1999
Cisapride (Propulsid)—January 2000
Fluvoxamine (Luvox)—2005
All relate to P450 enzymatic interactions with
other drugs
 Drug Interactions
(2006)
Most Dangerous Psychotropic Drug
Interactions
 Meperidine and phenelzine
 Libby Zion reaction (serotonin syndrome)
 Paroxetine and buspirone
 SSRIs,TCAs, divalproex, metoclopramide,
sumatriptan, tramadol (Ultram), mirtazapine
(Remeron)
 Serotonin syndrome
 Lamotrigine (Lamictal) and valproate (Depacon)
 Stevens Johnson syndrome
Overlooked Causes of Drug Toxicity and
Interactions
 P450 enzyme competition (2D6)—inducers,
inhibitors
 Drug/diet interactions
 Grapefruit juice, tobacco, St. John’s Wort
 Drug/OTC interactions
 Dextromethorphan (Dexedrine) and SSRIs
 Additive side effects
 anticholinergic
 Orthostatic hypotension due to TCAs,
metoclopramide, BPH medications and
haloperidol (Haldol)
Organization helps
1.

Pattern recognition is the key
There are essentially only 3 groups of meds
2.

(antidepressants, mood stabilizers and
antispsychotics)
Try to remember what the classes of drugs are
3.

both the indications and side effects are similar
…Samuel Johnson



Acknowledgements
Review Course in
Psychiatry: Dr.
Charbonneau
Dr. Huntington’s 2007
psychopharm lecture