PHRM845 Exam 4-Lectures 54 and 57 (Ott)

Question 1

Schizophrenia spectrum disorders
DSM-5 includes: ___

Answer 1

schizophrenia, schizotypal personality disorder,
schizoaffective disorder, delusional disorder, and schizophreniform disorder

Question 2

Key features that define psychotic disorders

Answer 2

• Delusions – fixed false beliefs that are not amenable to change even with
  conflicting evidence
• Hallucinations – perception-like experiences that occur without an external
  stimulus (usually auditory, but can also be visual, tactile (feel like bugs are crawling on them), or olfactory)
• Disorganized thinking and speech – switching from one topic to another,
  unrelated answers to questions
• Disorganized or abnormal motor behavior
• Negative symptoms

Question 3

Features supporting schizophrenia diagnosis

Answer 3

inappropriate affect, dysphoric
mood (may present as depression, anxiety, or anger), disturbed sleep
pattern, lack of interest in eating, cognitive deficits, lack of insight

Question 4

Disease course of schizophrenia

Answer 4

-Onset late adolescence to early adulthood
-Men – late teens, early 20’s
-Women – late 20’s, early 30’s
-While above age ranges are usual, the disease can present at any time
-Course – exacerbations and remissions
-Antipsychotic drug therapy is used to return the patient to previous level of
functioning before episode occurred – as close as possible; also to extend the time
until a next episode occurs
-Each psychotic episode worsens baseline functioning in most patients
-Aging patients – less psychosis and more prominent residual negative and cognitive
symptoms

Question 5

Link to substance use

Answer 5

-Substance use is a common form of self-medication
-The longer the illness goes untreated, the more likely it is that the patient will misuse a
substance
-More than 75% of people with schizophrenia use tobacco
-Smoking is associated with induction of 1A2, not due to nicotine, but because of
hydrocarbons produced and inhaled, which decreases the serum concentration of
1A2 substrate antipsychotics (olanzapine, asenapine, clozapine, loxapine)
-Common use of marijuana and alcohol
-Marijuana, cocaine, and amphetamine use can hasten the onset of schizophrenia,
exacerbate symptoms, and reduce time to relapse
-Substance use treatment can be successfully achieved along with mental health
treatment in patients with schizophrenia, should be undertaken at the same time

Question 6

Psychotic symptoms: come&go or persist

Answer 6

Come and go

Question 7

Negative symptoms are most ___

Answer 7

Problematic

Question 8

Medications normally only treat ___ symptoms, but normally do not make ____ symptoms worse.

Answer 8

Positive
Negative

Question 9

Why do women get schizophrenia later in life than men?

Answer 9

Estrogen is protective

Question 10

P2P methamphetamine can cause ____

Answer 10

Schizophrenia; newest way of making methamphetamine because it is cheap.

Question 11

Using marijuana 50 times increases risk of schizophrenia ___x in those who have genetic risk.
-If not intercepted, 80% of patients with schizophrenia will develop tobacco use which is bad because it will ___ serum concentration of drug.

Answer 11

2
decrease

Question 12

Smoking induces ___

Answer 12

1A2

Question 13

Antipsychotic drug therapy overview

Answer 13

All antipsychotic drugs are considered to be equally effective in
clinical trials and in generally equivalent doses in a large
population (exception – clozapine – most effective)
◦ Individual patients will respond to or tolerate antipsychotics
differently
◦ The individual patient parameters are how we initially make
drug therapy choices
◦ MUST CONSIDER:
◦ Doses per day
◦ Side effects – what will the patient tolerate? What are
their other disease states or risk factors?
◦ Previous drug therapy – success or failure? Do family
members have this disease? What did they take?
◦ Cost of drug therapy – How will the patient pay for it?
Oral or Intramuscular depot?
◦ Concomitant drug therapy
◦ Need for monitoring – labs? Weight? ECG?

Question 14

Antipsychotic drug selection (convenience dosing of long-acting injection)

Answer 14

-Oral antipsychotic drug therapy is generally considered first-line, unless the patient
presents with reasons to consider IM depot drug therapy first
-IM depot drug treatment is often considered to be a punishment in our current treatment
culture, which we’re working to change – present to patient as convenience treatment versus non-adherence to oral drug treatment
-MUST have patient buy-in for treatment

Question 15

Typical antipsychotics

Answer 15

◦ Older agents – primarily D2 receptor antagonists
◦ Efficacy for positive symptoms is similar to atypical antipsychotics
◦ Haloperidol, chlorpromazine, fluphenazine, loxapine, perphenazine, thioridazine

Question 16

Typical antipsychotics clinical pearls

Answer 16

◦ Clinical efficacy for positive symptoms is similar to
atypical antipsychotics (except clozapine)
◦ Haloperidol is most commonly used – routine
and PRN
◦ Thioridazine is rarely used due to a black box
warning for QTc prolongation
◦ More EPS with higher potency typicals – and
atypical antipsychotics risperidone and
paliperidone
◦ Often used after failure of atypical antipsychotic
◦ All are available in generic form, which is helpful
for patient cost considerations
◦ Are very effective for treating the positive
symptoms, but are likely to worsen negative
and cognitive symptoms

Question 17

Atypical antipsychotics

Answer 17

◦ D2 antagonists + 5HT2A antagonists
◦ Less EPS than typicals; more metabolic side effects
◦Aripiprazole, Asenapine, Brexpiprazole, Cariprazine, Clozapine, Iloperidone, Lumateperone, Lurasidone,
Olanzapine, Paliperidone, Quetiapine, Risperidone, Ziprasidone

Question 18

Partial agonists

Answer 18

◦ “Stabilize” dopamine transmission – not too much, not too little
◦ Associated with more akathisia than other antipsychotics
◦ Approved for adjunct treatment in depression so all have boxed warning for suicidal thoughts/behavior
◦ Aripiprazole, Brexpiprazole, Cariprazine

Question 19

The “Pines”

Answer 19

◦ Less D2 antagonism, more 5HT2A antagonist – so significantly less EPS
◦ Higher weight gain than other agents
◦ Asenapine, Clozapine, Olanzapine, Quetiapine
◦ Adjust dosing for a smoker (need a higher dose)

Question 20

Asenapine transdermal patch

Answer 20

*Apply one patch every 24 hours,
rotate patch site to minimize
application site reactions
* Apply to hip, abdomen, upper arm, upper
back area
* Do not apply heat to patch site – increases
rate and extent of absorption
*Elimination half-life 30 hours after
patch removal
*Warnings for QTc
prolongation, increased
effectiveness of antihypertensives
(orthostatic hypotension side
effect)
*UGT and 1A2 substrate –
reduce dose of patch if given
with strong 1A2 inhibitors (e.g.,
fluvoxamine)
*Decrease dose of paroxetine by
50% if used in combination –
asenapine enhances the inhibitory
effects of paroxetine on its own
metabolism

Question 21

Clozapine REMS

Answer 21

◦ Absolute neutrophil count (ANC) monitoring is required for prescription of clozapine; pharmacy cannot
dispense without an ANC lab report within the past 7 days
◦ ANC > 2000/µL used to be the cutoff, but too many patients (especially people of African descent) were
not eligible for treatment due to benign ethnic neutropenia (BEN); this expands those eligible for
treatment
◦ clozapine REMS online system streamlines reporting and reduces ANC to 1500/µL to initiate therapy;
monitoring timelines weekly x 6 months, biweekly x 6 months, then every 4 weeks
◦Pharmacies and pharmacists MUST have proof of training in community setting to dispense clozapine

Question 22

Olanzapine/Samidorphan (Lybalvi)

Answer 22

◦ Samidorphan added to mitigate weight gain and metabolic syndrome potential of olanzapine
◦ Fixed dose of 10 mg samidorphan with 5 mg, 10 mg, 15 mg, 20 mg olanzapine
◦ Samidorphan is an opioid antagonist with preferential activity at the mu opioid receptor
◦ Contraindicated in patients currently taking opioids or in opioid withdrawal (may cause severe withdrawal)
◦ Warning for risk of opioid overdose if there are attempts to overcome opioid receptor blockade, especially if
olanzapine/samidorphan therapy is interrupted or discontinued
◦ Limited effectiveness of opioids for pain management
◦ If olanzapine/samidorphan therapy is interrupted or discontinued and opioid treatment is restarted in a patient who
had taken chronic opioid therapy, will be decreased opioid tolerance and need to start at lower doses of opioid and
titrate slowly
◦ Clinical trials showed less weight gain with the combination versus olanzapine monotherapy

Question 23

The “Dones”

Answer 23

◦ D2 and 5HT2A antagonists
◦ Variable EPS and metabolic side effects
◦Iloperidone, lurasidone, ziprasidone

Question 24

Risperidone and Paliperidone

Answer 24

◦ Highest D2 blockade for atypical antipsychotics
◦ High risk EPS, moderate risk metabolic side effects

Question 25

Lumateperone (Caplyta)

Answer 25

-Primarily 5HT2A antagonism with postsynaptic D2 blockade and presynaptic D2 partial agonist
-Low risk for weight gain or metabolic side
effects
-Low risk for EPS or akathisia
-3A4 substrate
-Does not cause presynaptic increase in dopamine, so don’t have to worry about antipsychotic trying to play catch up
-Might work for negative symptoms

Question 26

Pimavanserin (Nuplazid)

Answer 26

◦ Antipsychotic medication that is FDA-approved for
the treatment of hallucinations or delusions in a patient with Parkinson’s Disease
◦ Does not interact with the dopamine receptor
◦ Mechanism of Action – inverse agonist and
antagonist at the serotonin (5HT) 2A and (to a
lesser extent) 2C receptors
◦ 3A4 substrate, dose adjustment needed if given with
strong 3A4 inhibitors
◦ Warning for QTc prolongation
◦ Side effects include peripheral edema, confusional
states, nausea, rare angioedema
◦ Some preliminary studies in schizophrenia

Question 27

Warnings for all antipsychotics

Answer 27

◦ Boxed Warning: Increased risk of death in elderly patients treated with antipsychotics for
dementia with related behaviors.
◦ Metabolic adverse effects
◦ EPS
◦ Risk of somnolence, postural hypotension, and motor and/or sensory instability increases the risk
for falls/fractures.
◦ Fall risk assessment should be performed for patients taking other medications or having other
disease states that also have a fall/fracture or somnolence/hypotension risk; assess when initiating
antipsychotic and repeat routinely if on continuous long-term treatment

Question 28

Fluphenazine

Answer 28

◦ Given every 2 weeks
◦ 10 mg oral = 12.5 mg IM
◦ Short onset of action – don’t need
oral overlap dosing
◦ Oil-based – need to Z-track
◦ Long-acting older antipsychotic
◦ Not first-line (mainly used if not responding well to atypical antipsychotics)

Question 29

What is Z-track? When is Z-track used?

Answer 29

It is used for oil-based injections
-Pull skin down laterally/downward. Hold it taught and quickly/smoothly insert needle at 90 degree angle.

Question 30

Haloperidol

Answer 30

◦ Given every 4 weeks
◦ Load: 20 times oral dose
◦ Maintenance: 10 times oral dose
◦ If only use maintenance, may
need oral overlap
◦ Oil-based – Z-track
◦ Long-acting older antipsychotic
◦ Not first-line (mainly used if not responding well to atypical antipsychotics)

Question 31

Risperdal®
Consta
(risperidone)

Answer 31

-MUST supplement with oral risperidone (or another oral antipsychotic) for the first few weeks of treatment – I tell providers until 3rd injection (week 4) (week 0->2 weeks later->2 weeks later)
-Must be refrigerated and reconstituted prior to injection – just prior to
giving

Question 32

Perseris (Risperidone) – long-acting injectable

Answer 32

◦ Every 4 week LAI dosage form of risperidone
◦ Clinically relevant serum concentration after first dose
◦ initial peak 4 – 6 hours after dose due to initial release of risperidone
during depot formation process after injection; 2nd peak 10 – 14 days
◦ 9-OH risperidone metabolite initial peak 4 – 48 hours; 2nd peak 7 – 11 days
◦ Abdominal subcutaneous injection – 90 mg (3 mg oral) and 120 mg (4 mg oral)
◦ Refrigerate, allow to come to room temperature for 15 minutes
◦ Liquid and powder syringes provided, have to couple syringes,
shake to mix (ensure well mixed), inject using the liquid syringe
◦ Dose adjustments with strong 2D6 inhibitors
◦ 3A4 inducers – use 120 mg dose or may need oral supplementation (either avoid 3A4 inducers or use higher med dose)
◦ Patients may have a lump at the injection site that will decrease over time; they should not rub the area
◦ Avoid belt line

Question 33

Rykindo (Risperidone) IM injection

Answer 33

-Every 2 week IM injection
-Oral dose overlap is shorter than Risperdal
Consta (7 days vs 21 days)
-Needs to be refrigerated for storage and
resconstituted with diluent (similar to Risperdal Consta)
-Gluteal injection only (Risperdal Consta is deltoid and gluteal)

Question 34

Uzedy (risperidone)

Answer 34

◦ Abdominal (belt line) or upper arm subcutaneous injection
◦ Initiate the day after the last oral dose
◦ Can switch to Uzedy only from oral risperidone
◦ Given once monthly or every 2 months
◦ Don’t double up on injections

Question 35

Invega®
Sustenna
(paliperidone)

Answer 35

**Favorite in our region
-Loading dose, then booster, then every 4 weeks (starting 5 weeks
after loading injection)
-Initial loading and booster doses must be given in deltoid to improve absorption consistency
-Subsequent doses may be given in deltoid or gluteal muscle
-If loading strategy followed, no need for oral overlap antipsychotic treatment
-Does not need to be refrigerated or reconstituted, but does have two
syringes in packaging (deltoid and gluteal)
-May require dose adjustment in moderate to severe renal impairment (renally eliminated so there are specific CrCl guidelines)
-No 3A4 interactions

Question 36

Invega®
Trinza
(paliperidone q3mo)

Answer 36

-May be initiated for a patient who has been on a stable monthly (every 4 week) IM
injection of Invega Sustenna (only way that it should be used), at least FOUR
stable Invega Sustenna doses
-“Shake vigorously to ensure a homogenous suspension” – in other words – 15 seconds
of wrist snapping – must be given within 5 minutes of shaking
-Recommended to be given deltoid; gluteal administration results in a lower Cmax
-Not recommended if CrCl < 50 mL/min
-VERY EXPENSIVE - ~ $5000 - $6000 per
-Very viscous-injections technique is important and a large bore needle is needed

Question 37

Invega® Hafyera

Answer 37

-Paliperidone q6mos
◦ May be initiated after stable Invega Sustenna for 4 months or stable Invega Trinza after one 3-month dose
◦ Shake syringe very fast x 15 seconds, rest briefly, shake very fast x 15 second again, give within 5 minutes
◦ Gluteal injection only! (due to large volume because forms a place of release for 6 mos)
◦ Inject slowly using slow, firm, constant pressure (may take up to 30 seconds)
◦ Not recommended in renal impairment (CrCl < 90 mL/min)
◦ Expensive - ~ $12,000 per dose

Question 38

Zyprexa®
Relprevv
(olanzapine)

Answer 38

• Dose given every 2 – 4 weeks, based on needed dose (gluteal injection)
• Side effects similar to oral olanzapine, REMS (Risk Evaluation Mitigation Strategy) requires registration of patient, facility giving injection, prescriber, and pharmacy with Eli Lilly
  -PDSS – post-dose delirium sedation syndrome
• Patients in clinical trials experienced significant sedation that caused a concern
  for the patient leaving the facility right after the dose
• Physician must obtain informed consent and obtain patient PIN number
• PIN number given to pharmacist prior to dispensing – pharmacist must check
  for patient registration
• Patient may not pick up dose, must be done by clinic staff
• Patient must stay in clinic and have side effect monitoring done routinely for 3
  hours; must have accompanied ride home
• Facility must have on-site access to emergency services
• Could happen multiple times/could happen again 48-72 hours later

Question 39

Abilify®
Maintena
(aripiprazole)

Answer 39

◦ MUST overlap with oral aripiprazole (or another oral antipsychotic) for at least 14 days after first injection – ensure no hypersensitivity reaction
◦ Deltoid or gluteal injection
◦ Must reconstitute prior to injection

Question 40

Abilify® Maintena –
Dose Adjustments for P450 Interactions

Answer 40

If taking 2D6 or 3A4 inhibitors or 3A4 inducers
for more than 14 days as concomitant therapy

Question 41

Abilify®
Asimtufii
(aripiprazole)

Answer 41

◦Every-2-month dosing – 720 mg, 960 mg
◦Gluteal injection only
◦Must establish tolerability to aripiprazole with oral dosing up to 2 weeks to assess; after tolerability is established, continue
oral aripiprazole for 2 weeks after first injection
◦Remember 2D6/3A4 drug interactions

Question 42

Aristada® (aripiprazole lauroxil)

Answer 42

-Prodrug so oral overlap is longer
-all doses may be given in gluteal muscle; deltoid injection only for 441 mg dose
-Overlap with oral aripiprazole for 3 weeks after first injection
-Same P450 interactions as Abilify Maintena with dose adjustments (see prescribing info if needed)

Question 43

Aristada Initio®

Answer 43

◦ Only get this the FIRST day + aripiprazole
◦ Developed to avoid need for 21-day oral overlap of antipsychotic (because patients aren’t always adherent)
◦ May be given IM in deltoid or gluteal muscle
◦ How to dose (must establish tolerability of aripiprazole first):
◦ Avoid in patients who are 2D6 poor metabolizers or with strong 3A4 or 2D6 inhibitors
◦ May also be used to reinitiate Aristada after missed doses depending on the Aristada maintenance dose and time since last injection
◦ Administration: prefilled syringe MUST be shaken for 30 seconds
◦ Avoid injecting Aristada maintenance dose into same muscle group as the Aristada Initio injection

Question 44

Immediate Release Antipsychotic Injections/
Psychiatric Emergencies

Answer 44

◦ Haloperidol, chlorpromazine, fluphenazine are used,
haloperidol most commonly
◦ Often given in same syringe with lorazepam
◦ Atypical IM injections: olanzapine, ziprasidone
◦ Ziprasidone most commonly used: 20 mg dose, not more
than 40 mg given in one 24 hour period
◦ Olanzapine immediate release IM – CANNOT be given
at the same time as a benzodiazepine immediate release
injection – boxed warning for respiratory depression
◦ Loxapine for inhalation (Adasuve®) – not commonly used
due to REMS, boxed warning for bronchospasm and need for
close monitoring – developed due to need for emergency
treatment that was not injection to improve patient acceptance

Question 45

Antipsychotic Polypharmacy

Answer 45

**Drive pt and prescriber to clozapine first instead of duplicate tx
-Evidence does not normally recommend 2 antipsychotic at the same time.
◦ Very common in clinical practice
◦ Clinical research and literature provides limited support
◦ Concern for increased side effects of combination with limited increased efficacy
◦ Recent retrospective database study suggests that the combination of clozapine + aripiprazole may be
more effective than clozapine alone in decreasing hospitalizations.
◦ Indiana Medicaid – Indiana Medicaid requires a prior authorization for use of two antipsychotics in
combination – must have failure of 2 courses of antipsychotic monotherapy and clozapine (or have a
very good clinical reason why clozapine is not an option for an individual patient)
◦ Significantly increases expense
◦ Significant pill burden for the patient contributes to non-adherence to treatment, side effects increase

Question 46

Other Drugs Used in Schizophrenia

Answer 46

Depression – Antidepressants
Schizoaffective Disorder – Mood Stabilizers
Insomnia – Sedative/Hypnotics
Anxiety – Anxiolytics
Can result in cumbersome drug regimens, be aware and help to minimize as much as possible, help patients develop a plan for taking medications, combine dosing into as few times a day as possible
*A lot of comorbidities
*Ppl with psychiatric disorders are no different than other people who aren’t adherent to meds

Question 47

VMAT Inhibitors

Answer 47

Tetrabenazine (Xenazine)
Valbenazine (Ingrezza)
Deutetrabenazine (Austedo)
◦ Inhibit the vesicular monoamine transporter to decrease storage/increase release of dopamine, serotonin,
norepinephrine
◦ Efficacy expected to be an ~ 50% reduction in AIMS score for tardive dyskinesia

Question 48

Neuroleptic Malignant Syndrome

Answer 48

◦ Life- threatening – IS a medical emergency
◦ Caused by effects of antipsychotics on dopamine blockade – most antipsychotics have been associated with it
◦ Not necessarily dose- or duration-related, but may happen with first dose, dose increase, or earlier in the course of treatment
◦ Hyperpyrexia, tachycardia, labile blood pressure
◦ Muscle rigidity – elevated (significantly) CK,
myoglobinuria
◦ Treatment is supportive – discontinue antipsychotics, consider dopamine agonists
◦ Future antipsychotic use is NOT contraindicated
◦ May use same drug, likely switch to another antipsychotic
◦ Clinical conundrum because we have to treat psychotic disorder
**Creatinine kinase is an indicator of muscle breakdown from muscles tensing and relaxing so much

Question 49

Metabolic Adverse Effects Do NOT pick clozapine or olanzapine if pt has one of these

Answer 49

◦ Hyperglycemia, hyperlipidemia, hypertension
◦ Weight gain
◦ Life-style contributors
◦ High rates of smoking
◦ Poor diets
◦ Mortality = Average life span in severe mental illness is about 25 years less than the average population
◦ Deaths not always due to metabolic problems or violent death –high rates of cancer, infections
◦ Atypical Antipsychotic Risk: clozapine = olanzapine >
quetiapine = risperidone = paliperidone = asenapine =
iloperidone = cariprazine = brexpiprazole >
ziprasidone = lurasidone = aripiprazole

Question 50

Metabolic monitoring

Answer 50

-Personal/family hx
-Weight (BMI)
-Waist circumference
-Blood pressure
-FPG/HgbA1c
-Fasting lipids