Antipsychotics 2nd Generation

Indications: Schizophrenia and other psychotic disorders [for more information please refer to Antipsychotics 1st generation]

2nd Generation antipsychotics Overview

• Blocks DA2 receptors in Mesolimbic pathway which will alleviate + symptoms
• DA2 receptors are found in the inhibitory neurons that regulate dopaminergic neurons. When atypical antipsychotics bind to these receptors and block them which cause an increase of Dopamine release. Thus, atypical antipsychotics alleviate NEGATIVE symptoms
• Also blocks 5HT2a receptors 
  • Drug specific:
    • Aripiprazole, brexpiprazole cariprazine ➡︎ act as D2 and 5HT1a partial agonist
    • Brexpiprazole ➡︎ acts as a 5HT2a antagonist
• ⬇︎ EPS ⬆︎ metabolic side effects ⬆︎ hormonal issues
  
  • Metabolic SEs: weight gain, lipid abnormality, and hyperglycemia (may lead to diabetes)
  • Hormonal imbalance SEs: increases prolactin level, causing gynecomastia, galactorrhea (abnormal breast milk production w/o pregnancy), sexual dysfunction, and irregular periods.
• Lesser degree of EPS occurrence but can happen with dose dependence
• CV risks can be seen in SGAs - ziprasidone has the highest risk
• Clozapine - has superior efficacy but it has limited usage due to severe side effects such as agranulocytosis (acute and severe leukopenia and neutropenia), seizures, and myocarditis - in addition to having high metabolic risk. Due to this reason "Clozapine" is NOT a first-line option but can be next option after multiple trials of other antipsychotic meds (should include at least 1 SGA).
• Monitoring and screening should be performed for SE risks: overweight, obesity, hyperglycemia, dyslipidemia, HTN, and personal or family history. 
• SGAs have several different formulations
  • IM injections: Olanzapine, paliperidone, ziprasidone, risperidone, aripiprazole
  • ODT (orally disintegrating tablet): Clozapine, olanzapine, risperidone, aripiprazole, and asenapine) 

Selecting a second-generation Antipsychotics: Depends on the patient 

• Patient's past antipsychotic profile - what agent helped ? or not helped at all ? 
• Side effects
  • metabolic issues: pt who is overweight - should not pick agents that will worsen metabolic issues 
  • EPS: pt with history of TD/any type of disorder - pts should avoid risperidone, paliperidone, lurasidone
  • Resistance and adequate drug response - has pt had adequate trials (at least 4-6wks) of antipsychotic ? adherence ?
• Cost/familiarity of drugs

Drugs

Atypical antipsychotics:

Aripiprazole (Abilify).   ODT, IM - solution and suspension     Abilify Maintena (IM)     Aristada (IM)	Abilify - 10-30 mg PO QAM Abilify maintena IM - give Qmonthly Aristada IM - Q4-8wks	Asenapine (Saphris) SL tablet	10-20 mg/day. divided BID NO fOOD/DRINK for 10 min after dose
Clozapine (Clozaril)     FazaClo (ODT)     Versacloz (suspension) *use only after 2 AP trials or had severe ADRs* *BBW*	300-900 mg/day; divided (start from 12.5 mg and titrate up, also need titration when DC to prevent seizure) Very effective and has decreased risk of having EPS but it still is a 3rd line agent due to severe metabolic effects and agranulocytosis; REMS program Smoking reduces drug level	Brexpiprazole (Rexulti) *also indicated for major depressive disorder (MDD)*	12-4 mg QD
Olanzapine (Zyprexa)     Zydis (ODT)     Relprevv (IM)	10-20 mg QHS Relprevv injection - lasts 2-4 wks; REMS program  Smoking reduces drug level	Cariprazine (Vraylar) *also indicated for bipolar disorder*	1.5-6 mg QD
Paliperidone (Invega)     Invega Sustenna (IM)     Invega Trinza (IM)	PO 3-12 mg QD   CrCl <50 ml/min: 3 mg QD   CrCl <10 ml/min: Avoid to use OROS (osmotic-controlled release oral delivery system) - QD dosing; do NOT break or crush Sustenna - Qmonthly Trinza - Q3months (start only after receiving Invega Sustenna x 4months	Iloperidone (Fanapt)	12-24 mg/day; divided. Titrate slowly due to orthostasis/dizz
Quetiapine (Seroquel)     Seroquel XR	400-800 mg/day; divided BID or XR QHS TAKE XR at HS w/o food or light meal	Lurasidone (Latuda)	40-160 mg/day, divided TAKE W/ FOOD
Risperidone (RisperDAL)     Risperdal M-TAB (ODT) *also approved for irritability associated with autism*	4-16 mg/day; divided Risperdal Consta - inject Q2wk 25-50 mg RisperDal oral solution - can take directly from calibrated pipette, or mixed with water, coffee, OJ, and low-fat milk. (no cola/tea)
Ziprasidone (Geodon)     Geodon (IM)	40-160 mg/day; divided BID Acute injection: Geodon IM 10 mg Q2H / 20 mg Q4H (MAX: 40 mg/day IM)  TAKE W/ FOOD

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Psychosis in Parkinson Disease:

• Pimavanserin (Nuplazid): 34 mg PO QD / 17 mg PO BID
  • Indication: approved for parkinson's psychosis - hallucination, delusions. Nuplazid does not affect DA receptors, this drug does not worsen motor symptoms of Parkinson's disease. 
  • MOA: 5HT2a receptor antagonist, weak 5HT2c receptor antagonist
  • SEs: peripheral edema, confusion 
  • Warnings: NOT approved for dementia-related psychosis (BBW), QTc prolongation. 

Side Effects:

Aripiprazole(Abilify).	Akathisia, anxiety, insomnia, constipation	Asenapine (Saphris) SL tablet	Tongue numbness, somnolence, EPS, QTc prolongation [avoid use with QT risk] CONTRAINDICATION: - Severe hepatic impairment
Clozapine(Clozaril)     FazaClo (ODT)     Versacloz (suspension) *use only after 2 AP trials or had severe ADRs* *BBW*	BBW - life-threatening agranulocytosis (Low WBCs), tachycardia, orthostasis hypotension, syncope, cardiac arrest (syncope and cardiac arrest can happen a lot with rapid initial dosing). Should DC when myocarditis and cardiomyopathy suspect. Dose-related seizures - start at no higher than 12.5 mg QD/BID and titrate slowly Wt gain, inc lipids and glucose, sialorrhea=hypersalivation, agranulocytosis, dizz, insomnia, GI upset, QTc prolongation, seizures, myocarditis	Brexpiprazole(Rexulti) *also indicated for major depressive disorder (MDD)*	Wt gain, dyspepsia, diarrhea, akathisia
Olanzapine (Zyprexa)     Zydis (ODT)     Relprevv (IM)	BBW for Zyprexa Relprevv - should be monitored for 3 hrs post-injection including sedation, coma, delirium, agitation, anxiety, confusion, disorientation Somnolence, wt gain, inc lipid and glucose, EPS, QTc prolongation (lower risk), multiorgan-hypersensitivity DRESS reaction  (Drug Reaction with Eosinophilia and Systemic Symtpoms Syndromes)	Cariprazine(Vraylar) *also indicated for bipolar disorder*	EPS, dystonias, HA, insomnia
Paliperidone(Invega)     Invega Sustenna (IM)     Invega Trinza (IM)	Increased prolactin - sexual dysfunction, galactorrhea, irregular/missed periods, EPS ( @ higher dose), tachycardia, headache, sedation, anxiety,QTc prolongation, wt gain, increased lipid and glucose  After the body absorbed the medicine, it may pass into your stool. Nothing to worry about.	Iloperidone(Fanapt)	Dizz, somnolence, orthostasis, tachycardia, QT prolongation
Quetiapine(Seroquel)     Seroquel XR	Somnolence, orthostasis, wt gain, increased lipids and glucose, LOW EPS risk	Lurasidone(Latuda)	CONTRAINDICATIONs Strong CYP3A4 inducer and inhibitor Somnolence, EPS, dystonia, nausea, agitation, akathisia,  Nealry weight, lipid and BG neutral
Risperidone(RisperDAL)     Risperdal M-TAB (ODT) *also approved for irritability associated with autism*	EPS (@higher doses), increased prolactin - sexual dysfunction, galactorrhea, irregular/missed periods, wt gain, increased lipids and glucose, somnolence, orthostasis, QT prolongation
Ziprasidone(Geodon)     Geodon (IM)	CONTRAINDICATIONs QT prolongation somnolence/insomnia, RTI, HA, dizz, nausea

Drug interactions:

• All APs can cause QTc prolongation. FGA - thioridazine has high risk for QT prolongation, SGAs - All have higher risk QTc prolongation. 
• Smoking can reduce drug level - olanzapine and clozapine
• High levels of Risperidone and paliperidone can increase prolactin and cause EPS. Risperidone should be used cautiously with cYP2D6 inhibitors including paroxetine and fluoxetine. 
• Clozapine has seizure risk, thus avoid drugs that lower the seizure threshold. 
• Concurrent AP with BZD can increase the risk of respiratory depression and hypotension. A monitor is required.
• Use with caution with other dopamine blocking agents such as metoclopramide (Reglan). It will increase the risk of EPS an TD side effects. However, Reglan has lower NMS side effects.

Clozapine, Olanzapine, Risperidone, Paliperidone, and Quetiapine

• Have a risk of weight gain, elevated - cholesterol, BP, BG