Lecture 54-57 - Pharmacotherapy of Schizophrenia Flashcards

1
Q

Key features that define psychotic disorders:

A
  • 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, or olfactory)
  • Disorganized thinking and speech – switching from one topic to another, unrelated answers to questions
  • Disorganized or abnormal motor behavior
  • Negative symptoms
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2
Q

Disease Course in Schizophrenia

A

Onset late adolescence to early adulthood
Men – late teens, early 20’s
Women – late 20’s, early 30’s

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3
Q

Link to Substance Use

A

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)
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

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4
Q

Antipsychotic Drug Therapy Overview

A

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?

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5
Q

Antipsychotic Drug Selection

A

Oral antipsychotic drug therapy is generally considered first-line, unless the patient presents with reasons to consider IM depot drug therapy first

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6
Q

Typical Antipsychotics

A

◦ Older agents – primarily D2 receptor antagonists
◦ Efficacy for positive symptoms is similar to atypical antipsychotics
Haloperidol, Fluphenazine, Loxapine, Chlorpromazine, perphenazine, thioridazine

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7
Q

Typical Antipsychotics Clinical Pearls

A

◦ Haloperidol is most commonly used – routine and PRN
◦ More EPS with higher potency typicals
◦ Are very effective for treating the positive
symptoms, but are likely to worsen negative
and cognitive symptoms

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8
Q

Atypical Antipsychotics

A

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

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9
Q

Partial Agonists

A

◦ “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

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10
Q

Aripiprazole

A
  • 2D6 and 3A4 substrate
  • Moderate akathisia
  • Low weight gain
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11
Q

Brexpiprazole

A
  • 2D6 and 3A4 substrate
  • Moderate akathisia
  • Low-moderate weight gain
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12
Q

Cariprazine

A
  • 3A4 substrate
  • Moderate akathisia
  • Low-moderate weight gain
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13
Q

The “Pines”

A

◦ Less D2 antagonism, more 5HT2A antagonist – so significantly less EPS
◦ Higher weight gain than other agents
asenapine, clozapine, olanzapine, quetiapine

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14
Q

Asenapine

A
  • Sublingual and
    patch formulations
  • 1A2 substrate
  • QTc prolongation
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15
Q

Clozapine

A

1A2 substrate
* Boxed warnings:
neutropenia, orthostasis, bradycardia, syncope, seizures, myocarditis, cardiomyopathy
* Side effects: sedation,
weight gain, constipation, hypersalivation, dry
mouth, GI hypomotility
with obstruction risk
* QTc prolongation

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16
Q

Olanzapine

A
  • 1A2 substrate
  • Significant weight gain and sedation
  • High risk metabolic syndrome
  • DRESS warning
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17
Q

Quetiapine

A
  • 3A4 substrate
  • QTc prolongation
  • Weight gain and sedation
  • Boxed warning for suicidal ideation
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18
Q

Asenapine Transdermal Patch (Secuado®)

A

Apply one patch every 24 hours, rotate patch site to minimize application site reactions
Warnings for QTc prolongation
UGT and 1A2 substrate – reduce dose of patch if given with strong 1A2 inhibitors (e.g., fluvoxamine)

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19
Q

Clozapine REMS

A

Reduces ANC to 1500/μL to initiate therapy; monitoring timelines weekly x 6 months, biweekly x 6 months, then every 4 weeks

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20
Q

Olanzapine/Samidorphan (Lybalvi®)

A

◦ Samidorphan is an opioid antagonist with preferential activity at the mu opioid receptor
samidorphan added to mitigate weight gain
do not take if pt already on opioids

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21
Q

The “Dones”

A

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

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22
Q

Iloperidone

A
  • High risk for orthostasis and syncope
  • QTc prolongation
  • 2D6 substrate
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23
Q

Lurasidone

A
  • 3A4 substrate
  • Higherriskforakathisia
  • Warning for suicidal thoughts – adjunct for bipolar depression
  • Take with food (350 calories) to increase bioavailability
24
Q

Ziprasidone

A
  • QTc prolongation (contraindication)
  • DRESS warning
  • Take with food to increase absorption and bioavailability
  • 3A4 substrate (1/3) and aldehyde oxidase (2/3) (less worry for P450 interactions)
25
More "Dones"
◦ Highest D2 blockade for atypical antipsychotics ◦ High risk EPS, moderate risk metabolic side effects Risperidone Paliperidone
26
Risperidone
* 2D6 substrate (minor 3A4 substrate) * EPS, hyperprolactinemia, weight gain, sedation, orthostasis
27
Paliperidone
* Renally eliminated – dose adjustments in renal impairment * Similar side effects with risperidone * QTc prolongation
28
Lumateperone (Caplyta®)
Low risk for weight gain or metabolic side effects Low risk for EPS or akathisia 3A4 substrate
29
Pimavanserin (Nuplazid®
◦ Antipsychotic medication that is FDA-approved for the treatment of hallucinations or delusions in a patient with Parkinson’s Disease MOA: inverse agonist and antagonist at the serotonin (5HT) 2A 3A4 substrate
30
Warnings for all Antipsychotics
◦ 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
31
Haloperidol decanoate
◦ 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
32
Risperdal® Consta (risperidone)
MUST supplement with oral risperidone (or another oral antipsychotic) for the first few weeks of treatment – I tell providers until 3rd injection (week 4)
33
Perseris® (risperidone
◦ Abdominal subcutaneous injection - must be given in transpyloric plane ◦ 3A4 inducers – use 120 mg dose or may need oral supplementation
34
Rykindo® (risperidone
Every 2 week IM injection Oral dose overlap is shorter than Risperdal Consta (7 days vs 21 days)
35
Uzedy® (risperidone)
◦ Abdominal or upper arm subcutaneous injection * Given once montly or every 2 months
36
Invega® Sustenna (paliperidone
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 If loading strategy followed, no need for oral overlap antipsychotic treatment May require dose adjustment in moderate to severe renal impairment
37
Invega® Trinza (paliperidone q3mo)
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 Recommended to be given deltoid; gluteal administration results in a lower Cmax Not recommended if CrCl < 50 mL/min
38
Invega® Hafyera (paliperidone q6mo)
◦ May be initiated after stable Invega Sustenna for 4 months or stable Invega Trinza after one 3- month dose * Gluteal injection only
39
Zyprexa® Relprevv (olanzapine)
PDSS – post-dose delirium sedation syndrome
40
Abilify® Maintena (aripiprazole)
◦ MUST overlap with oral aripiprazole (or another oral antipsychotic) for at least 14 days after first injection ◦ Deltoid or gluteal injection
41
Abilify® Maintena – Dose Adjustments for P450 Interactions
If taking 2D6 or 3A4 inhibitors or 3A4 inducers for more than 14 days as concomitant therapy, must look at dosing table
42
Abilify® Asimtufii (aripiprazole)
Every 2 month dosing 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
43
Aristada® (aripiprazole lauroxil)
Overlap with oral aripiprazole for 3 weeks after first injection
44
Aristada Initio®
* Developed to avoid need for 21-day oral overlap of antipsychotic * Avoid in patients who are 2D6 poor metabolizers or with strong 3A4 or 2D6 inhibitors
45
Immediate Release Antipsychotic Injections/ Psychiatric Emergencies
* Haloperidol, chlorpromazine, fluphenazine are used, haloperidol most commonly ◦ 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®)
46
Clinical Treatment Strategies for EPS
acute dystonia drug-induced parkinson's akathisia tardive dyskinesia
47
Acute dystonia
Not life-threatening, but very frightening * IM anticholinergic NOW dose (benztropine 2mg, diphenhydramine 50mg)
48
Drug-induced parkinson's
longer-term side effect – months into antipsychotic treatment * Oral anticholinergic (benztropine, trihexyphenidyl, diphenhydramine)
49
Akathisia
subjective feeling of restlessness; increases risk for suicidal thinking/behaviors Beta-blocker: propranolol preferred for 1st line Benzodiazepine: usually lorazepam
50
Tardive dyskinesia
lower dose of antipsychotic if possible, or switch to antipsychotic with less risk VMAT inhibitors
51
VMAT Inhibitors
◦ Inhibit the vesicular monoamine transporter to decrease storage/increase release of dopamine, serotonin, norepinephrine tetrabenazine, valbenazine, deutetrabenazine
52
Valbenazine
2D6/3A4 substrate QTc prolongation
53
Deutetrabenazine
2D6 substrate QTc prolongation
54
Neuroleptic Malignant Syndrome
* Life threatening - IS a medical emergency ◦ 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
55
Metabolic Adverse Effects
◦ Hyperglycemia, hyperlipidemia, hypertension greastest risk in clozapine and olanzapine least risk in ziprasidone, luradisone, aripiprazole
56
Metabolic monitoring: FPG/HgbA1c
baseline 12 weeks yearly