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Antipsychotics and Mood Stabilizers
Julius Elefante 2014
Outline
• Antipsychotics
• Names: first-generation, second-generation, typical,
atypical, etc.
• MOA, Pharmacokinetics, Indications/Contraindications
• Evidence
• Side Effects
• Mood stabilizers
• Lithium
• Background, PK, side-effects
• Anticonvulsants
• Evidence
Antipsychotics: names
First generation
• Typicals, FGAs
• Also divided into highpotency and low-potency
• High-potency: Haloperidol
• Low-potency:
Chlorpromazine
Second generation
• Atypicals, SGAs
Anti-Psychotics
Typical
•
•
•
•
•
•
•
Chlorpromazine
Flupenthixol
Fluphenazine
Haloperidol
Loxapine
Methotrimeprazine
Zuclopenthixol
• Acetate and decanoate forms
Atypical
• Olanzapine (Zyprexa)
• Risperidone (Risperidal)
• Quetiapine (Seroquel)
• Aripiprazole (Abilify)
• Ziprazidone (Zeldox)
• Paliperidone (Invega)
• Clozapine (Clozaril)
Mechanism of Action: The big picture
• Dopamine (DA) key role in
schizophrenia
• Key dopamine pathways in
efficacy and side effect:
• Mesolimbic (behaviour and
mood)
• Nigrostriatal (movement)
• Tuberoinfundibular (prolactin
release)
• All antipsychotics are antagonists at the D2 receptors
• Mesolimbic antagonism = alleviation of + symptoms
• 65% to be effective; 80% motor side effects
Mechanism of Action
Typical/FGA
Atypical/SGA
• Primarily DA blockade
• Primarily DA and serotonin
(5-HT)
• Not just D2
• Numerous other receptors
• H1
• Adrenergic
• Cholinergic
• Active antagonism of 5HT2A receptors
• Less negative symptoms?
• Causes DA release at
nigrostriatum? Less EPS?
• Many other receptors
Pharmacokinetics
Typical/FGA
Atypical/SGA
• Highly lipophilic
• Highly lipophilic
• Active metabolites:
haloperidol, chlorpromazine,
thioridazine
• Variable bioavailability, halflife, metabolism
• Elimination is 12-24 hrs
• All are hepatically
metabolized CYP450
• Except Paliperidone – Why?
Indications and Contraindications
FGA
• Psychosis
SGA
• Psychosis
• Acute agitation, delirium
• BPSD
• Nausea and vomiting
• Acute mania
• Rarely: Tourette’s,
intractable hiccups
• Contra: NMS
• Contra: severe CNS
depression (decreased LOC),
NMS
• Clozapine: myeloproliferative
disorders, liver disease, renal or
cardiac disease, ileus, seizure
disorders
• Ziprazidone: QT prolongation
Efficacy vs. effectiveness
Efficacy vs. effectiveness
• Leucht, Lancet, June 2013: Comparative efficacy and toleralability of
15 antipsychotics in a multiple-treatments meta-analysis
• 22 trials
• 43,049 participants
• Despite the current dogma that all SGAs, are the same, the best, most
recent evidence is – they are not!
• Food for thought: have you heard of ASE, ARI, ZIP, LURA being used? Ask
why. There could be a good clinical reason.
• Food for thought # 2: what are the limitations of meta’s?
• For the interested, get the article or email me:
[email protected]
11
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Olanzapine
• Route: po, dissolvable (“Zyprexa, Zydis”), SA inj
• Side-Effects to consider:
• Most metabolic: weight gain, diabetes, hyperlipidemia, Liver
• Moderate sedation
• IM + Ativan = resp failure! **BLACK BOX WARNING**
• Sure, but what is the NNH?
•
•
•
•
1 adverse event per 3,369 IM Olanzapine exposures
1 serious event in 6,494
1 fatality per 18,586
Key point: Respect black box warnings, but know the
evidence behind them. In cases where BBWs limit tx (AD
and suicidality in adolescents, AD and QTc), knowing the
evidence helps in justifying going against BBW. This is not
the case for parenteral OLA + BDZ.
Olanzapine
• Indications:
• Schizophrenia/psychosis
• BP I – acute mania and/or maintenance
• Dose Range:5 to 30 mg
• Up to 40mg/d
Risperidone
• Route: po, dissolvable “M-tab”, liquid or LA inj (Consta)
• Side-Effects to Consider:
• Metabolic: as previously mentioned
• Most “typical” of atypicals
• May elevate Prolactin levels
• Sexual
• Indications:
• Schizophrenia/psychosis
• BP I – acute mania and/or maintenance
• Dose range:
• PO 2-8 mg
• 25-50 mg IM q2wks
Quetiapine (Seroquel)
• Route: po (regular and XR)
• Side-Effects to consider:
• Metabolic
• Most sedating of the atypicals
• Indications:
• Schizophrenia/Psychosis
• BP I – acute mania and/or acute depression
• Depression/anxiety Adjuvant
• Usual dose range:
• 300 to 900 (multiple times a day dosing)
• 300 to 900 (once daily dosing for XR form)
• Lower doses of 25-100 if used as prn or augmentation
Aripiprazole (Abilify)
• Route: PO
• Side-effects to consider:
• Less metabolic SE
• Less sedation
• Indications:
• Schizophrenia/psychosis
• BP I disorder – acute mania
• Depression Adjuvant
• Dose range:
• 10 to 30 mg
Paliperidone (Invega)
• Route: PO or LA inj
• Side-Effects to consider:
• Less metabolic side-effects
• Less drug-drug interactions
• Indications:
• Schizophrenia/psychotic disorders
• Dose range:
• 3 to 9 mg
Ziprazidone (Zeldox)
• Route: PO
• Side-Effects to consider:
• Less metabolic SE
• Less sedation
• QT prolongation
• Indications:
• Schizophrenia/psychosis
• BP I disorder – acute mania
• Dose range:
• 40 mg BID to 80 mg BID
Clozapine (Clozaril)
• Route: PO
• Indications:
• Schizophrenia/psychosis
• Treatment refractory
only after failed at least 2
other anti-psychotics
• Not a first line treatment
• Dose range:
• 100 to 800 mg (starting
dose 25 mg)
• Side-Effects to Consider:
• Metabolic
• Sedation
• Increased Sz risk at doses
> 500 mg
• Agranulocytosis
• Cardiac myotosis
Side-Effects to Consider
• More EPS: parkinsonism, akathisia, dystonia, TD
• Benztropine for acute dystonia
• NMS – neuroleptic malignant syndrome
• Rare, stop AP
• Da agonist, e.g. bromocriptine, and symptom management
• Increased Prolactin:
• Galactorrhea, amenorrhea & sexual
• Prolonged QT
• ECG, ECG, ECG!
Other Common IM’s
• Loxapine IM:
• PRN for agitation when po not an option
• 5 mg to 20 mg
• Haldol IM:
• Prn for agitation when po not an option
• 2.5 mg to 10 mg
sga
Risperidone
0.5 t0 1.0
2 to 6
Increase by 0.5 to 3 to 4 days
Risperidone LA
25 IM q 2 weeks
PO x 3 weeks
37.5 mg IM q 2w
Increase by 12.5 every 4 to 8
weeks
Olanzapine*
5 to 10
10 to 20
Increase by 2.5 to 5 q 3 to 4
days
Quetiapine**
100
600
A hundred daily
Clozapine
12.5 to w5
300 to 600
12.5 to 25 on the second
day, then up to 25 to 50 daily
30
depot
• Flupentixol, Haloperidol, Fluphenazine, Pipotiazine
• Zuclopenthixol
• Risperidone Consta
• Olanzapine (USA), Aripirazole (USA)
31
Acute phase
• Emergency
• Non-emergency
• First episode, no previous tx
• Multi-episode
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Acute phase
• Emergency
•
•
•
•
PO, IM options
5 mg Haldol IM + 2 mg Ativan IM > Haldol alone
IM Olanzapine 2.5 to 10 mg is as effective as Haloperidol alone
No benefit of adding BDZ to OLA, and there is package insert
warning not to co-administer
• 1:3000, 1:6000, 1:18000 of AE, serious AE, mortality, respectively
• Oral risperidone or Zydis is as effective as Haloperidol IM
• Accuphase peaks in 24 to 48 hours and declines to 1/3 of peak in
72 hours. Avoid in drug-naïve patients.
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Acute phase
• First episode, no previous tx
• Delay in tx is associated with distress and risk
• Duration of untreated schizophrenia is related to less
favourable outcome
• SGA is indicated for first episode psychosis
• Drug naïve are susceptible to EPS and sedation
• BDZ to control agitaiton while initiating low dose SGA
34
Acute phase
• Multi-episode
• Drug history
• Adequate trial: 4 to 8 weeks on maximum tolerated dose within
the recommended range
• Duration of adequate trial of Clozapine is considered to be 4-6
months
• General principle is to titrate up to an initial traget dose range
in 1 – 2 weeks and monitor for side effects
35
Stabilization phase
• First episode
• Multi-episode
• 4 – 8 weeks to reduce acute psychosis
• Other symptoms (-) take longer
• Improvement may carry over the year
• Premature discontinuation = risk of relapse
36
Stable phase
• First episode
• Multi-episode
• Inadequate response
• Persistent positive symptoms
• Persistent negative symptoms
• Depression
• SI
• Violence
• Sex Differences
37
EPS, prolactin, TD
Clozapine
Quetiapine
Olanzapine
Risperidone
FGA
38
Weight gain at 10 months
~0.5 kg
~2 – 2.5 kg
>3 kg
Loxapine
Risperidone
Thioridazine
Haloperidol
Chlorpromazine
Aripirazole
Quetiapine
Olanzapine
Clozapine
39
Anticholinergic and cognitive
Risperidone
Quetiapine
High potency FGA
Low potency FGA
Clozapine
40
Sedation
High potency FGA
Low potency FGA
Risperidone
Clozapine
Aripirazole
Quetiapine
Ziprasidone
Olanzapine
41
Seizure risk
Risperidone
Quetiapine
Olanzapine
Haloperidol
Clozapine
42
Cardiac (QTC)
• Review Article
• QTc Prolongation,
Torsades de Pointes,
and Psychotropic
Medications
• Psychosomatics 2013;
54:1–13
43
Clozapine side effects
• Agranulocytosis 0.5% to 2%
• First 6 mos: weekly bloodwork, then q2w
• WBC must be >3000 and ANC > 1500
• Carbamazepine may induce agranulocytosis if given with
CLO
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Clozapine side effects
• Seizures 2% to 3%
• >500 mg dose
• Smoking cessation increases seizures
• Dose reduction up to 50% with smoking cessation
• Myocarditis, cardiomyopathy – rare
• Ssx: fever, chest pain, peripheral edema, tachycardia,
respiratory distress
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Clozapine side effects
• Weight gain, lipids, glucose
• Sialorrhea, sedation, hypotension, tachycardia
• Anticholinergic: constipation, dry mouth, blurred
vision, gastroparesis, enuresis
• Low propensity to elevate PRL or induce EPS
46
Outline
• Antipsychotics
• Names: first-generation, second-generation, typical,
atypical, etc.
• MOA, Pharmacokinetics, Indications/Contraindications
• Evidence
• Side Effects
• Mood stabilizers
• Lithium
• Background, PK, side-effects
• Anticonvulsants
• Evidence
Mood Stabilizers
Lithium
Anticonvulsants
• Valproic acid
• Lamotrigine
• Carbamazepine
lithium
• Therapeutically used in 1850’s
• Salt substitute for hypertension
• Narrow therapeutic index
• Dr. John Cade discovered
antimanic properties in 1949
• Not approved by FDA until 1970
Lithium – clinical uses
• First line agent for
bipolar disorders
• Acute mania
• Bipolar depression
• Maintenance
Lithium – clinical uses
Lithium – clinical uses
• Adjunct to antidepressants in treatmentresistant depression
• Suicide prevention
• Cluster headaches
Lithium - pharmacology
• Rapidly absorbed after oral administration
• Max concentrations 1-5 hours after intake
• Minimally protein bound
• Excreted unchanged in the urine
Lithium - pharmacology
• Half-life 18-36 hours
• Almost entirely renally secreted
• Cleared 10-40 mL/hour (20%-30% of GFR)
• In chronically exposed groups clearance decreases to about
12 mL/hour
• 50% to 80% is excreted in 24 hours
Lithium - pharmacology
• Acute 0.8-1.2 mEq/L
• Maintenance 0.6-0.8 mEq/L
• Steady state in 5-6 days
• Peak levels 2-3x steady state especially early in
therapy
Lithium - pharmacology
• Na+ depletion promotes Li retention
• Volume contraction which activates Na+ conserving
mechanism also promotes Li retention
Lithium
• Cellular uptake of Li is higher when there is hypokalemia and
hypocalcemia
• Hyperthyroidism increases Li reuptake at the kidneys
Lithium
• Drugs may precipitate Li toxicity
• NSAIDS, ACE inhibitors, Thiazides
• More drugs in later slides
lithium
• Brain Li levels do not correlate well with serum Li
levels
• Brain-serum ratio is 0.4 to 0.75
• Brain levels can fluctuate even without any change in
serum levels
• Brain concentrations lag behind plasma by about
24 hours, and may exceed plasma concentrations
Clinical subtypes of lithium toxicity
1. Acute
2. Acute on chronic
3. Chronic
Acute toxicity
• Toxicity that occurs in lithium-naïve patients
• Prototypical symptoms
• GI: nausea, vomiting, diarrhea
• Neuro: drowsiness, slurred speech, apathy, confusion
Acute on chronic
• Acute overdose in a lithium-treated patient
• Sudden salt restriction
• Drugs that raise serum lithium levels
Chronic
• Toxicity that occurs insidiously, often due to
decreased renal clearance
• Distinction between acute-on-chronic or chronic
can be blurred
•Severe neurotoxicity, including persistent symptoms, primarily
occur in acute-on-chronic and chronic lithium intoxication
•May occur even when serum lithium levels are normal
Acute vs. chronic signs and
symptoms
Lithium Toxicity
• Neurotoxicity
• Toxicity profile of other body systems
Acute neurotoxicity
• Tremor, sedation, delirium
• Hyperreflexia, myoclonus, opsoclonus,
anisocoria, gaze palsies
• Fasciculations, proximal muscle weakness,
paresthesias
• Nystagmus, dysarthria, ataxia
• Choreathetosis
• Seizures, coma, death
From Dr. Bob Stowe’s presentation
Acute neurotoxicity
• EEG changes
• Alpha, bitemporal theta slowing, paroxysmal sharp waves,
periodic patterns, burst suppression
• Baseline EEG abnormalities after a 750mg dose may
predict toxicity
• Action myoclonus
From Dr. Bob Stowe’s presentation
Acute on chronic/chronic
• Cerebellar toxicity*
• EPS*
• Brainstem dysfunction*
• Dementia*
• Persistent delirium
• Parkinsonian symptoms
Typical
presentations
of Syndrome
of Irreversible
LithiumEffectuated
Neurotoxicity
(SILENT)
Lithium systemic toxicity profile
GFR and renal failure
• GFR impairment is not clinically significant in most
patients
• Swedish cohort study
• Renal failure was 0.5% of patients on a lithium registry
(18/3369) versus 0.2% of general population
Tubular renal function
• Urinary concentrating ability
decreased by 15%
• Li inhibition of G-protein coupled
pathway activated by ADH to
increase aquaporins
Thyroid function
• Hypothyroidism is increased six-fold
• Most are asymptomatic and diagnosis is purely biochemical
• Mood symptoms are harder to treat in low normal range of thyroid
function
• RCT meta-analysis accorded with observational data: 4% of patients
given Li developed hypothyroidism vs. none with placebo
hyperparathyroidism
• Absolute risk of 10%
for patients on Li
compared to 0.1% in
general population
• Possible risk of
decreased renal
function due to longterm hypercalcemia
Weight gain
• Clinically significant weight gain (>7%) more
frequent in patients with Li vs. placebo
• OR 1.89, 95% CI 1.27 – 2.82, p=0.002
• Weight gain is lower with Li compared to
Olanzapine
• n =285; OR=0.32, 95% CI 0.21-0.49, p<0.0001
Congenital malformations
• Nora et al., 1974, Lancet
• 400-fold increase of Ebstein’s anomaly
• Czeizel et al., 1990, Teratology
• No significant association between Li and
congential abnormalities
• McKnight et al., 2012, Lancet
• Odds of exposure to Li in cases of Ebstein’s did
not differ from controls
• Estimates are unstable because of low event
rate
No significant increased risks with
• Congenital malformations
• Alopecia
• Skin disorders
• Little evidence for a clinically significant reduction
in renal function in most patients
Management of lithium toxicity
Management of lithium toxicity
Anticonvulsants MOA
Valproic acid
Lamotrigine
Carbamazepine
All three are Na-channel blockers
GABA enhancement
by inhibition of
breakdown and
promotion of
synthesis
Calcium channel
inhibition
Potentiates synaptic
actions of GABA
Blocks glutamate
(excitatory)
Inhibition of
glutamate release
from presynaptic
terminals
May also potentiate
glutamate
transmission
Anticonvulsants PK
Valproic acid
Lamotrigine
Carbamazepine
Exclusively
hepatically
metabolized
Increased by
valproate
Erratically absorbed.
Has an active
metabolite that
contributes to its
activity.
CYP2C9 inhibitor
which means it can
interfere with other
antiseizure
medications like
phenytoin and
phenobarbital
Decreased by
carbamazepine
Induces CYP3A and
CYP2C – interferes
with many
medications
An autoinducer
Anticonvulsants Side Effects
Valproic acid
Lamotrigine
Carbamazepine
Hepatotoxicity
(transaminase rises and
bilirubin rise common
but severe
hepatotoxicity is rare)
SJS
TEN
SJS
TEN
Agranulocytosis,
aplastic anemia,
leukopenia,
thrombocytopenia
Hepatocellular and
cholestatic jaundice
and hepatitis
Nausea, vomiting
CNS: dizziness, ataxia,
blurred vision, double
vision
Drowsiness, dizziness,
ataxia, blurred vision
Nausea, vomiting
Nausea, vomiting
Evidence
Cipriani A, Barbui C,
Salanti G, et al.
Comparative efficacy and
acceptability of antimanic
drugs in acute mania: a
multiple-treatments metaanalysis.
Lancet 2011; 378: 1306–15.
Acute Mania
Acute Bipolar Depression
Maintenance
My neat and tidy synthesis