Download B2B Psychopharmacology

Psychopharmacology
What you need to know to survive the LMCC
and Internship
Khalid Bazaid, MD, FRCPC
Assistant Professor
Child & Adolescent Psychiatrist
Children’s Hospital of Eastern Ontario
March 23rd, 2017
Based on the 2014 lecture by Dr. Lisa McMurray and 2015/2016 lecture
by Dr. Khalid Bazaid
Faculty Disclosure
I have no financial relationships to
disclose relating to the subject
matter of this presentation
Objectives
To review:
• indications for
• mechanism of action
• side effects (remember not everyone gets
these)
• monitoring parameters
for the major classes of psychotropic
medications
To practice applying this knowledge
MCC Objectives for the Qualifying Examination
(with updates for DSM-5)
• Initiate pharmacologic treatment of
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–
–
ADHD
Agitation in Delirium
Dementia/Major Neurocognitive Disorder
Major Depressive Disorder
Manic Episode
Anxiety Disorders
Obsessive-Compulsive Disorder (formerly an anxiety
disorder)
– Substance withdrawal
– Substance Use disorders (e.g. nicotine replacement)
MCC Objectives for the Qualifying Examination
..Cont’d
• Judicious use of pharmacotherapy in
personality disorders
– Attention to risk of abuse, overdose
• Recognize Medication-Induced Movement
disorders
– e.g. dystonia due to antipsychotics
General Pharmacology strategies -1
1. Indication: Establish a diagnosis and identify the target
symptoms that will be used to monitor therapy response.
2. Choice of agent and dosage:
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•
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Select an agent with an acceptable side effect profile
Use the lowest effective dose.
Delayed response for many psych meds and drug-drug
interactions.
General Pharmacology strategies -2
1. Establish informed consent:
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•
•
The patient should understand the benefits and risks of the medication.
Document this discussion including patient’s understanding and
agreement.
In fertile women make sure to document teratogenicity discussion.
2. Implement a monitoring program:
•
Track and document compliance, side effects, target symptom
response, blood levels and blood tests as appropriate.
General Pharmacology strategies - 3
1. Management:
• Adjust dosage for optimum benefit, safety and
compliance.
• Use adjunctive and combination therapies if needed
however always strive for the simplest regimen.
• Keep your therapeutic endpoint in mind.
General Pharmacology strategies - 4
Bioavailability
• Amount of drug that reaches systemic
circulation unchanged
• Often used to compare one drug to another,
usually the higher the bioavailability, the
better.
General Pharmacology strategies - 5
Cytochrome P450
• Many process carried out by enzyme class
Cytochrome P-450
– high affinity for fat-soluble drugs
– involved in metabolism of most psychiatric
medications
– Example: SSRIs inhibitors of the subfamily P4502D6
General Pharmacology strategies - 6
Elimination
• Clearance: Total amount of blood, serum, or plasma from
which a drug is completely removed per unit time.
• Half-life: Time required for plasma concentrations of the
drug to be reduced by 50%.
• Only a few drugs eliminated by kidneys (lithium)
• Most excreted in the liver
– excreted in the bile and delivered to the intestine
– may be reabsorbed in intestine and “re-circulate” (up to
20%)
Pharmacokinetics: Cultural
Considerations
• 9% of whites - genetically defective P-4502D6
• Asian descent
– Metabolize ethanol to produce higher concentrations of
acetaldehyde (flushing, palpitations)
– Require 1/2 to 1/3 dose antipsychotics and more severe
side effects
• Cardiovascular effects of propranolol
– Asian descent - more sensitive
– African descent - less sensitive
General Pharmacology strategies
Phases of Drug Treatment
•
•
•
•
Initiation
Stabilization
Maintenance
Discontinuation
What is a ‘drug’?
• A very vague term
• all ingested substances alter bodily function
• ‘drug’ is reserved for things that have
pronounced effects when ingested in small
quantities
Basic classification of drug
actions
• Agonists stimulate or activate
• antagonists prevent
Ways that drugs can agonize
•
•
•
•
•
Stimulate release
receptor binding
inhibition of reuptake
inhibition of deactivation
promote synthesis
Ways that drugs can antagonize
• Block release
• receptor blocker
• prevent synthesis
Drug Interactions
• Synergism (e.g. alcohol + sedative)
• Induction of enzymes and increased
metabolism
• Inhibition of enzymes and delayed metabolism
• In vitro versus clinical significance
• FDA approval vs. clinical use
(“Off-label use”)
Selecting a Psychotropic Agent
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•
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Diagnosis/symptom complex
Patient’s prior response
Family member’s experience
FDA approved indication
Pharmacologic actions
Documented efficacy
Side effect profile
Insurance coverage/finances
Patient preference
Main Psychopharmacological Drugs
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Antidepressants
Mood stabilizers
Antipsychotics
Anxiolytics
Hypnotics
Cognitive enhancers
Psychostimulants
What is the most common excitatory
neurotransmitter in the brain?
•
•
•
•
•
a.
b.
c.
d.
e.
Serotonin
Glutamate
Norepinephrine
GABA
Dopamine
Antidepressants
• Most antidepressants block the re-uptake of
a neurotransmitter of one or more of the
bioamines: serotonin, norepinephrine,
dopamine.
• SSRIs - selective to the serotonin
General guidelines for antidepressant use
• Antidepressant efficacy is similar so selection is based
on past history of a response, side effect profile and
coexisting medical conditions.
• There is a delay typically of 3-6 weeks after a
therapeutic dose is achieved before symptoms
improve.
• If no improvement is seen after a trial of adequate
length (at least 2 months) and adequate dose, either
switch to another antidepressant or augment with
another agent.
Indication of Antidepressants
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Depressive Disorders
Bipolar Disorders
Obsessive-Compulsive Disorders
Panic Disorders
Eating Disorders
Somatic Symptom Disorders
Posttraumatic Stress Disorder
Alcohol and Drugs Withdrawal Symptoms
Pain disorders (DSM-5 Somatic Symptom Disorder
with predominant pain)
• Enuresis
• Narcolepsy
Neurotransmitter Reuptake Inhibition
and Binding Affinity to Receptors
Receptors:
SE Serotonergic
NE Noradrenergic
M Muscarinic
H Histaminic
-N alpha
noradrenergic
Antidepressants:
Monoamine Reuptake Inhibitors
1st Generation of Antidepressants (TCA, TeCA)
Generic Name
Trade Mark
Doses (mg)
amitriptyline
AMITRIPTYLIN
75-200
nortriptyline
NORTRILEN
50-150
imipramine
MELIPRAMIN
75-250
clomipramine
ANAFRANIL,
HYDIPHEN
75-225
dosulepin
PROTHIADEN
100-300
dibenzepine
NOVERIL
240-720
maprotiline
LUDIOMIL,
MAPROTILINE
75-150
Mechanism of
Efficacy
Inhibition of
Serotonin
and/or
Norepinephrine
Reuptake
Followed by
Increase of their
Concentrations
in Synaptic Cleft
Tricyclic antidepressants (TCA):
Mechanism of Action
3° amines (eg amitriptyline, imipramine, doxepine)
2° amines (eg nortriptyline, desipramine)
• Originally developed as treatment for schizophrenia (similar
3-ringed chemical structure); found ineffective for psychosis
but helpful for depression.
• Therapeutic effects and side effects from blocking Serotonin,
Norepinephrine & Dopamine Reuptake
• Some also have 5HT2 blocking ability (blocks sex & sleep
side effects)
• Side effects from blocking H1 histamine receptors,
muscarinic receptors, alpha one adrenergic receptors
TCAs
• Very effective but potentially unacceptable side effect
profile
i.e.
antihistaminic,
anticholinergic,
antiadrenergic
• Lethal in overdose: can lead to seizures and arrhythmias
due to blockade of ion channels
• Can cause QT lengthening even at a therapeutic serum
level
• Desipramine and Notrtriptyline:
 Secondary TCAs
 Primarily block norepinephrine
 Side effects are the same as tertiary TCAs (Imipramine,
Amitriptyline, Doxepin, Clomipramine), but generally are less
severe
TCA: Side Effect Profile
• Antihistamine – weight gain & sedation
• Anticholinergic – dry mouth, constipation,
ocular side effects and urinary hesitancy
• Anti-alpha adrenergic – dizziness, orthostatic
hypotension
TCA: Rare but Dangerous Side Effects
•
•
•
Torsades de Pointes (due to blockade of fast
sodium channels)
• EKG – rule out bradycardia and prolonged
QTc
• Lytes – rule out electrolyte imbalance
• Make sure not on type 1 or 3 antiarrythmic
drugs
SIADH
Serotonin Syndrome
Antidepressants
Monoamine Oxidase Inhibitors (MAOIs)
• Action: Inhibit enzyme responsible for the
metabolism of serotonin, dopamine,
norepinephrine, and tyramine.
• Increases levels of norepinephrine and
serontonin in the CNS
• Interacts with food -- low tyramine diet
(Table 18.3)
MAO Inhibitors
Non Selective and Irreversible: (IMAO A, IMAO B)
phenelzine
NARDIL
isocarboxazid
MARPLAN
nialamide
NIAMID, NUREDAL
tranylcypromine
PARNATE
Selective and Reversible
MAO A
moclobemide
AURORIX
brofaromine
CONSONAR
toloxatone
MAO B
selegiline (L-deprenyl)
HUMORYL
SEPATREM, JUMEX
MAOI: Mechanism of Action
Monoamine oxidase inhibitors:
“the classics” (phenylzine/nardil, tranylcypromine/parnate)
Reversible inhibitor: (moclobemide/mannerix)
HISTORY:
• The first clinically effective antidepressants
• Originally, an anti-tuberculosis drug, found to decrease
comorbid depression
• Irreversibly bind MAO (2 wks) & destroy its function,
therefore decrease monoamine breakdown, increasing
5HT, NE & DA
MAOI: Side Effect Profile
• Side effects related to increase in serotonin
norepinephrine & dopamine (see SSRI’s & NDRI’s)
• Orthostatic hypotension
MAOI: Rare but Dangerous Side Effects
• Hyperthermia i.e.Serotonin Syndrome
• even more susceptible than with other serotonergic
antidepressants; need to avoid anything that has serotonergic
effects such as antidepressants and opioids)
• When you see an MAOI, get a pharmacy consult, the patient
should consult their pharmacist about any over - the – counter
medications
• Hypertensive crisis
• Consult the dietician Re: MAOI diet
• Patients need to avoid all foods with tyramine (aged foods such as
aged cheeses and wines or tap beer) and any medications with
noradrenergic effects (cold remedies, stimulants etc)
• Hepatotoxicity
• Blood dyscrasias
Hypertensive Crisis
• Norepinephrine (NE) is the amine most closely linked with
control of blood pressure
• MAO normally inactivates norepinephrine (NE)
• Tyramine, an amine present in aged foods, causes release
of norepinephrine (NE)
• In the presence of MAOI, this increased NE cannot be
broken down, resulting in a hypertensive crisis
Serotonin Selective
Reuptake Inhibitors
(SSRI)
3rd Generation of Antidepressants
Generic Name
Trade Mark
Mean Doses
(mg)
Mechanism
SSRI
fluvoxamine
FEVARIN
100-300
fluoxetine
DEPREX, DEPRENON,
PROZAC, PORTAL,
FLOXET, FLUXONIL,
MAGRILAN
20-60
citalopram
SEROPRAM, CITALEC,
CEROTER, PRAM
20-60
escitalopram
CIPRALEX
10-20
paroxetine
SEROXAT, PAROLEX,
APO-PAROX, REMOD
20-60
sertraline
ZOLOFT, SERLIFT,
ASENTRA, STIMULOTON
50-200
Selective
Serotonin
Reuptake
Inhibition
SSRIs
• The exact mechanism of SSRIs is
unknown.
• SSRIs are believed to increase the
extracellular level of the neurotransmitter
serotonin by limiting its reabsorption
into the presynaptic cell, increasing the
level of serotonin in the synaptic
cleft available to bind to the postsynaptic
receptor.
• They have varying degrees of selectivity
for the other monoamine transporters,
with pure SSRIs having only weak
affinity
for
the
norepinephrine
and dopamine transporters.
Which of the following is NOT a
common side effect of SSRI’s?
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a.
b.
c.
d.
e.
Nausea
Headache
Rigidity
Anxiety
Sleep disruption
Side Effects -- SSRIs
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Headache
Anxiety
Transient nausea
Vomiting
Diarrhea
Weight gain
Sexual dysfunction
SSRI: Rare but Dangerous Side Effects
• UGI bleeding (platelet dysfunction), esp. in
combo with NSAID’s or other bloodthinning agents
• SIADH
• Osteoporosis and fractures in the elderly
• Serotonin syndrome
• Increase suicide in children and adolescents
SSRI discontinuation syndrome
• Incidence: 20% after 6 weeks of use
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Flu-like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbances
Hyperarousal (agitation/anxiety)
Prevent with slow taper
Serotonin Syndrome: HARMED
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Hyperthermia
Agitation/Autonomic instability
Rigidity/Reflexes increased
Myoclonus/tremors
Encephalopathy
Diaphoresis
4th Generation of Antidepressants
Dual acting antidepressants
Mixed reuptake inhibitors
Generic Name
Trade Mark
Mean Doses
(mg)
Mechanism
SNRI
venlafaxine
EFECTIN
75-375
venlafaxine ER EFECTIN ER
(extended
relesase)
75-225
milnaciprane
50-100
IXEL,
DALCIPRAN
Serotonin and
Norepinephrine
Reuptake Inhibition
DNRI
bupropione
WELLBUTRIN
ZYBAN
150-300
Dopamine and
Norepinephrine
Reuptake Inhibition
Norepinephrine & Dopamine Reuptake
Inhibitor:Mechanism of Action
(Bupropion/Wellbutrin)
• Blockade of norepinephrine and dopamine
reuptake pumps, leads to similar cascade as with
SSRI’s
NDRI: Side Effect Profile
• Seizures (not with extended release formulations &
following correct dosing; contraindicated with Bulimia
or electrolyte disturbances)
• Headache, Hypertension (SNS activation)
• Agitation (mood and psychomotor circuits) and
• Anticholinergic (relative decrease in parasympathetic
tone)
• Rash
• Emesis, decreased appetite and weight loss (SNS
activation)
• Sleep disruption, Shaking and Sweating (sleep and
psychomotor circuits and SNS activation)
Serotonin & Noradrenergic reuptake
Inhibitors: Mechanism of Action
(Venlafaxine/Effexor, Desvenlafaxine/Pristiq, Duloxetine/Cymbalta)
• Blockade of serotonin reuptake at lower dose
range
• Blockade of serotonin and norepinephrine
reuptake in mid dose range
• Blockade of serotonin, norepinephrine and
dopamine reuptake at very high dosages
SNRI: Side Effect Profile
• As with SSRI’s in lower to mid dose range
• As with NDRI in mid to high dose range
SNRI: Rare but Dangerous Side Effects
• As with SSRI’s
4th Generation of Antidepressants
Generic Name
Trade Mark
Mean Doses
(mg)
Mechanism
Blockade of 2-adrenoceptors
mianserin
LERIVON,
MIABENE
60-90
mirtazapine
REMERON,
ESPRITAL,
REMERON
sol. tab.
15-45
Increasing Synthesis and
Releasing of
Norepinephrine, Blockade
Alpha-2 Adrenoceptors
on Serotonergic Neurons
and Increasing
Production and Releasing
of Serotonin
Other Monoamine Reuptake Inhibitors
hypericum
perforatum
JARSIN
900
Weak Inhibitor of NA, 5HT, DA
NaSSA: Mechanism of Action
• Blocks Alpha 2 autoreceptors on norepinephrine neurons &
heteroreceptors on Serotonin neurons, causing more NE & 5HT to be
released
• NE neurons from the locus coeruleus innervate midbrain raphe 5HT
neurons. Therefore, increased NE causes a further increase in 5HT
release
• Blocks 5HT2 receptors, having an anxiolytic effect & blocking sleep
& sexual side effects
• Blocks 5HT3, blocking GI side effects from peripheral receptors &
from brainstem chemoreceptor trigger zone
• Blocks H1 histamine receptors, causing sedation & weight gain
NaSSA: Side Effect Profile
• Weight gain (H1 blockade)
• Anticholinergic (relative decrease in parasympathetic tone)
– very weak effect
• Drowsiness (H1 blockade)
• Equilibrium
NaSSA: Rare but Dangerous Side Effects
• Neutropenia
• Serotonin syndrome
• Hepatotoxicity
• SIADH
• QT prolongation (Health Canada, 28 March 2014,
post-marketing)
SARI: Mechanism of Action
Serotonin 2A antagonists/reuptake inhibitors (Trazodone/Desyrel)
• Primarily blocks 5HT2A, reducing sexual dysfunction &
sleep disruption & increasing effect of 5HT1A stimulation
(5HT2A & 5HT1A oppose one another’s actions in several
ways)
• Weak 5HT reuptake inhibitor, increasing 5HT stimulation
of 5HT1A (therapeutic effects)
• H1 blockade causes sedation
• Alpha One blockade leads to orthostatic hypotension
SARI: Side Effect Profile
• Orthostatic hypotension
• Sedation
• Rare but Dangerous Side Effects:
– Serotonin syndrome
– Priapism
Starting Antidepressants: General Guidelines
• Start with a reuptake inhibitor or mirtazapine (not a TCA or
MAOI)
• Start at lowest possible dose (half of this with anxiety and in
the elderly and medically frail)
• Increase by this increment about every five half lives (or
about once a week) until one of the following endpoints:
• Intolerable side effects
• Full response
• Maximum dose
• Continue to monitor for therapeutic effects, side effects and
safety
• How you use them is more important than which one you
choose
Course of Recovery From
Depression
Response
2-3 weeks:
3-4 weeks:
6-8 weeks:
Improved
sleep,
appetite,
vegetative
shifts
objective
improvement
energy
suicidal
ideation may 
subjective
improvement
Choice of Initial Antidepressant in Adults
• There is comparable efficacy between and within classes of medication,
therefore, initial selection is based on:
• Symptom profile
• Side effect profile in relation to the individual patient
• Patient preference
• Cost
• History of previous response of the patient or family members
• Comorbid psychiatric or medical illnesses
• Potential drug-drug interaction
• The BEST antidepressant is the one that a patient will
actually take acutely and for the long haul…and one that you
know well
Treatment choices in children
• Concerns were raised about the safety of antidepressants
(Paroxetine and Venlafaxine) in children and youth in 2004
• Further metaanalyses and epidemiologic studies now confirm
that antidepressants in children and youth are safe with close
(weekly) monitoring.
• Problems with Venlafaxine and Paroxetine may have been
related to poor adherence and discontinuation symptoms
Choice of Initial Treatment in children/youth
• Mild to moderate depression:
– Start with psychotherapy or non-medication interventions
as first line
– Second line is to add medication; best evidence is for
Fluoxetine; other SSRI’s could be considered next
• Moderate to severe depression:
– First line is to consider medication but depending on
patient/family preference, may also start with
psychotherapy or monitoring
• Note that the clinical presentation in children and youth can
change quickly; they may appear severely depressed one week
then by the next week be in a new relationship and everything
is better…
FDA Suicide Warning
• Black Box Warning
• All antidepressants
• Increased risk of suicidal thinking and
behaviors
• Affects 18-24 y/o
Antidepressant-Induced Sexual Dysfunction
Desire  Decreased libido
Arousal  Difficulties w/ erection/lubrication
Orgasm  Delayed orgasm/anorgasmia
Management
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–
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–
Spontaneous resolution
Decrease dose
Change agent
Adjunctive medication
Selective PDE5 Inhibitor
Cyproheptadine (Periactin)
Bupropion (Wellbutrin)
Goals of antidepressant therapy
• REMISSION of symptoms and maintaining that level of
improvement in order to prevent relapse and recurrence
• Rate of relapse is significantly less for patients who
achieve full remission of symptoms
• Patients who have been ill longer tend to be more
treatment resistant; there is also evidence of hippocampal
atrophy with prolonged illness, leading to the concept of
disease progression and the hope that this can be modified
by treating all mood episodes to the point of remission
Treatment Resistant Depression
1. Is the patient medication compliant?
2. Is the diagnosis correct?
3. Change agents-Within/between classes
4. Antidepressant combinations
-Complementary mechanisms of action
5. Add psychotherapy
6. Augmentation strategies
– Lithium
– Antipsychotic
Thyroid hormone
Estrogen
7. ECT/Focal Brain Stimulation
Recommended Site
http://psychopharmac
ologyinstitute.com/a
ntidepressants/
At which dose level does Venlafaxine/Effexor XR
typically begin to have a noradrenergic effect?
•
•
•
•
a.
b.
c.
d.
75mg
150mg
225mg
300mg
Which of the following receptors does
Mirtazepine/Remeron NOT block?
•
•
•
•
•
a.
b.
c.
d.
e.
Histamine
5HT1
5HT2
5HT3
Alpha 2
Fluoxetine (Prozac)
• Pros
– Long half-life so decreased incidence of discontinuation
syndromes. Good for pts with medication noncompliance
issues
– Initially activating so may provide increased energy
– Secondary to long half life, can give one 20mg tab to taper
someone off SSRI when trying to prevent SSRI
Discontinuation Syndrome
• Cons
– Long half life and active metabolite may build up (e.g. not a
good choice in patients with hepatic illness)
– Significant P450 interactions so this may not be a good choice
in pts already on a number of meds
– Initial activation may increase anxiety and insomnia
– More likely to induce mania than some of the other SSRIs
Citalopram (Celexa)
• Pros
– Low inhibition of P450 enzymes so fewer drug-drug
interactions
– Intermediate ½ life
– Cons
• Cons
– Dose-dependent QT interval prolongation with doses of
10-30mg daily- due to this risk doses of >40mg/day not
recommended!
– Can be sedating (has mild antagonism at H1 histamine
receptor)
– GI side effects (less than sertraline)
Escitalopram (Cipralex)
• Pros
– Low overall inhibition of P450s enzymes so fewer drugdrug interactions
– Intermediate 1/2 life
– More effective than Citalopram in acute response and
remission
• Cons
– Dose-dependent QT interval prolongation with doses of
10-30mg daily
– Nausea, headache
Sertraline (Zoloft)
• Pros
– Very weak P450 interactions (only slight CYP2D6)
– Short half life with lower build-up of metabolites
– Less sedating when compared to paroxetine
• Cons
– Max absorption requires a full stomach
– Increased number of GI adverse drug reactions
Fluvoxamine (Luvox)
• Pros
– Shortest ½ life
– Found to possess some analgesic properties
– Cons
• Cons
– Shortest ½ life
– GI distress, headaches, sedation, weakness
– Strong inhibitor of CYP1A2 and CYP2C19
Paroxetine (Paxil)
• Pros
– Short half life with no active metabolite means no buildup (which is good if hypomania develops)
– Sedating properties (dose at night) offers good initial
relief from anxiety and insomnia
• Cons
– Significant CYP2D6 inhibition
– Sedating, weight gain, more anticholinergic effects
– Likely to cause a discontinuation syndrome
• Pros
Venlafaxine (Effexor)
– Minimal drug interactions and almost no P450 activity
– Short half life and fast renal clearance avoids build-up
(good for geriatric populations)
• Cons
– Can cause a 10-15 mmHG dose dependent increase in
diastolic BP.
– May cause significant nausea, primarily with immediaterelease (IR) tabs
– Can cause a bad discontinuation syndrome, and taper
recommended after 2 weeks of administration
– Noted to cause QT prolongation
– Sexual side effects in >30%
Desvenlafaxine (Pristiq)
• Pros
– Minimal drug interactions
– Short half life and fast renal clearance avoids build-up
(good for geriatric populations)
• Cons
– GI distress in 20%+
– Dose related increase in total cholesterol, LDL and
triglycerides
– Dose related increase in BP
Duloxetine (Cymbalta)
• Pros
– Some data to suggest efficacy for the physical symptoms
of depression
– Thus far less BP increase as compared to venlafaxine,
however this may change in time
• Cons
– CYP2D6 and CYP1A2 inhibitor
– Cannot break capsule, as active ingredient not stable
within the stomach
– In pooled analysis had higher drop out rate
• Pros
Novel antidepressants
Mirtazapine (Remeron)
– Different mechanism of action may provide a good
augmentation strategy to SSRIs. Is a 5HT2 and 5HT3 receptor
antagonist
– Can be utilized as a hypnotic at lower doses secondary to
antihistaminic effects
• Cons
– Increases serum cholesterol by 20% in 15% of patients and
triglycerides in 6% of patients
– Very sedating at lower doses. At doses 30mg and above it can
become activating and require change of administration time to
the morning.
– Associated with weight gain (particularly at doses below 45mg
Which mood stabilizer can reduce the risk
of suicide in Bipolar Disorder?
•
•
•
•
a.
b.
c.
d.
Valproic Acid/Epival
Lamotrigine/Lamictal
Lithium
Carbamazepine/Tegretol
The Heterogeneity of Bipolar Disorder
Taken from:
http://www.psychosisbipolar.com/information-aboutpsychoses-57.htmlTaken
Mood Stabilizers: Indications
• A heterogeneous group of medications
• Used to treat diverse conditions, including
•
•
•
•
•
•
Bipolar Disorder
Migraine or cluster headaches
Chronic aggression or impulsivity
Seizure disorders
Pain conditions (TGN, migraine)
Lithium reduces suicidal risk in Bipolars and
augments antidepressants in MDD
Goals of treatment in BD
• Treat to complete remission
• It has been theorized that under-treated discrete
depressive and manic episodes may progress to
mixed and dysphoric episodes, rapid cycling and
treatment resistance
• The hope is that recognition and full treatment of
mood episodes may prevent progression to more
difficult mood states
Choice of Treatment in BD
(Bipolar Disorder)
•
First line for acute mania:
• Lithium,
• Valproic Acid
• atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone,
aripiprazole lurasidone)
– taper and discontinue antidepressants
•
First line for acute bipolar depression:
• Lithium
• lamotrigine
• quetiapine
• Lurasidone (July 2013)
– do not use antidepressant monotherapy
•
First line for maintenance therapy:
– Lithium
– Valproic acid
– Lamotrigine
– Atypical antipsychotics quetiapine, risperidone LAI and Olanzapine
Lithium: Mechanism of Action
• MOA is unclear
• Thought to be involved in:
• Modulating second messenger systems (ie G protein-coupled receptors,
through which most hormones and neurotransmitters mediate their
effects) which leads to:
•
•
•
•
Increasing GABA activity
Reducing glutamate activity
Stabilizing catecholamine receptors
Blocking the effects of some hormones (eg. ADH and TSH) on end organs
• Works in acute bipolar mania, depression and maintenance
phases
• Decreases suicide, deliberate self harm and death from all
causes in patients with mood disorders
Lithium: Side Effect Profile
• Lethargy
• Insipidis (diabetes insipidis)
• Tremor/Teratogen (increased risk Ebstein’s
anomaly (0.1% vs 0.005%) in first trimester)
• Hypothyroid
• Increased weight
• Vomiting, nausea, GI
• Miscellaneous: EKG changes (T wave flattening
or inversion, sick sinus syndrome), acne, hair loss,
hypercalcemia
Lithium: Toxicity
• Narrow therapeutic index!!!
• Anything that affects water and electrolyte imbalance can
contribute to Lithium toxicity (CAUTION with flu, dehydration,
meds)
• Levels are increased by NSAIDS, diuretics, ACE inhibitors,
tetracycline, anticonvulsants
• Levels are decreased by caffeine and salt
Lithium: Toxicity
• There is delayed distribution and elimination in the brain
relative to serum therefore early signs are peripheral and later
signs are central unless high level is chronic, in which case
peripheral and central symptoms will occur simultaneously
• Peripheral symptoms: nausea, vomiting, cramping, diarrhea
• Central symptoms: tremulousness, hyperreflexia, ataxia,
mental status changes, coma, seizures
• Can lead to irreversible neurotoxicity including cognitive
impairment, peripheral neuropathy and cerebellar dysfunction
• Hospitalize for levels >2.0 or based on clinical symptoms
Lithium: Initial Work-up
•
•
•
•
Lytes, BUN, Cr (renally excreted)
Calcium
TSH (5% hypothyroidism)
EKG with rhythm strip (contraindicated with sick sinus
syndrome)
• B-hcg
• Metabolic baseline including baseline weight and BMI;
consider checking for diabetes/pre-diabetes and
hypercholesterolemia in those who are overweight (BMI
25-30) or obese (BMI>30)
Lithium: Ongoing Monitoring
• Lithium level every five days until steady state is reached then at
3-6 months, with signs of dehydration or toxicity or with change
in medications or salt intake
• Repeat kidney functions, TSH and EKG every 6-12 months,
Calcium
• Monitor weight and BMI during treatment and re-check for
diabetes/pre-diabetes and hypercholesterolemia if >5% weight
gain
• Avoid during pregnancy.
Lithium : Rx
• Adult
• Acute mania about 1800mg/day (bid-tid dosing)
• Acute mania level 1.0 – 1.5
• Maintenance usually about 900-1200 mg/d; give at hs
for renal protection
• Maintenance level 0.6-1.0
• Geriatric
• Dosing 150 – 600 mg/d (bid dosing)
• Level 0.4 – 0.8
• For maintenance, give at hs for renal protection
Valproic Acid: treatment effects
• Treats bipolar mania
• First line for bipolar depression in
combination with lithium or
SSRI/bupropion
• Second line monotherapy for bipolar
depression
• Indicated for maintenance phase
Valproic Acid: Acute Side Effect Profile
STUN
•
•
•
•
Sedation (31%)
Tremor (10-29%)
Unsteadiness (dizziness)
Nausea (20%) /GI
Valproic Acid: longer term side effects
• On the surface:
– Acne , hair loss
• Under the surface:
– weight gain, edema
• Systemic:
– thrombocytopenia
– liver dysfunction +/- elevated ammonia levels
– reproductive changes including menstrual irregularities
(up to 45%), PCOS, teratogenicity (5-15%)
• Avoid use in women of childbearing age
Valproic Acid: Initial Work-up &
Ongoing Monitoring
Initial
• CBC + LFT’s
• Epival level every 3-4 days until steady state reached
• Metabolic baseline including baseline weight and BMI; consider
checking for diabetes/pre-diabetes and hypercholesterolemia in those
who are overweight (BMI 25-30) or obese (BMI>30)
Ongoing
• Repeat tests monthly x 6 months then Q6mos or if symptoms develop
• Monitor weight and BMI during treatment and re-check for
diabetes/pre-diabetes and hypercholesterolemia if >5% weight gain
Valproic Acid: Rx Reference only
• Starting dose:
• 250 qhs (geriatrics)
• 250 bid-tid (adults)
• 15-30 mg/kg/day in bid dosing for acute mania in adults
• Levels: 350 – 800 umol/l
Lamotrigine: Treatment effects
• Treats bipolar depression (modest effect)
• First line maintenance treatment
Lamotrigine: Side Effect Profile
• Rash – 0.3% adults / 1% in children. With slow titration
risk was
reduced to 0.01% comparable to other
anticonvulsants. Can develop into Stevens-Johnson
Syndrome (increased risk with Valproate)
• Activation (3-8%), Ataxia
• Spaced out (cognitive slowing), Sedation, Sleep
disturbances
• H/A, Hypersensitivity reactions
Lamotrigene: Rx
• Start with 25 mg/d
• Double the dose every 2 weeks
• Usual maintenance dose is 200 mg in 2 divided doses
(reached by week six)
Atypical Antipsychotics:
Olanzapine and Quetiapine
• All atypical antipsychotics are indicated to
treat bipolar mania
• Quetiapine is first line monotherapy for
bipolar depression; so is Lurasidone
• Olanzapine, Quetiapine, Aripiprazole, and
Risperidone LAI are first line maintenance
treatments
Schizophrenia
• Affects about 1/100 people
• Begins in 20’s
• Often triggered by stress, illness, etc. but
there’s also a genetic predisposition
The Disease Process
Positive Symptoms
• Hallucinations
• Delusions
• Disorganization
• Agitation
Negative symptoms
• Blunted affect
• Emotional withdrawal
• Social withdrawal
• Anhedonia
Beyond dopamine
New generation antipsychotics affect
serotonin as well
Glutamate antagonists can help with negative
symptoms
Schizophrenia likely affects a host of systems
perhaps by disturbing a fundamental balance
among neurotransmitters
Overview of Antipsychotics
Conventional Antipsychotics
Chem. Group
Generic Name
Trade Mark
chlorpromazine
CHLORPROMAZIN,
LARGACTIL,
PLEGOMAZIN,
MEGAPHEN,
THORAZIN
levomepromazine
TISERCIN, NOZINAN
thioridazine
THIORIDAZIN,
MELLERIL
periciazine
NEULEPTIL
chlorprothixene
CHLORPROTHIXEN,
TRUXAL
clopenthixol
CISORDINOL,
CLOPIXOL
Dose (mg)
200-800
50-400
Phenothiazines
Thioxanthes
100-600
10-40
100-600
20-100
Overview of Antipsychotics
Conventional Antipsychotics
Chem. Group
Generic Name
Trade Mark
Dose (mg)
16-24
flufenazine
PERFENAZIN, TRILAFON,
PERATSIN
PROCHLORPERAZIN,
STEMETIL
MODITEN
trifluoperazine
STELAZIN
10-50
flupenthixol
FLUANXOL
6-18
haloperidol
melperone
HALOPERIDOL, HALDOL,
APO-HALOPERIDOL
BURONIL
pimozide
ORAP
2-10
Diphenylbutyl
piperidines
fluspirilen
IMAP
2-10
penfluridol
SEMAP
2-60
Perathiepines
oxyprothepin
MECLOPIN
5-20
perfenazine
Phenothiazines
Thioxanthenes
Butyrophenones
prochlorperazine
20-80
2-16
2,5-10
50-300
Antipsychotics
of the 2nd Generation
Generic Name
Trade Mark
Dose (mg)
D2, D3 selective antagonists
sulpiride
DOGMATIL, PROSULPIN
50-1200
amisulpride
SOLIAN, DENIBAN
50-1200
SDA
risperidone
RISPERDAL, RISPEN,
RISPERDAL QUICKLET
4-8
ziprasidone
ZELDOX
40-160
sertindole
SERDOLECT
12-20
MARTA
clozapine
LEPONEX
200-600
olanzapine
ZYPREXA i.m. inj. 10 mg
5-20
quetiapine
SEROQUEL
300-600
zotepine
ZOLEPTIL
75-300
Antipsychotics
of the 2nd Generation
Efficacy
1. Positive symptoms are influenced significantly better than
placebo, and equally or more then by the classical
antidopaminergic neuroleptics.
2. Negative symptoms are reduced significantly better than by
placebo or classical antidopaminergic neuroleptics.
3. Affective symptoms are influenced better than by placebo or
classical antidopaminergic neuroleptics.
4. They significantly reduce or prevent the cognitive
impairment. The reduction is higher in comparison to
classical antidopaminergic neuroleptics.
5. The treatment resistant patients with schizophrenia are
improved significantly better than by placebo and at least
equally as by clozapine.
6. Maintenance treatment is more effective than maintenance
on placebo and at least as effective as maintenance on
classical neuroleptics.
Antipsychotics of the
generation
Generic Name
název
Trade Mark
Dose (mg)
rd
3
Mechanism of Efficacy
Dopamine-serotonin
stabiliser
aripiprazol
ABILIFY
15-30
Parcial agonist of D2
and 5-HT1A receptors
Antagonist of 5-HT2A
receptors
Depot Antipsychotics
Generic Name
Trade Mark
Mean Dose
(mg)
flufenazin
MODITEN DEPOT
25
oxyprothepin
MECLOPIN
25
haloperidol
HALDOL DEPOT
flupenthixol
FLUANXOL DEPOT
zuclopenthixol
CISORDINOL DEPOT
fluspirilen
IMAP
risperidone
RISPERDAL CONSTA
100
Interval
14-28 days
40
200
6
7 days !!
20-30
14 days
Rapid Tranquilizers
pro dosi (mg)
pro die (mg)
chlorpromazin
100-200
800-1200
levopromazin
(TISERCIN)
50-100
500-600
haloperidol
5-10
40-100
chlorprothixen
100-150
500-600
zuclopenthixol
50-150
(CISORDINOL ACUTARD)
(24-72 hours)
tiapride
(TIAPRIDAL)
600-1200
Typical Antipsychotics: Side effects
High potency
EPS
Haldol
Loxapine
Perphenazine
Low potency
Chlorpromazine
QT prolongation with pimozide, CPZ
Antihistamine
AntiAlphaAdrenergic
Anticholinergic
Antipsychotics: Indications
•
•
•
•
Psychotic illness
Delirium
Mood disorder with psychosis
Severe agitation or aggression
Typical Antipsychotics:
Mechanism of action
• D2 blockade
• Produces antipsychotic effect in the mesolimbic pathway
• Causes worsening of negative and cognitive symptoms in the
mesocortical pathway, where a dopamine deficit is thought to
cause these symptoms
• Causes EPS (dystonia, dyskinesia, akathesia, parkinsonism) in
the nigrostriatal pathway
• Causes increased prolactin in the tuberoinfundibular pathway
(gynecomastia, galactorrhea and sexual dysfunction)
FDA Approved Indications for Atypical Antipsychotics
Indication
OLA
RIS ILO QUE
Schizophrenia
Schizoaffective
Disorder
X
X
X
X
Bipolar
Mania/Mixed
X
X
Bipolar
Depression
X
X
Adjunct in
MDD
X
X
ZIP
ARI ASEN
X
X
X
X
X
X
X
X
X
OLA = Olanzapine, RIS = Risperidone, ILO = Iloperidone, QUE = Quetiapine,
ZIP = Ziprasidone, ARI = Aripiprazole, ASEN = Asenapine
Features of
Atypical Antipsychotics
• Block both D2 and 5HT2A
• Cause less EPS than typical antipsychotics
• Improve positive symptoms as well as
typical antipsychotics
Atypical Antipsychotics:
Mechanism of action
• 5HT2A, when stimulated, normally stops
dopamine release; when this is blocked, it
causes dopamine release
• The different dopamine pathways have
varying amounts of D2 and 5HT2A
receptors
Atypical Antipsychotics:
Side Effects
Less effects on:
• EPS, negative symptoms and cognition
A different set of concerns:
• Weight gain (get baseline weight)
• Akathisia
• Sedation
• Hyperglycemia/Hyperlipidemia(baseline fasting lipids
and glucose)
• Dizziness (orthostatic hypotension; check BP)
• In dementia increase mortality and risk of
cardiovascular events
• Risk of agranulocytosis and seizure (dose dependent)
with Clozapine
Atypical (2nd Generation) Antipsychotics
Side Effect
HL
CPZ
CLZ
RIS
OLZ
QTP
ZIP
-
+++
++++
-
+++
-
-
+++++
+++
+
++
+
+
++
Sedation
+
++++
+++++
+
+++
+++
++
Orthostasis
+
+++
++++
+
+
+
+
Weight gain
+
+++
++++
++
+++
+
-
Lipid increase
-
??
+++
??
++
??
-
+++
++
-
+++
+
-
+
Anticholinergic
EPS
Prolactin elevation
HL=haloperidol (Haldol), CPZ=chlorpromazine (Thorazine), CLZ=clozapine (Clozaril),
RIS=risperidone (Risperdal), OLZ=olanzapine (Zyprexa), QTP=quetiapine (Seroquel),
ZIP=ziprasidone (Geodon)
(Taken from: Jam, MW. Advances in the treatment of psychosis:
a multidisciplinary continuing education program. Power-Pak CE, New York, NY 2001, p. 8.)
Metabolic Syndrome & Atypical Antipsychotics
Medication
Clozapine
Olanzapine
Quetiapine
Risperidone
Aripiprazole
Ziprasidone
Weight Gain
+++
+++
++
++
0
0
↑FBS
+++
+++
++
++
0
0
Risk of adverse effects at therapeutic doses:
0 = None, ++ = Sometimes, +++ = Frequently
J. Clin. Psych 2004: 66; 267-272
↑ Lipids
+++
+++
++
++
0
0
Atypical Antipsychotics:
Monitoring
• Baseline personal and family history of vascular
risk factors
• Obtain baseline weight and calculate BMI; BMI
monthly for three months and then 3x per year
• Baseline waist circumference at the umbilicus, BP,
fasting glucose and lipid profile; repeat at 3
months and then annually
Neuroleptic Malignant
Syndrome
• Antipsychotic use (+) fever (+) rigidity (+) 2
others of:
•
•
•
•
•
Fever
Encephalopathy (neuro s/s or change in mental status)
Vital signs unstable
Elevated CPK/ WBC
Rigidity
Which of these is the most prominent side
effect of atypical antipsychotics?
•
•
•
•
a.
b.
c.
d.
Rigidity
Dystonia
Dyskinesia
Akathisia
Which of the following is an example of a low
potency typical antipsychotic?
•
•
•
•
•
a.
b.
c.
e.
f.
Haloperidol (Haldol)
Pimozide (Orap)
Olanzapine (Zyprexa)
Clomipramine (Anafranil)
Chlorpromazine (Thorazine)
Which is NOT an indication for the
use of Benzodiazepines?
•
•
•
•
•
a.
b.
c.
d.
e.
Catatonia
Long term hypnotic
Mania
Alcohol withdrawal
Anxiety
Benzodiazepine Anxiolytics
Indication:
• States of Anxiety
• Sleeplessness
• Withdrawal Symptoms
• Depressive States
• Epilepsy
• Convulsions
• Tetanus Neonatorum
• Extrapyramidal Undesirable Side Effects of Antipsychotics
• Premedication in Anaestesiology
• Panic States (Alprazolam, Bromazepam, Clonazepam in High
Doses)
• Algidic Syndromes (Stomatodynie, Neuralgie Trigemini,
Cephalgia)
Anxiolytics
Generic Name
Trade Mark
Form
Mean Doses (mg)
 Propandiol Derivates
guaiphenesine
GUAJACURAN
drg. 200,400mg
inj. 1 g
400 - 3000
Mephenoxalone
DORSIFLEX,
DIMEXOL
tbl. 200 mg
400 - 1200
meprobamate
MEPROBAMAT
LÉČIVA
tbl. 400 mg
800 - 2400
 Piperazin Derivates
hydroxyzine
ATARAX
tbl. 10, 25 mg
inj. 100 mg
sir.
20 – 100
300 - 400
 Azapiron Derivates
buspirone
ANXIRON,
BUSPIRON-EGIS
tbl. 5, 10 mg
15-30
Anxiolytics (Benzodiazepine Derivates)
Generic Name
diazepam
Trade Mark
Form
Mean Doses
(mg)
10 - 60
DIAZEPAM SLOVAKOFARMA
APO-DIAZEPAM
APAURIN, SEDUXEN
DIAZEPAM DESITIN
DIAZEPAM DESITIN SUPP.
DEFOBIN, ELENIUM
RAPEDUR
OXAZEPAM LÉČIVA
tbl.
2.5; 10 mg
inj. 10 mg
tbl. 0.25 mg ; 1 mg
tbl. 0.25; 0.5; 1; 2 mg
1 - 10
bromazepam
NEUROL
XANAX
FRONTIN, HELEX
LEXAURIN
tbl. 1; 5; 3 mg
3 - 36
medazepam
ANSILAN, RUDOTEL
tbl. 10 mg
20 - 40
tofisopam
GRANDAXIN
tbl. 50 mg
100 - 400
K+ clorazepate
TRANXENE
lorazepam
TAVOR
tbl. 5; 10; 50 mg
inj. 20; 50; 100 mg
tbl. 1; 2,5 mg
clobazam
FRISIUM
tbl. 10 mg
20 - 60
prazepam
DEMETRIN
tbl. 10 mg
20 - 40
clonazepam
RIVOTRIL
tbl. 0.5 ; 2 mg
gttae 10-25 mg/ml
inj. 1 mg
tbl. 0.25; 1 mg
chlordiazepoxide
oxazepam
alprazolam
ANTELEPSIN
supp. 5 mg
tbl. a drg.
10 mg
tbl. 10 mg
20 - 60
10 - 60
15 – 30
50 - 300
2
1-4
Action Profiles of Benzodiazepines
Relief of anxiety
Anticonvulsant
action
Sedation
Induction of sleep
Muscle relaxation
Ansseau, M., Doumont, A., Diricq, S.: Methodology required to show clinical
differences between benzodiazepines. Curr Med Res Opin 8, Suppl. 4, 108114 (1984). (Except <Dormicum> and <Dalmadorm>)
Anxiolytics: Indications
e.g. Benzodiazepines (lorazepam)
• Short term hypnotic (But decrease REM,
Stages 3 & 4 sleep)
• Anxiolytic
• Acute mania
• Alcohol withdrawal
• Catatonia
Anxiolytics: Mechanism of action
• ↑ Affinity of GABA-A receptor for GABA
(a positive allosteric modulator)
• GABA-A receptors with alpha one subunits
most important for sleep
• GABA-A receptors with alpha two or three
subunits are most important for anxiety (but
all available at this time are non-selective
and therefore also sedating)
Benzodiazepines
Benzodiazepine
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Clorazepate (Tranxene)
Diazepam (Valium)
Lorazepam (Ativan)
Oxazepam (Serax)
Half-life
(hr)
12
100
34
100
100
15
8
Active
metabolites
Yes
Yes
No
Yes
Yes
No
No
Anxiolytic dose
range (mg/day)
0.5-4
15-100
0.5-10
7.5-60
2-40
2-4
30-120
Approximate dose
equivalency (mg)
0.25
10
0.5
7.5
5
1
15
Taken from: Kaplan SI, Sadock BJ. Kaplan & Sadock’s Synopsis of Psychiatry, 8 th ed.,
Lippincott, Williams & Wilkins, Philadelphia, 1998, p. 996.
Advantages
-Rapid onset of action
-Highly effective
Disadvantages
-Physiologic dependence
-Addicting
-Impaired cognition
Anterograde amnesia
Anxiolytics: Side effects
•
•
•
•
Memory decline
Addiction(dependency &withdrawal)
Ataxia/Falls
Drowsiness/dizziness/disinhibition
Anxiolytics: Contraindications
• With COPD or sleep apnea
• Avoid in the elderly; with long term use
taper by 25 % q-monthly after treating the
underlying anxiety disorder with an SSRI as
indicated
How are the novel hypnotics (e.g. Zopiclone,
Zolpidem) different from Benzodiazepines?
•
•
•
•
a. Do not cause falls
b. Do not lead to tolerance
c. Used as long term hypnotics
d. More selective for the alpha one subtype
of GABA-A receptor
Novel hypnotics
(e.g. Zopiclone/Imovane)
Indications: short term hypnotic agents
Mechanism of action:
Some are selective for the alpha 1 subtype of
GABA-A receptor (sedating effects) and not
the alpha 2 (anxiolytic, muscle relaxant and
alcohol potentiating) or alpha 5 (linked to
memory)
Side Effects:
Similar to benzodiazepines
FDA Approved Indications MDD PD OCD SP PTSD GAD PMDD BN ND FM
SSRI
Citalopram (Celexa)
X
Escitalopram (Lexapro)
X
X
Fluoxetine (Prozac)
X
X
X
X
X
Paroxetine (Paxil/CR)
X
X
X
X
X
X
X
Sertraline (Zoloft)
X
X
X
X
X
X
SNRI
Duloxetine (Cymbalta)
X
X
X
Venlafaxine (Effexor/XL) X
X
X
X
Tricyclic Antidepressant
Fluvoxamine (Luvox)
X
Other
Bupropion (Wellbutrin)
X
X
Buspirone (BuSpar)
X
Mirtazapine (Remeron)
X
MDD=major depressive disorder, PMDD=peri-menstrual dysphoric disorder, PD = panic
disorder, PTSD=post-traumatic stress disorder, GAD=generalized anxiety disorder,
OCD=obsessive-compulsive disorder, SP=social phobia, BN = bulimia nervosa, ND =
nicotine dependence, FM = fibromyalgia
SSRI/SNRIs in Anxiety Disorders
Advantages
• High efficacy
• Non-addicting
• Effective for a number
of conditions
Disadvantages
• Can take 2-8 weeks or
longer to be effective
• Side effects
• Drug interactions
• Discontinuation
syndrome
Other Options for Anxiety Disorders
• Buspirone (BuSpar)
• Beta blockers
• Combinations
– SSRI/SNRI + Benzodiazepine
• Antipsychotics
– Trifluoperazine (Stelazine)
– Quetiapine (?)
• Pregabalin (?)
Psychotropic Choices for Specific Conditions
Condition
Pharmacotherapy Option
Obsessive compulsive disorder
SSRI
Clomipramine
Social anxiety disorder
SSRI/SNRI
Panic disorder
SSRI/SNRI
TCA
Benzodiazepine
PTSD
SSRI
Generalized anxiety disorder
SSRI/SNRI
Benzodiazepine
Buspirone
Alzheimer’s Disease
First described by Alois Alzheimer in 1907
Course of disease:
- initially, some memory loss (new
memories and disorientation
- persistently progressive until one
loses identity
Neuropathology in Alzheimer’s
disease
Cognitive Enhancers
Cholinergic Agents
- Donepezil/Aricept
- Rivastigmine/Exelon
- Galantamine/Reminyl
NMDA Antagonist
- Memantine/Ebixa
Cognitive Enhancers: Indications
AChEI: early to moderate Alzheimer’s
severe Alzheimer’s
Some evidence for:
Lewy Body Dementia
Galantamine in Mixed Dementia
Donepezil in Vascular Dementia
Memantine: Moderate to severe AD
Cholinesterase Inhibitors: Effects
• Abilities
• Behaviour
• Cognition
• Decrease in caregiver time
• Entry into Nursing Home
Cholinesterase Inhibitors
Mechanism of Action
• Inhibits centrally-acting acetylcholinesterase,
making more acetylcholine available
• This compensates in part for degenerating
cholinergic neurons that regulate memory
AChEI: Common Side Effects
Muscle Cramps
Insomnia/incontinence
Nausea
Diarrhea
•
•
•
•
•
•
•
•
Diarrhea
Urination
Miosis/muscle weakness
Bronchorrhea
Bradycardia
Emesis
Lacrimation
Salivation/sweating
Cholinesterase Inhibitors:
use caution or consultation with:
• History of seizures
• History of bradycardia, sinus node
dysfunction or other serious conduction
abnormality
• History of PUD or other risk factors for GI
bleeding
• History of COPD or asthma
Memantine:
Mechanism of action
• A dysfunction of glutamatergic neurotransmission,
manifested as neuronal excitotoxicity, is hypothesized to
be involved in the etiology of Alzheimer’s disease
• Memantine binds the NMDA receptor with a higher
affinity than Mg2+ (which are normally there), inhibiting a
prolonged influx of Ca2+ (thereby preventing
excitotoxicity)
• The receptor can still be activated by the relatively high
concentrations of glutamate released following
depolarization of the presynaptic neuron
Memantine: Common Side Effects
Confusion
Headache
Equilibrium (dizziness)
Constipation
Kidney function
(But in large studies had a similar rate of
treatment emergent side effects as placebo)
Cognitives
ACETYLCHOLINESTERASE INBITORS
rivastigmine
EXELON
8 -12 mg
donepezil
ARICEPT
5 - 10 mg
galantamine
REMINYL
8 - 24 mg
NMDA (N-methyl-D-aspartate) RECEPTOR
ANTAGONISTS
memantine
EBIXA
10 - 30 mg
Which class of cognitive enhancers is indicated
in mild to moderate Alzheimer’s Disease?
• a. Cholinesterase inhibitor
• b. NMDA receptor antagonist
Attention Deficit Hyperactivity Disorder
1. Stimulants
–
–
–
–
Amphetamine salts (Adderall)
Methylphenidate (Ritalin, Concerta, Focalin)
Dextroamphetamine (Dexedrine)
Pemoline (Cylert)
2. Non-stimulants
– Atomoxetine (Strattera)
– Guanfacine extended release (Intuniv)
– Others
• Bupropion(Wellbutrin)
• Tricyclic antidepressants
• Venlafaxine (Effexor)
3. New Delivery Systems
– Methylphenidate patch (Daytrana)
– Pro-drug: lisdexamfetamine (Vyvanse)
Psychostimulants
Generic Name
Trade Mark
Doses (mg)
amphetamine
PSYCHOTON,
ADDERAL
5 – 50
dexamphetamine
DEXEDRON
5 – 30
ephedrine
EPHEDRIN
12,5 – 50
mezocarb
SYDNOCARB
5 – 50
methylphenidate
RITALIN,
CENTEDRIN
10 – 40
modafinil
VIGIL, PROVIGIL 200 – 400
Stimulants: Indications
•
•
•
•
ADHD
Narcolepsy
(treatment resistant depression)
(apathy in elderly)
Stimulants: Mechanism of action
(1)
• Increases dopamine and NE actions by blocking their
reuptake and facilitating their release
• Improves the efficiency of information processing in the
frontal subcortical circuits, relieving frontally mediated
symptoms of inattention, hyperactivity and impulsivity.
Stimulants: Mechanism of action
(2)
• Action in DL prefrontal cortex improves attention,
concentration, executive function and wakefulness
• Action in cortical and subcortical motor areas may
improve hyperactivity
• Action in the orbital frontal cortex may improve
impulsivity
• Action in medial prefrontal cortex may improve
depression, fatigue and sleepiness
Stimulants: Common Side Effects
• Headaches and Heart concerns (palpitations,
tachycardia and hypertension)
• Insomnia, Irritibility and Increased stimulation
• Dizziness
• Exacerbation of tics, tremor
• Stomach: anorexia, nausea, abdo pain, weight
loss, possibly slowing of normal growth in
children
Stimulants: Rare Side Effects
•
•
•
•
Psychosis
Leukopenia
Anemia
Seizures
Stimulants: Ongoing Monitoring
• Blood pressure at baseline and with dose
increases
• In children, ongoing monitoring of height
and weight
PRACTICE CASES
CDMQ 1
A 25 year old man (who was previously a PhD candidate at McGill
but has been unemployed and not seeking work for the last two
years) is brought in to the emergency by police.
Police were called as he had been breaking into the homes of
strangers saying that he was looking for “Amour”. They were
concerned by his disorganized speech and brought him into
hospital for assessment.
When seen in the emergency, he is not concerned about being in
hospital. He says that he has been possessed by the goddess of
love, “Amour”, and is looking for others like himself. When
introduced to the assessing psychiatrist, he tells her that he heard
her say the number 17 which alerted him to the fact that there is
a special connection between his circumstance and the television
show “House”.
Which of the following is the
most likely diagnosis?
A. Major depressive disorder
B. Schizophrenia
C. Delirium
D. ADHD
E. Dissociative identity disorder
Which of the following medications would be most
appropriate to discuss starting with the patient?
A. Olanzapine/Zyprexa 5 mg at bedtime
B. Haldoperidol/Haldol 10 mg twice daily
C. Chlorpromazine/Thorazine 100 mg at
bedtime
D. Risperidone/Risperdal Consta 50 mg IM
q2wks
E. Quetiapine/Seroquel XR 900 mg at
bedtime
Which of the following side effects
would you counsel the patient about?
A. Headaches, agitation, nausea, diarrhea
B. Tremor, increased blood pressure, increased
sweating
C. Insomnia, decreased appetite, elevated blood
pressure, tics
D. Weight gain, akathisia, sedation, increased lipids
and sugars
E. Sedation, increased thirst, tremor,
hypothyroidism, nausea, hair loss
CDMQ 2
• A 30 year old woman presents to your family
medicine clinic after several visits to the local
emergency department for episodes of racing
heart, shortness of breath, nausea and a sense
that she was dying. Cardiograms and bloodwork
(CBC, TSH) were normal. As a result of these
episodes, she has become reluctant to leave the
house as she is afraid this will happen when she
is driving or when in a situation where she will
not be able to access help.
Which of the following is the
most accurate diagnosis?
A. Hyperthyroidism
B. Generalized anxiety disorder
C. Panic disorder
D. Agoraphobia
E. Major depressive disorder
In the emergency, this lady received some lorazepam/ativan which
she found quite helpful. She would like a prescription for this
medication. How would you respond to this request?
A. Describe to her that although benzodiazepines can help
reduce anxiety symptoms acutely that they are not in fact
first line treatment. They can best be used as an adjunct
to the first line SSRI while waiting for these to become
effective
B. Give her a prescription for ativan 0.5 mg bid for one
month and follow up at that time to reassess
C. Reinforce with her that benzodiazepines are the best way
of dealing with panic attacks and give her a prescription
of ativan 1 mg bid prn to be used as soon as she
experiences symptoms so that she never needs to
experience the trauma of a full blown panic attack again.
You give her a prescription for escitalopram 10 mg daily and
lorazepam 0.5 mg bid for one week at which point you will follow
up with her. Which of the following side effects should you
discuss with her in regards to the lorazepam?
A. This medication can cause drowsiness and incoordination.
Longer term use will lead to dependence.
B. The most common side effects are weight gain and sedation
C. The most common side effects are drowsiness and orthostatic
hypotension
D. The most common side effects are restlessness, nausea,
diarrhea and sexual dysfunction
E. This medication can rarely cause a serious rash and must be
adjusted upwards slowly
CDMQ 3
• A forty five year old woman with a history of multiple previous
psychiatric hospitalizations is brought in to hospital by police
• They were called by her mother who says she has been calling at
all hours of the day and night, very upset and talking really
quickly. She has been borrowing large sums of money which
her mother later found out she used to gamble, which is out of
character for her. Tonight she showed up at her mother’s home
and was yelling in the street that her father was a menace to
society and she would save everyone by killing him.
• In the emergency room, she is irritable, crying and cannot sit
still. She is speaking so quickly that it is difficult to follow what
she is saying. She describes her mood as depressed. She
admits she has not been eating well in a few weeks and feels so
worthless that she has been thinking about killing herself.
Which of the following is the most accurate
description of her current episode?
A. Major depressive episode
B. Bipolar affective disorder, current episode
depressed
C. Bipolar affective disorder, current episode
manic
D. Bipolar affective disorder, current episode
mixed
E. Borderline personality disorder
You decide to start a mood stabilizer; she tells you that she has had
a bad reaction with one of these medications in the past where she
had to pee a lot and her sodium level was really high. Which of the
following most likely caused this?
A. Lamotrigine/Lamictal
B. Valproic acid/Epival
C. Quetiapine/Seroquel
D. Risperidone/Risperdal
E. Lithium
You decide to start Quetiapine as well as standard admission
prn medication, given her significant agitation and recent threats
of violence. You are called by nursing staff in the middle of the
night to inform you that the patient is acutely distressed, with
her head arched back and her tongue protruding. What is the
best treatment for this condition?
A. Haloperidol/Haldol 10 mg IM STAT
B. Lorazepam/Ativan 2 mg IM STAT
C. Propranolol 20 mg PO tid
D. Benztropine/Cogentin 2 mg PO bid
E. Benztropine/Cogentin 2 mg IM STAT
CDMQ 4
• A 70 y.o. man reluctantly attends your family medicine clinic with
his daughter. She is concerned as he has not been getting out for the
last few months and has lost a lot of weight, about 20 lbs. She
continues to invite him to spend time with her and her family but he
has recently been declining, preferring to stay home and do nothing.
He seems tired and sad all of the time.
• When you see him, you note that he moves and speaks more slowly
than he did in the past .
• When you ask him if he feels that he may be ill, he responds that he
knows that he is being punished for having shoplifted once when he
was a teenager and that he deserves to feel this way.
Which of the following would be the
best treatment for this condition?
A. Start Citalopram/Celexa 20 mg daily
B. Start Seroquel XR/Quetiapine 100 mg qhs
C. Start both A&B simultaneously
D. ECT/electroconvulsive therapy
E. Start Donepezil/Aricept 5 mg qhs
You continue to follow up with this patient after he is in
complete remission from his depression. Which of the
following conditions will he be at increased risk for in follow
up given his late presentation with depression?
A. Delirium
B. Schizophrenia
C. Dementia
D. Panic disorder
E. Borderline personality disorder
Over the next few years, he gradually begins to complain of
memory deficits, shows evidence of word finding problems and
now requires assistance with grocery shopping and paying his bills.
His MMSE score has dropped from 30 to 23 during this time
period.
Which of the following treatments would be most
appropriate?
A. Start Citalopram/Celexa 20 mg daily
B. Start Seroquel XR/Quetiapine 100 mg qhs
C. Start both A&B simultaneously
D. ECT/electroconvulsive therapy
E. Start Donepezil/Aricept 5 mg qhs
THANK YOU!
GOOD LUCK