Schizophrenia- Krysiak

Describe the 4 major dopaminergic pathways involved in schizophrenia:

• what kind of symptoms are involved with each?

• mesolimbic: positive sym

• mesocortical: negative sym

• nigrostriatal: EPS, movement

• tuberoinfundibular: prolactin release

Result of D2 receptor antagonism on the mesolimbic area:

decreased positive symptoms

Result of D2 receptor antagonism on the mesocortical area:

• production of secondary negative symptoms

• may/may not worsen cognitive or affective symptoms

Result of D2 receptor antagonism on the nigrostriatal pathway:

EPS

Result of D2 receptor antagonism on the tuberoinfundibular pathway:

hyperprolactinemia

PRACTICE:

Which dopamine pathway is involved with positive symptoms of

schizophrenia?

A. Mesocortical

B. Nigrostriatal

C. Mesolimbic

D. Tuberoinfundibular

C

Schizophrenia is a chronic disorder of __________ and __________.

thought and affect

List positive, negative, and cognitive symptoms:

Positive	Negative	Cognitive
suspiciousness delusions (unusual thought content) hallucinations conceptual disorganization	affective flattening (Reduced emotional expressiveness) alogia (few words) anhedonia (no interest in things) avolition (Lack of motivation)	impaired attention impaired working memory impaired executive function

What are the time frames for each of the following:

• brief psychotic episode

• schizophreniform

• schizophrenia

• chronic schizophrenia

• brief psychotic episode: <2w

• schizophreniform: ≥2w and <6m

• schizophrenia: ≥6m

• chronic schizophrenia: >2yrs

How is schizophrenia diagnosed according to DSM-V:

• characteristic symptoms: 2 or more of the following

  • delusions*

  • hallucinations*

  • disorganized speech*

  • grossly disorganized or catatonic behavior

  • negative symptoms

• each symptom must persist for a significant portion of at least a 1-month period

• MUST have at least one the symptoms with an *

PRACTICE:

Which of the following is a negative symptom of schizophrenia?

A. hallucinations

B. delusions

C. avolition

D. disorganization

C.

is schizophrenia curable?

no

Nonpharm for schizophrenia:

• psychosocial rehab programs

  • case management, education, targeted therapy, basic living and social skills, work programs, housing

• assertive community treatment (ACT)

  • teams available 24/7—> help with meds, crises, and daily living

List the typical or first gen antipsychotics:

• also say whether they are high, mid, or low potency

• Chlorpromazine (Thorazine)- low

• Thioridazine (Mellaril)- low

• Perphenazine (Trilafon)- mid

• Loxapine (Loxitane, Adasuve Inhaled Powder)- mid

• Thiothixene (Navane)- high

• Trifluperazine (Stelazine)- high

• Molindone (Moban)- high

• Haloperidol (Haldol, Haldol-D)- high

• Fluphenazine (Prolixin, decanoate)- high

MOA of FGAs:

DA receptor antagonists—> high affinity to D2

What FGA has a REMS program due to risk of bronchospasm, pulmonary distress, and pulmonary arrest?

Loxapine

Loxapine Staccato (Adasuve) is what kind of dosage form? indication?

• inhaled powder

• indication: acute agitation associated with schizo and BPD

List the SGAs:

• Aripiprazole (Abilify, Abilify Maintena, Abilify Aristada, Initio, Asimtufii, MyCite)

• Asenapine (Saphris, Secuado)

• Brexpiprazole (Rexulti)

• Cariprazine (Vraylar)

• Clozapine (Clozaril)

• Iloperidone (Fanapt)

• Lumateperone (Caplyta)

• Lurasidone (Latuda)

• Olanzapine (Zyprexa, Zydis, Relprevv)

• Paliperidone (Invega, Invega Sustenna, Invega Trinza, Invega Hafyera)

• Pimavanserin (Nuplazid)

• Quetiapine (Seroquel, XR)

• Risperidone (Risperdal, M-Tab, Risperdal Consta, Perseris, Uzedy)

• Ziprasidone (Geodon)

How do SGAs effect each of the following:

• mesolimbic

• mesocortical

• nigrostriatal

• tuberoinfundibular

• limbic: decreases DA= relieves + sym

• cortical: increases DA= relieves - sym

• nigro: increase DA= less chance of EPS

• tube: less prolactin release

MOA of SGAs:

• which have greater affinity for 5HT2A receptors > D2 receptors

• which are partial agonists?

• ALL HAVE UNIQUE PROPERTIES!!!!!!!!!!!!

• In common: 5HT2 and D2 antagonism

• ALL SGAs have greater affinity for 5HT_2A >D₂ EXCEPT aripiprazole and brexipiprazole

• Partial D2 agonists: Aripiprazole, brexipiprazole, cariprazine

  • two “pips” and a “rip”

List the SGA for each of the following questions:

• What SGA is sublingual only and no food/drink 10min after admin?

• Due to a long half-live steady state with what SGA is not reached for several weeks?

• Which SGA needs care with dosing in CYP2D6 slow metabolizers?

• Which SGA’s bioavailability is increased by 9% when administered with high fat meal?

• Which SGA’s bioavailability is increased when administered with food?

• Asenapine

• Cariprazine

• Iloperidone

• Lumateperone

• Paliperidone

What 2 SGA’s must be taken with food?

• Lurasidone

• Ziprasidone

Which SGA has a REMS program for neutropenia/agranulocytosis?

• what is defined as severe neutropenia?

• At what ANC level can it be initiated?

• Clozapine

• severe neutropenia is ANC <500

• ANC ≥1500 it can be initiated

Which SGA is avoided in first episode because of weight gain?

olanzapine

PRACTICE:

In addition to dopamine blockade, second generation antipsychotics as a class

have a mechanism of:

A. Dopamine agonism

B. Serotonin antagonism

C. Alpha blockade

D. Histaminergic blockade

B.

Side effects associated with Aripirazole?

• akathisia (movement disorder)

• others: HA, anxiety, lower risk of weight gain

When is clozapine indicated? advantages and disadvantages of use? BBW?

• only if pt. fails 2 treatments

• advantages: lowest risk of EPS, very effective tx

• disadvantages: side effect profile

  • BBW:

    • neuropenia/agranulocytosis—> REMS

    • myocarditis/cardiomyopathy

    • orthostatic hypotension

    • seizures

  • other ADRS: severe weight gain, constipation, drooling

C/I of lurasidone?

strong CYP450 3A4 inhibitors/inducers

Paliperidone is the active metabolite of ____________.

Risperidone

BBW with Zyprexa?

• Zyprexa Relprevv (ER injection formulation)—> BBW for sedation and delirium following injection

Quetiapine XR is oral only and taken when?

at night WITHOUT food

Ziprasidone is C/I in what?

QT prolongation

PRACTICE:

At what ANC level may clozapine be initiated?

A. 900

B. 1000

C. 1200

D. 1500

D.

PRACTICE:

When educating a patient on a new prescription for lurasidone, which statement would be considered the most appropriate regarding taking the medication?

A. Take the dose prior to bedtime for full effect

B. Avoid grapefruit and grapefruit juices

C. All side effects are short lived

D. Take dose on an empty stomach

B. (bc it’s contraindicated with 3A4 inhibitors/inducers)

PRACTICE:

A patient presents to your clinic and is found to have hyperprolactinemia from his risperidone. What additional antipsychotic should be avoided?

A. Clozapine

B. Olanzapine

C. Paliperidone

D. Quetiapine

C.

ALL ANTIPSYCHOTICS HAVE WHAT BBW?

increased risk of mortality if used for dementia-related psychosis

What endocrine ADRs are seen with antipsychotics?

• prolactin elevation (bc of DA antagonism in tuberoinfundibular tract)

• weight gain (bc of antihistamine, antimuscarinic, and blocking 5HT_2C)

• Type 2 DM (increases insulin resistance and impairs b-cell fxn)

What CV ADRs are seen with antipsychotics?

• orthostatic hypotension (bc of a-adrenergic blockage)

• ECG changes (bc of anticholinergic and alpha affects)

  • QT prolongation, reflex tachycardia

  • d/c if QTc interval exceeds 500msec

• myocarditis (mainly w/ clozapine, <1% of pts.)

• lipid changes (increased appetite and weight gain contributes, elevated TGs and CHO)

Describe the CNS ADR seen with antipsychotics called EPS.

• prevention?

• EPS—> extrapyramidal system, term used to describe anti-psychotic induced movement disorders

  • includes:

    • dystonia (involuntary movements/spasms)

    • akathisia (Unbearable inner restlessness with compulsive movements (pacing, foot-tapping, inability to sit still))

    • parkinsonism (Bradykinesia, rigidity, and resting tremor mimicking idiopathic Parkinson’s disease)

    • tardive dyskinesia (Involuntary, repetitive movements (tongue writhing, lip smacking, grimacing) that develop after months/years of antipsychotic use)

• prevent by

  • initiating at low dose, and titrating up slowly

  • choose antipsychotic with low EPS risk

PRACTICE:

A 67yo patient that has been taking risperidone 0.5 PO BID x 4 weeks presents to your outpatient clinic with bradykinesia and tremor at rest. What is the most likely EPS the patient is experiencing?

A. Akathisia

B. Dystonia

C. Tardive dyskinesia

D. Pseudoparkinsonism

D.

PRACTICE:

Which of the following is a black boxed warning of clozapine? SATA

A. Constipation

B. Myocarditis

C. Agranulocytosis

D. Death with dementia related psychosis

B, C, D

What drugs can be used to prevent tardive dyskinesia (an ADR of antipsychotics)?

• What is the MOA?

• ADRs?

• C/Is?

• Valbenazine and Deutetrabenazine

• MOA: VMAT2 inhibitors

• ADRs: somnolence

• C/Is: Deute in hepatic impairment

Treating parkinson’s and psychosis is difficult because it’s a balancing act between dopamine and acetylcholine.

What drug can be used for psychosis in Parkinson’s Disease?

MOA?

Warnings?

SE?

• drug: Pimavanserin (Nuplazid)

• MOA: inverse agonist and antagonist at 5-HT2A receptors

• Warnings: not for dementia related psychosis, QT prolongation

• SE: peripheral edema, confusion

Describe the CNS ADR seen with antipsychotics called NMS.

• treatment?

• NMS—> neuroleptic malignant syndrome, disruption of thermoregulatory process or excess heat production second to muscle contractions

• tx:

  • D/C ALL DOPAMINE blockers

  • supportive care

  • DA agonists: bromocriptine

  • Dantrolene for skeletal relaxation

What Derm ADRs are seen with antipsychotics?

• BBW on what drug?

• DRESS—> drug reaction with eosinophilia and systematic symptoms

  • BBW on olanzapine

• photosensitivity

REVIEW:

Answer the following about FGAs and SGAs and ADR risk:

SE/Risk	Meds
EPS	lowest risk: highest risk:
Metabolic	lowest risk: mod risk: highest risk:
QT prolongation	highest risk:
Hematological	highest risk:
increase prolactin	highest risk:
seizure	highest risk:
Cerebrovascular events	highest risk:

SE/Risk	Meds
EPS	lowest risk: quetiapine, clozapine highest risk: FGAs, risperidone, paliperidone
Metabolic	lowest risk: aripiprazole, ziprasidone, lurasidone, asenapine mod risk: risperidone, paliperidone highest risk: clozapine, olanzapine, quetiapine
QT prolongation	highest risk: thioridazone, haloperidol, ziprasidone
Hematological	highest risk: clozapine
increase prolactin	highest risk: risperidone, paliperidone
seizure	highest risk: clozapine
Cerebrovascular events	highest risk: risperidone

Another review table for ADRs krysiak gave us:

Smoking induces what enzyme? what SGA interacts then?

smoking—> CYP1A2—> can increase clozapine levels = increased seizure risk

For initial treatment of schizophrenia:

• 1st episode pts. should be started at ___% of normal dose range

• adequate trial is how long?

• after tx of first psychotic episode, pt. should continue on medication for at least __ months after remission

• 1st episode pts. should be started at 50% of normal dose range

• adequate trial—> 4-6 weeks

• after tx of first psychotic episode, pt. should continue on medication for at least 18 months after remission

What dosage form can a pt. take that may help with adherence in schizo pts.?

long-acting injectable antipsychotics (LAIA) or Abilify MyCite (a biosensor inside a tablet)

List the FGAs and SGAs that come in long-acting injectable form:

FGAs:

• Fluphenazine decanoate

• Haloperidol decanoate

SGAs

• Risperidone IM (Risperdal Consta, Rykindo)

• Risperidone SQ (Perseris, Uzedy)

• Paliperidone (Sustenna, Trinza, Hafyera)

• Aripiprazole (Maintena, Aristada, Asimtufii, Initio)

• Olanzapine (Zyprexa Relprevv)

  • remember BBW with it

What is the definition of treatment-resistant schizophrenia?

What is the only antipsychotic that has shown superiority in tx for this?

• def: persistent symptoms despite 2 different antipsychotics at adequate dosage for at least 6 weeks

• clozapine