Psychopharmacology
What you should know to survive the
LMCC and Internship
Dr. Kate Huntington
khunting@rohcg.on.ca
April 2011
Objectives
To review:
• indications for
• mechanism of action
• side effects (remember not everyone gets
these)
• monitoring parameters
for the major classes of psychotropic
medications
Which of the following is not a
common side effect of SSRI’s?
•
•
•
•
•
a.
b.
c.
d.
e.
Nausea
Headache
Rigidity
Anxiety
Sleep disruption
Which of the following receptors
does Mirtazepine not block?
•
•
•
•
•
a.
b.
c.
d.
e.
Histamine
5HT1
5HT2
5HT3
Alpha 2
At which dose level does
Venlafaxine typically begin to have
a noradrenergic effect?
•
•
•
•
a.
b.
c.
d.
75mg
150mg
225mg
300mg
Which is not an indication for the
use of Benzodiazepines?
•
•
•
•
•
•
a.
b.
c.
d.
e.
Catatonia
Long term hypnotic
Mania
Alcohol withdrawal
Anxiety
How are the novel hypnotics
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
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.
Haldol
Pimozide
Olanzapine
Clomipramine
Chlorpromazine
Which class of cognitive enhancers
is indicated in mild to moderate
Alzheimer’s Disease?
• a. Cholinesterase inhibitor
• b. NMDA receptor antagonist
Which mood stabilizer can reduce
the risk of suicide in Bipolar
Disorder?
•
•
•
•
a.
b.
c.
d.
Valproic Acid
Lamotrigene
Lithium
Carbamazepine
What is the most common excitatory
neurotransmitter in the brain?
•
•
•
•
•
a.
b.
c.
d.
e.
Serotonin
Glutamate
Norepinephrine
GABA
Dopamine
SSRI’s: Indications
•
•
•
•
•
•
•
MDD
Premenstrual Dysphoric Disorder
GAD
Social phobia
PTSD
OCD
Panic Disorder
SSRI: Mechanism of Action
• In depression, the serotonin neuron has a relative deficiency of
serotonin and the autoreceptors and postsynaptic receptors are
increased in number & sensitivity
• When the reuptake pump is blocked, the level of serotonin increases in
the somatodendritic area, causing autoreceptors (the brakes) to
decrease in number & sensitivity
• This turns off the brake on the serotonin neuron and electrical impulses
flow down the axon, releasing more serotonin at the axon terminal
• Increased levels of serotonin in the synapse leads to down regulation
(decreased number and sensitivity) of postsynaptic receptors & other
downstream changes
SSRI: Side Effect Profile
•
•
•
•
•
Headache
Anxiety (limbic projections) and Agitation (basal ganglia projections)
Nausea (chemoreceptor trigger zone)
Diarrhea (peripheral GI 5HT3 & 5HT4 receptors)
Sexual dysfunction (spinal projections) and Sleep disruption or
Somnolence (Brainstem sleep centre)
SSRI: Rare but Dangerous Side Effects
• UGI bleeding (platelet dysfunction)
• SIADH
• SSRI discontinuation syndrome (slow taper)
–
–
–
–
–
–
Flu like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbance
Hyperarousal (anxiety/agitation)
• Serotonin syndrome
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 (frontal and limbic projections) and Anticholinergic (relative
decrease in parasympathetic tone)
• Rash
• Emesis, decreased appetite and weight loss (SNS activation)
• Sleep disruption, Shaking and Sweating (sleep center and cerebellar
projections 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
NaSSA: Mechanism of Action
• Blocks Alpha 2 autoreceptors on norepinephrine neurons &
heteroreceptors on Serotonin neurons, causing more NE & 5HT to be
released (puts the brakes on the brakes)
• 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: constipation, urinary retention, dry mouth,
blurred vision, drowsiness, sinus tachycardia,
confusion/delirium, fever (red as a beet, dry as a bone, blind as
a bat, mad as a hatter, hot as a hare; bowel & bladder lose
their tone & the heart goes off alone)
• Drowsiness (H1 blockade)
• Equilibrium
NaSSA: Rare but Dangerous Side Effects
• Neutropenia
• Serotonin syndrome
• Hepatotoxicity
• SIADH
SARI: Mechanism of Action
Serotonin 2A antagonists/reuptake inhibitors (Trazadone/Desyrel)
• Primarily blocks 5HT2A, reducing sexual dysfunction & sleep
disruption & increasing effect of 5HT1A stimulation (5HT2A &
5HT1A oppose one another)
• 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
SARI: Rare but Dangerous Side Effects
• Serotonin syndrome
TCA: Mechanism of Action
Tricyclic antidepressants:
3° amines (eg amitriptyline, imipramine, doxepine)
2° amines (eg nortriptyline, desipramine)
• 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 & sodium channels in the
heart & brain
TCA: Side Effect Profile
• Antihistamine – weight gain & sedation
• Anticholinergic – (remember toxidrome from NaSSA)
• Anti-alpha adrenergic – dizziness, orthostatic hypotension
• Blockade of fast sodium channels – prolongation of QTc (risk of
Torsades)
TCA: Rare but Dangerous Side Effects
•
•
•
Torsades de Pointes
•
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
MAOI: Mechanism of Action
Monoamine oxidase inhibitors:
“the classics” (phenylzine/nardil, tranylcypromine/parnate)
Reversible inhibitor: (moclobemide/mannerix)
• 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 norepinepherine &
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 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
• Teratogenicity
• Blood dyscrasias
Serotonin Syndrome: HARMED
•
•
•
•
•
•
Hyperthermia
Agitation/Autonomic instability
Rigidity/Reflexes increased
MyoClonus/tremors
Encephalopathy
Diaphoresis
For reference only
Hypertensive Crisis
• Norepinephrine is the amine most closely linked with control of blood
pressure
• MAO normally inactivates norepinepherine
• Tyramine, an amine present in aged foods, causes release of
norepinepherine
• In the presence of MAOI, this increased NE cannot be broken down,
resulting in a hypertensive crisis
Starting Antidepressants: General Guidelines
• Start with a reuptake inhibitor or mirtazepine (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
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…
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
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
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
Stimulants: Indications
• ADHD
• Narcolepsy
• (treatment resistant depression)
Stimulants: Mechanism of action
(1)
• Increases dopamine and NE actions by blocking
their reuptake and facilitating their release
• Improving the efficiency of information
processing in the frontal subcortical circuits by
targeting the arousal neurotransmitters dopamine
and NE can relieve 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 supplementary or prefrontal motor
cortex 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
Stimulants:
Ongoing Monitoring
• Blood pressure at baseline and with dose
increases
• In children, ongoing monitoring of height
and weight
ECT: Indications
• Common
• MDE
• Mania
• Mixed state
• Catatonia
• Schizophenia with
prominent affective
symptoms
• Schizoaffective disorder
• Uncommon
• Delirium
• NMS
• Parkinson’s Disease
ECT: Indications (cont.)
• Indications for First Line Use:
• Need for rapid improvement (suicide, malnutrition, catatonia,
severe psychosis or agitation)
• When other treatments are more risky (elderly)
• Patient preference
• Psychotic depression (gold standard – 95% response)
ECT: Relative Contraindications
(weigh pros & cons)
•
•
•
•
•
•
•
Space occupying cerebral lesions
Increased ICP
Recent MI
Recent CVA
Aneurysm
Retinal detachment
Pheochomocytoma
ECT: Mechanism of Action
• Neurotransmitter theory
• Enhances DA, 5HT & NE neurotransmissiom
• Neuroendocrine theory
• Increased release of neurohormones including prolactin, TSH,
ACTH & endorphins
• Neurogenesis theory
• Increased neuroplasticity
• Release of BDNF
• Anticonvulsant theory
• Increase in seizure threshold during course of ECT; CSF of
animals receiving ECS is anticonvulsant when given IV to
recipient animals
ECT: Side Effect Profile
• Common
• Headache
• Muscle ache
• Nausea
• Memory impairment
• Delirium
• Amnesia (anterograde & retrograde)
• No longterm deficits
ECT: Side Effect Profile
• Rare:
• Mortality 2 / 1 000 000
• Cardiovascular
• initial vagal stimulation
• Bradycardia / asystole / ectopic activity
• sympathetic stimulation during tonic clonic phase of seizure
• Increased HR & increased BP
• Sometimes parasympathetic rebound with second phase of
bradycardia
• Prolonged apnea
• Pseudocholinesterase deficiency
• Prolonged seizure
• Treat with IV benzo
Mood Stabilizers: Indications
•
•
•
•
Bipolar Affective Disorder (BPAD)
Migraine or cluster headaches
Chronic aggression or impulsivity
Lithium reduces suicidal risk in BPAD and
augments antidepressants in MDD and
OCD
What is a “mood stabilizer”?
• Originally , these medications treated mania
and prevented its recurrence, thus treating
and stabilizing the manic pole of bipolar
disorder
• More recent medications can be thought of
as treating one of the following phases:
– Acute bipolar depression
– Acute bipolar mania
– Maintenance
Choice of Treatment in BPAD
(Bipolar Affective Disorder)
•
•
•
First line for acute mania:
• Lithium,
• Valproic Acid
• atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone,
aripiprazole)
taper and discontinue antidepressants
•
First line for acute bipolar depression:
• Lithium
• lamotrigine
• quetiapine
do not use antidepressant monotherapy
•
•
•
•
•
First line for maintenance therapy:
Lithium
Valproic acid
Lamotrigine
Atypical antipsychotics quetiapine, risperidone LAI and Olanzapine
Goals of treatment in BPAD
• Again, the goal is to treat to complete
remission of all mood symptoms
• 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
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
• Tremor/Teratogen (increased risk Ebstein’s
anomaly (0.1% vs 0.005%) in first trimester)
• Hypothyroid
• Increased weight
• Vomitting, nausea, GI
• Miscellaneous: EKG changes (T wave flattening
or inversion), acne, hair loss
Lithium: Toxicity
• Narrow therapeutic index!!!
• Anything that affects water and electrolyte imbalance can contribute to Lithium
toxicity (CAUTION with flu, dehydation, meds)
• Levels are increased by NSAIDS, thiazide diuretics, ACEI, tetracycline,
anticonvulsants
• Levels are decreased by osmotic diuretics (mannitol), carbonic anhydrase
inhibitors, caffeine, increased 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, vomitting, 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)
• TSH (5% hypothyroidism)
• EKG with rhythm strip (contraindicated with sick sinus
syndrome)
• Metabolic baseline including baseline weight , BMI, waist
circumference , BP, fasting glucose and lipid profile
• Personal and family history of obesity, dyslipidemia,
hypertension and cardiovascular disease
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
• BMI monthly for three months and then q4mths
• Waist circumference at the umbilicus, BP, fasting glucose
and lipid profile repeat at 3 months and then annually
Lithium : Rx
• Adult
• Dosing 600 – 1500 mg/d (bid dosing)
• Level 0.5 – 1.2
• Geriatric
• Dosing 150 – 600 mg/d (bid dosing)
• Level 0.4 – 0.8
Why Use an Anticonvulsant as a Mood
Stabilizer: The Kindling Hypothesis
• Term first coined by Graham Goddard in 1967 while
studying learning in rats using low intensity electrical
brain stimulation
• Over time the rats became sensitized to this and
began to have seizures when they received this low
intensity signal
• Likened to kindling in starting a fire in that the
stimulus is not enough to cause the event on its own
but when repeated enough leads to an episode
Why Use an Anticonvulsant as a Mood
Stabilizer: The Kindling Hypothesis
• Robert Post drew the parallel to BPAD where the initial
episode is often precipitated by a stressor but when cycles
continue untreated, the brain can become “kindled” and future
episodes can occur with little or no precipitant
• Dysfunctional cation (Na &Ca) pumps leading to an
imbalance between excitatory (glutamate) & inhibitory
(GABA) neurotransmitters may contribute to this kindling
phenomenon
• Anticonvulsants are thought to prolong inactivation of cation
channels during activity, preventing spread of activity &
leading to downstream changes in GABA & glutamate
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 effect
monitoring
• On the surface:
– Acne , hair loss
• Under the surface:
– weight gain, edema
• Systemic:
– blood dyscrasias (esp plt dysfn)
– liver dysfunction =/- elevated ammonia levels
– reproductive changes incl menstrual irregularities (up to
45%), PCOD, teratogenicity (5-15%)
Valproic Acid: Initial Work-up & Ongoing
Monitoring
Initial
•
•
•
•
CBC + LFT’s
Epival level weekly until steady state reached
Metabolic baseline including baseline weight and calculate BMI
Baseline personal and family history of obesity, dyslipidemia,
hypertension and cardiovascular disease
• Baseline waist circumference at the umbilicus, BP, fasting glucose
and lipid profile
Ongoing
• Repeat tests monthly x 6 months then Q6mos or if symptoms develop
• BMI monthly for three months and then q4mths
• Waist circumference at the umbilicus, BP, fasting glucose and lipid
profile repeat at 3 months and then annually
Valproic Acid: Rx
Reference only
• Starting dose:
• 250 qhs (geriatrics)
• 250 bid-tid (adults)
• Dose range: 750 – 3000 mg/d (bid dosing)
• Levels: 350 – 800 umol/l
Lamotrigine: Treatment effects
• Treats bipolar depression
• First line maintenance treatment
Lamotrigene: Side Effect Profile
• Rash – 0.3% adults / 1% in children. With slow titration risk was
reduced to 0.01% comparable to other anticonvulsants.
• Activation (3-8%), Ataxia
• Spaced out (cognitive slowing), Sedation, Sleep disturbances
• H/A, Hypersensitivity reactions
Lamotrigene: Rx
• Start with 25-50 mg/d
• Increase every 2 weeks by 25-50 mg
• Usual maintenance dose is 200 mg in 2 divided doses
Atypical Antipsychotics:
Olanzapine and Quetiapine
• All atypical antipsychotics are indicated to
treat bipolar mania
• Quetiapine is first line monotherapy for
bipolar depression
• Both olanzapine and quetiapine are first line
maintenance treatments
Anxiolytics: Indications
eg. Benzodiazepines (lorazapam)
• 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)
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
Novel hypnotics
(e.g. Zopiclone/Imovane)
Indications: short term hypnotic agents
Mechanism of action:
Some are selective for the alpha one 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:
Reported to be less tolerance, dependence and
withdrawal on discontinuation than BZD
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)
Typical Antipsychotics: Side effects
High potency
EPS
Haldol
Loxapine
Perphenazine
Low potency
Chlorpromazine
QT prolongation with pimozide, CPZ
Antihistamine
AntiAlphaAdrenergic
Anticholinergic
Atypical Antipsychotics:
Indications
• Same as typicals
• Agitation/aggression in dementia NOT
responding
to
adequate
nonpharmacological interventions
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:
Mechanism of action cont…
• In pathways with more 5HT2A receptors to block, SDA’s
lead to dopamine release(i.e. the mesocortical pathway,
reducing negative and cognitive symptoms)
• In pathways with more D2 receptors to block, SDA’s cause
dopamine blockade (i.e.the mesolimbic pathway, with
antipsychotic effects)
• In pathways where receptor numbers are relatively equal,
there is no change in the amount of dopamine (i.e. in the
tuberoinfundibular pathway, preventing increased
prolactin)
• In the nigrostriatal pathway, there are just enough 5HT2
receptors to bring the D2 blockade down below 80%, the
critical number to prevent EPS.
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 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
Cognitive Enhancers
Cholinergic Agents
- Donepezil
- Rivastigmine
- Galantamine
NMDA Antagonist
- Memantine
Cognitive Enhancers:
Indications
AChEI: early to moderate AD
Lewy Body Dementia
Galantamine in Mixed Dementia
Donepezil in Vascular Dementia
Memantine: Moderate to severe AD
Cholinesterase Inhibitors: Indications
• 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: Indications
Socialization
Household tasks
ADL
Persecutory ideation
Excessive activity (agitation)
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)
Cognitive enhancers:
monitoring
• Response may be seen 1 month, typically 3
months
• Realistic expectation is to “maintain”
Which of the following is not a
common side effect of SSRI’s?
•
•
•
•
•
a.
b.
c.
d.
e.
Nausea
Headache
Rigidity
Anxiety
Sleep disruption
Which of the following receptors
does Mirtazepine not block?
•
•
•
•
•
a.
b.
c.
d.
e.
Histamine
5HT1
5HT2
5HT3
Alpha 2
At which dose level does
Venlafaxine typically begin to have
a noradrenergic effect?
•
•
•
•
a.
b.
c.
d.
75mg
150mg
225mg
300mg
Which is not an indication for the
use of Benzodiazepines?
•
•
•
•
•
•
a.
b.
c.
d.
e.
Catatonia
Long term hypnotic
Mania
Alcohol withdrawal
Anxiety
How are the novel hypnotics
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
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.
Haldol
Pimozide
Olanzapine
Clomipramine
Chlorpromazine
Which class of cognitive enhancers
is indicated in mild to moderate
Alzheimer’s Disease?
• a. Cholinesterase inhibitor
• b. NMDA receptor antagonist
Which mood stabilizer can reduce
the risk of suicide in Bipolar
Disorder?
•
•
•
•
a.
b.
c.
d.
Valproic Acid
Lamotrigene
Lithium
Carbamazepine
What is the most common excitatory
neurotransmitter in the brain?
•
•
•
•
•
a.
b.
c.
d.
e.
Serotonin
Glutamate
Norepinephrine
GABA
Dopamine