# Antipsychotics

Stacy Elder Dalpoas, PharmD, BCPS, Matthew E. Peters, M.D., Christopher Marano, M.D.

## 

INDICATIONS

## 

FDA

  * Schizophrenia
  * Bipolar affective disorder
  * Major depressive disorder (adjunctive therapy)
  * Agitation associated with schizophrenia or bipolar mania
  * Autism
  * Tourette’s syndrome
  * Psychosis
  * **See TableTable 2. for specific FDA indications for each antipsychotic.**



## 

NON-FDA APPROVED USES

  * Dementia (behavioral disturbances)
  * Substance abuse (reduction in use)
  * Anorexia nervosa (increase body weight)
  * Obsessive-compulsive disorder
  * Post-traumatic stress disorder
  * Generalized anxiety disorder
  * Hiccups
  * Nausea/vomiting
  * ICU delirium



## 

MECHANISM

  * The first-generation antipsychotics ("typicals" or "traditional") and second-generation antipsychotics ("atypicals") block post-synaptic dopamine receptors in the mesolimbic system, which has been correlated with antipsychotic effect.
  * The first-generation antipsychotics have minimal antagonism of serotonin receptors, whereas the second-generation antipsychotics have greater antagonism of serotonin receptors.
  * Side effects of both first- and second-generation antipsychotics are due to antagonism at histamine, muscarinic, and alpha adrenergic receptors.
  * Pimavanserin is a novel atypical antipsychotic with inverse agonist and antagonist activity at 5-HT2A , with low/no affinity for 5-HT2C, sigma 1, 5-HT2B, dopaminergic, muscarinic, histaminergic or adrenergic receptors.



## 

FORMS

  * See "Usual Adult Dosing" section/Table Table 1.



## 

USUAL ADULT DOSING

Table 1.**Drug**| **Forms**| **Initial Dose**(mg/day)| **Maintenance****Dose**(mg/day)| **Max Dose**(mg/day)| **Depot?**| **How Supplied**| **Example Cost****Dose (pill count): price in USD**  
---|---|---|---|---|---|---|---  
**FIRST-GENERATION ANTIPSYCHOTICS ("TYPICALS")**  
Chlorpromazine(Thorazine®)| TABLETACUTE IM| 75| 200-600| 2000| NO| Tab: 10, 25, 50, 100, 200mgIM: 25mg/mL| 10mg (100): $20.79; 25mg (100): $27.03; 50mg (100): $38.24; 100mg (100): $43.52; 200mg (100): $56.77  
Fluphenazine(Prolixin®)| TABLETACUTE IMLIQUID| 2.5-10| 1-5| 40| YES| Tab: 1, 2.5, 5, 10mg IM: 2.5mg/mLLiq: 2.5mg/5mL, 5mg/mL| 1mg (90): $17.99; 2.5mg (60): $15.99; 5mg (60): $18.99; 10mg (60): $24.99**Fluphenazine Decanoate: 25mg/mL (5mL): $82.99**  
Haloperidol(Haldol®)| TABLETACUTE IMLIQUID| 1.5-15| 1-30| 30| YES| Tab: 0.5, 1, 2, 5, 10, 20mgIM: 5mg/mLLiq: 2mg/mL| 0.5mg (90): $16.99; 1mg (90): $19.99; 2mg (90): $20.99; 5mg (90): $25.99; 10mg (60): $72.99; 20mg (60): $124.99  
**Haloperidol Decanoate:****100mg/mL (1mL): $50.99**  
Loxapine(Loxitane®)| CAPSULE| 20| 60-100| 250| NO| Cap: 5, 10, 25, 50mg| 5mg (30): $28.99; 50mg (30): $39.99  
Perphenazine(Trilafon®)| TABLET| 12-24| 16-32| 64| NO| Tab: 2, 4, 8, 16mg| 2mg (60): $51.99; 4mg (60): $69.99; 8mg (60): $76.99; 16mg (60): $107.99  
Pimozide(Orap™)| TABLET| 1-2| 2-4| 10| NO| Tab: 1, 2mg| 1mg (60): $85.99; 2mg (60): $109.99  
Thioridazine(Mellaril®)| TABLET| 150-300| 200-800| 800| NO| Tab: 10, 25, 50, 100mg| 10mg (90): $23.99; 25mg (90): $28.99; 50mg (90): $35.99; 100mg (90): $34.99  
Thiothixene(Navane®)| CAPSULE| 6-10| 20-30| 60| NO| Cap: 1, 2, 5, 10mg| 1mg (90): $22.99; 2mg (90): $29.69; 5mg (90): $37.99  
Trifluoperazine(Stelazine®)| TABLET| 4-10| 15-20| 40| NO| Tab: 1, 2, 5, 10mg| 2mg (60): $36.99; 5mg (60): $35.99; 10mg (60): $55.99  
**SECOND-GENERATION ANTIPSYCHOTICS ("ATYPICALS")**  
Aripiprazole(Abilify®)| TABLETODT*ACUTE IMLIQUID| 10-15| 10-15| 30| NO| Tab: 2, 5, 10, 15, 20, 30mgODT*: 10, 15mgIM:7.5mg/mLLiq: 1mg/mL| 2mg (30): $570.01; 5mg (30): $558.02; 10mg (30): $584.00; 15mg (30): $560.01; 20mg (30): $793.98; 30mg (30): $815.98ODT* --> 10mg (30): $631.30  
Asenapine(Saphris®)| SUBLINGUAL| 10| 10-20| 20| NO| SL: 5, 10mg| 5mg (6 boxes, 10 ea): $676.02  
Clozapine(Clozaril®)| TABLETODT*| 12.5-25| 300-450| 900| NO| Tab: 25, 50, 100, 200mgODT*: 12.5, 25, 100, 150, 200mg| 25mg (100): $242.17  
Iloperidone(Fanapt®)| TABLET| 2| 12-24| 24| NO| Tab: 1, 2, 4, 6, 8, 10, 12mg| 2mg (100): $174.00; 4mg (100): $174.00; 6mg (90) $208.00  
Lurasidone(Latuda®)| TABLET| 40-80| 40-80| 160| NO| Tab: 20, 40, 80, 120mg| 80mg (30 ea): $535.98  
Olanzapine(Zyprexa®)| TABLETODT*ACUTE IM| 5-10| 10-20| 20| YES| Tab: 2.5, 5, 7.5, 10, 15, 20mgODT*: 5, 10, 15, 20mgIM: 5mg/mL| 10mg (30): $379.98; 15mg (30): $490.03 ODT* --> 5mg (30): $470.01; 10mg (30): $659.97**Zyprexa® Relprevv™: 210mg (1 kit): $425; 300mg (1 kit): $599.00; 405mg (1 kit): $750.00**  
Paliperidone(Invega®)| TABLET| 6| 3-12| 12| YES| ER Tab: 1.5, 3, 6, 9mg| 3mg (100): $1688.96; 6mg (100): $1879.48; 9mg (100): $2461.97**Invega® Sustenna®: 78mg/0.5mL (0.5mL): $617.02**  
Pimavanserin (Nuplazid®)  
Quetiapine(Seroquel®)| TABLET| 50| 300-800| 800| NO| Tab: 25, 50, 100, 200, 300, 400mgXR Tab: 50, 150, 200, 300, 400mg| 25mg (60): $212.09; 50mg (100): $625.00; 100mg (60): $396.98; 200mg (60): $715.99; 300mg (60): $969.96; 400mg (30): $575.97XR --> 50mg (60): $337.99; 150mg (60): $597.99; 200mg (60): $673.96; 300mg (60): $880.02; 400mg (60): $1022.95  
Risperidone(Risperdal®)| TABLETODT*LIQUID| 2| 2-8| 16| YES| Tab: 0.25, 0.5, 1, 2, 3, 4mgODT*: 0.25, 0.5, 1, 2, 3, 4mgLiq: 1mg/mL| 0.25mg (60): $145.97; 0.5mg (60): $179.99; 1mg (60): $195.99; 2mg (60): $289.96; 3mg (60): $300.01; 4mg (60): $399.98 ODT* --> 0.5mg (28): $171.98; 1mg (28): $195.00; 4mg (28): $542.99Liquid**\-- >**1mg/mL (30mL): $125.98**Risperdal® Consta®: 12.5mg (2 kits): $316.71; 25mg (2 kits): $625.74; 37.5 (2 kits): $933.62; 50mg (2 kits): $1241.54**  
Ziprasidone(Geodon®)| CAPSULEACUTE IM| 40| 40-160| 200| NO| Tab: 20, 40, 60, 80mgIM: 20mg/mL| 20mg (60): $545.97; 40mg (60): $520.97; 60mg (60): $664.97; 80mg (60): $664.97  
* ODT = orally disintegrating tablet\- _Data in above table from:_ Micromedix® 2.0 and Lexicomp Online™; _Data in above table reviewed by_ Sujin Lee, Pharm.D. BCPP  
  
  * Potency of first-generation antipsychotics is compared in Chlorpromazine equivalents: 
    * 100mg of Chlorpromazine is equal to: 2mg of Haloperidol, 2mg of Fluphenazine, 2mg of Pimozide, 4mg of Thiothixene, 5mg of Trifluoperazine, 10mg of Perphenazine, 10mg of Loxapine, 100mg of Thioridazine.
    * The "high-potency" agents have equivalent dose to 1mg of Chlorpromazine of _< _5mg and "low-potency" of _>_ 40mg.
  * DEPOT FORMULATIONS 
    * FLUPHENAZINE Decanoate (25mg/mL): Initial dose 1.25x daily oral dose; Maintenance dose based on patient response; Maximum dose 50mg; Interval is 2-4 weeks.
    * HALDOL Decanoate (50mg/mL, 100mg/mL): Initial dose 10-20x daily oral dose; Maintenance dose 10-15x daily oral dose; Maximum dose 100mg (if >100mg needed, administer in separate injections one week apart); Interval is _< _4 weeks
    * OLANZAPINE (Zyprexa® Relprevv™): Available in 150, 210, 300, and 405mg kits. Conversion from daily oral dosing as follows: 
      * 10mg = Initial dose 210mg q2weeks x4 doses OR 405mg q4weeks x2doses; Maintenance dose 150mg q2weeks OR 300mg q4weeks
      * 15mg = Initial dose 300mg q2weeks x4 doses; Maintenance dose 210mg q2weeks OR 405mg q4weeks
      * 20mg = Initial dose & Maintenance dose 300mg q2weeks
    * PALIPERIDONE (Invega® Sustenna®): Available in 39, 78, 117, 156, and 234mg kits. 
      * Initial Dose (same no matter what the oral dose): 234mg on Day 1, then 156mg one week later
      * Maintenance dose (based on daily oral dose): 3mg=39-78mg, 6mg=117mg, 12mg=234mg
    * RISPERIDONE (Risperdal® Consta®): Available in 12.5, 25, 37.5, and 50mg kits. 
      * No formal conversion from oral dose. Most patients maintained on 25mg or 37.5mg q2weeks



## 

DOSING IN SPECIAL POPULATIONS

## 

RENAL

  * FIRST GENERATION: 
    * All first generation antipsychotics can be used with caution in those with renal impairment without dosage adjustment. However, recommend initiation at lowest dose (especially in patients with concurrent hepatic impairment).
  * SECOND GENERATION: 
    * Lurasidone if ClCr < 50mL/min initial 20mg, maximum 80mg
    * Paliperidone if ClCr 50-79mL/min initial 3mg, maximum 6mg; if ClCr 10-49 initial 1.5mg, maximum 3mg; if ClCr < 10 don’t use
    * Risperidone if ClCr < 30mL/min initial 0.5mg twice daily with slow titration, maximum 3mg
    * No dosage adjustment necessary for the remainder of the second generation antipsychotics. However, recommend initiation at lowest dose (especially in patients with concurrent hepatic impairment).



## 

HEPATIC

  * FIRST GENERATION: 
    * No dosage adjustment necessary for use of the first generation antipsychotics. However, recommend initiation at lowest dose (especially in patients with concurrent renal impairment).
  * SECOND GENERATION: 
    * Asenapine use not recommended in patients with severe hepatic impairment (Child-Pugh Class C)
    * Iloperidone use not recommended in any level of hepatic impairment due to lack of evidence supporting safety
    * Lurasidone if moderate impairment (Child-Pugh Class B) initial 20mg, maximum 80mg; if severe impairment (Child-Pugh Class C) initial 20mg, maximum 40mg
    * Paliperidone use not recommended in severe impairment (Child-Pugh Class C) due to lack of evidence supporting safety
    * Risperidone if severe impairment (Child-Pugh Class C) initial 0.5mg twice daily with slow titration, maximum 3mg
    * No dosage adjustment necessary for the remainder of the second generation antipsychotics. However, recommend initiation at lowest dose (especially in patients with concurrent hepatic impairment)



## 

ELDERLY

  * All antipsychotic agents (both first and second generation) are associated with increased risk of mortality in elderly patients with dementia-related psychosis (BLACK BOX WARNING).
  * Increased incidence of cerebrovascular events (e.g. TIAs, stroke) has been seen among elderly patients on antipsychotics.
  * When benefits outweigh risks, use lower doses, slower titration schedules, and periodic reassessment for necessity.
  * In addition be mindful of drug interactions.



## 

PREGNANCY

  * FDA Risk Category B (safe for use in pregnancy, but limited human data available; use with caution.): Clozapine, Lurasidone
  * FDA Risk Category C (not safe in pregnancy, use only if benefit outweighs risk): The remainder of the first- and second-generation antipsychotics.



## 

BREASTFEEDING

  * All antipsychotics are proven, or presumed, to be excreted into breast milk. Breastfeeding while receiving antipsychotics is not recommended.
  * However, if benefit outweighs risk, or the patient prefers to breastfeed despite risk, the baby should be monitored for side effects secondary to antipsychotic exposure.



## 

ADVERSE DRUG REACTIONS

## 

GENERAL

  * Extrapyramidal side effects (EPS) include dystonia, akathisia, pseudo-Parkinsonism, tardive dyskinesia, etc. 
    * Agents with greatest risk are high potency first generation agents. Lower risk are second generation agents. Quetiapine and Clozapine lowest risk. The risk is dose-related.
    * Can treat EPS with anticholinergic agents (i.e. benztropine, diphenhydramine, trihexyphenidyl), dopaminergic agents (i.e. amantadine), beta blocker (i.e. propranolol), or benzodiazepine (i.e. lorazepam).
    * Incidence of tardive dyskinesia is 3-5% per year of exposure for first 5-8 years of treatment with first generation and 0.5-1% per year with second generation agents.
  * Metabolic syndrome is characterized by elevated lipid profile, hypertension, hyperglycemia, and obesity (especially abdominal weight gain). Antipsychotic agents with greatest risk are Clozapine, Olanzapine, and Quetiapine. Aripiprazole, Asenapine, Lurasidone, and Ziprasidone have least risk.
  * Anti-cholinergic effects are seen, especially with the second-generation and low-potency first-generation antipsychotics (e.g. confusion, agitation, constipation, xerostomia, blurred vision, urinary retention). Most notably associated with Asenapine, Clozapine, Quetiapine, and Olanzapine.



## 

COMMON

  * Dose-related sedation with initial treatment, but improves over time. Most noteable are Chlorpromazine, Clozapine, Olanzapine, and Quetiapine.



## 

OCCASIONAL

  * New-onset diabetes (view "comments" section).
  * May prolong the QTC interval. Most notable are Chlorpromazine, IV Haloperidol, Iloperidone, Pimozide, Rhioridazine, and Ziprasidone.
  * Hyperprolactinemia has been observed. Most notable are first generation high potency antipsychotics and Risperidone. The least is with Aripiprazole.
  * Orthostatic hypotension (secondary to alpha-1 blockade) +/- reflex tachycardia. Most notable are Asenapine, Clozapine, Iloperidone, Quetiapine, and Risperidone.
  * Sexual dysfunction including loss of libido and anorgasmia.
  * LFT elevations and hepatitis. May be transient or may necessitate discontinuation of medication.



## 

RARE

  * Neuroleptic malignant syndrome (NMS) presenting as confusion, fever, tachycardia, muscle rigidity, and labile blood pressure.
  * Ophthalmologic Complications: Retinitis pigmentosa, a Black Box Warning, is associated with Thioridazine, especially with doses >800mg/day. Lens changes have been observed with Quetiapine. Benign pigmentary deposits on the retina are associated with Chlorpromazine.
  * Photosensitivity and pigmentary changes have been observed.
  * Agranulocytosis reported in 0.8% (1-year risk) of patients treated with Clozapine during the first 4-6 months of therapy. Monitor weekly CBC for the first 6 months, then every two weeks for next 6 months, and then monthly indefinitely during treatment. Transient leukopenia also reported with phenothiazines.
  * Impaired core body temperature regulation, including hyperpyrexia (more commonly reported in hot weather or during exercise).
  * Use with caution in patients with a seizure history, head trauma, brain damage, alcoholism, or concurrent medications that may lower seizure threshold. Most notable is Clozapine with dose-related risk.



## 

DRUG INTERACTIONS

  * Metabolism data for each antipsychotic is listed in table.
  * Potent inducers and inhibitors of CYP450 may decrease and increase antipsychotic serum concentrations, respectively. Of particular interest are the 1A2, 2D6, 3A4 genotypes of CYP450. 
    * Examples of CYP1A2 inhibitors: ciprofloxacin, cimetidine, fluvoxamine, fluoxetine
    * Examples of CYP2D6 inhibitors: bupropion, fluoxetine, paroxetine, duloxetine, quinidine, ritonavir
    * Examples of CYP3A4 inhibitors: erythromycin, clarithromycin, azole antifungals, HIV-protease inhibitors
    * Examples of CYP450 inducers: carbamazepine, phenobarbital, phenobarbital, primidone, and rifampin
  * There are special Aripirazole dosing recommendations when it is used with concomitant CYP3A4 or CYP2D6 inhibitors[8].


  * Anti-hypertensive Agents: may increase risk of orthostatic hypotension with antipsychotics co-administration (especially Asenapine, Clozapine, Iloperidone, Quetiapine, Risperidone)
  * Benzodiazepines: may increase risk of over sedation (especially Clozapine, Olanzapine, Quetiapine)
  * Drugs with anti-cholinergic properties (e.g. tricyclic antidepressants, antihistamines) may increase risk of anticholinergic side effects and impair cognition with antipsychotic co-administration (especially Asenapine, Clozapine, Olanzapine, Quetiapine)
  * Agents known to increase QTc (e.g. high dose methadone, clarithromycin, erythromycin, tricyclic antidepressants) may increase risk of QTc prolongation. Avoid co-administration with baseline QTc prolongation, patients on medications that also prolong QTc, and patients with cardiovascular risk factors.
  * Metoclopramide: may increase risk of akathisia and other extrapyramidal side effects with antipsychotic co-administration.
  * Antipsychotics have not been found to significantly interact with oral hypoglycemic agents.



## 

PHARMACOKINETIC

## 

Absorption

  * Oral bioavailability ranges from 2.7-100%. 
    * Fluphenazine has erratic and variable bioavailability.
    * Asenapine must be sublingual or else availability decreases to < 2%.
  * Food decreases absorption of: Aripiprazole (high fat meal), Asenapine, and Iloperidone.
  * Food increases absorption of: Lurasidone, Paliperidone, Quetiapine, Ziprasidone. 
    * Lurasidone and Ziprasidone should always be given with food.



## 

Metabolism and Excretion

  * Metabolized primarily via CYP2D6, CYP3A4, and CYP1A2. Chlorpromazine, Fluphenazine, Haloperidol, Loxapine, Thioridazine, Trifluoperazine, Aripiprazole, Asenapine, Clozapine, Iloperidone, Lurasidone, Risperidone, and Ziprasidone have active metabolites.



## 

Protein Binding

  * Moderate-to-high protein binding (most >90%).



## 

Cmax, Cmin, and AUC

  * Cmax range from 0.5 hours to 24 hours for oral antipsychotics.
  * Only Clozapine plasma concentrations routinely performed in clinical practice. 
    * Some association between clozapine concentrations >350mcg/mL and treatment response.



## 

T1/2

  * See Table Table 2..



Table 2.**Drug**| **FDA Indications**| **Metabolism/Excretion/Half-Life (T 1/2)**  
---|---|---  
**FIRST-GENERATION ANTIPSYCHOTICS ("TYPICALS")**  
Chlorpromazine(Thorazine®)| SchizophreniaBipolar - ManiaNausea/VomitingAcute Intermittent PorphyriaTetanusIntractable hiccupsPre-surgical apprehensionProblem Behavior (pediatric)| METABOLISM: liver extensively, intestinal wall to variable extent; CYP2D6; active metabolitesEXCRETION: renal (23%), bile, fecesT1/2: 6 hours (parent), 10-40 hours (active metabolite)  
Fluphenazine(Prolixin®)| Schizophrenia| METABOLISM: liver extensively; CYP2D6; active metabolites  
EXCRETION: urine, bile, feces  
T1/2: 33 hours; 14-26 days (decanoate)  
Haloperidol(Haldol®)| SchizophreniaTourette’sHyperactive Behavior (pediatric)| METABOLISM: liver extensively, evidence of partial extrahepatic metabolism; CYP1A2, CYP2D6, CYP3A4; active metabolites  
EXCRETION: renal (33-40%), feces (15%)T1/2: 21-24 hours; 21 days (decanoate)  
Loxapine(Loxitane®)| Schizophrenia| METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4; active metabolites  
EXCRETION: renal, feces  
T1/2: 7 hours  
Perphenazine(Trilafon®)| SchizophreniaNausea/Vomiting| METABOLISM: liver extensively, some intestinal wall, possible enterohepatic cycling; CYP1A2, CYP2D6, CYP3A4  
EXCRETION: urine primarily, some bile and feces  
T1/2: 8.4-12.3 hours  
Pimozide(Orap™)| Tourette’s| METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4  
EXCRETION: renal (40%), feces (15%)  
T1/2: 55-66 hours  
Thioridazine(Mellaril®)| Schizophrenia| METABOLISM: liver extensively, GI tract; CYP2D6; active metabolites  
EXCRETION: renal primarily, bile, feces  
T1/2: 21-24 hours  
Thiothixene(Navane®)| Schizophrenia| METABOLISM: liver extensively; CYP1A2, CYP2D6  
EXCRETION: bile, feces  
T1/2: initially 3.4 hours, later 34 hours  
Trifluoperazine(Stelazine®)| SchizophreniaAnxiety| METABOLISM: liver extensively, some GI tract; CYP1A2; active metabolitesEXCRETION: urine, bile, feces  
T1/2: 24 hours  
**SECOND-GENERATION ANTIPSYCHOTICS ("ATYPICALS")**  
Aripiprazole(Abilify®)| SchizophreniaBipolar - ManiaDepression (adjunct)Autism| METABOLISM: liver, extent unknown; CYP2D6, CYP3A4 (poor CYP2D6 metabolizers have 60% increased active drug); active metabolites  
EXCRETION: feces (55%), renal (25%)  
T1/2: 75 hours (parent drug), 94 hours (metabolite), 146 hours (CYP2D6 poor metabolizers)  
Asenapine(Saphris®)| SchizophreniaBipolar| METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4; active metabolites  
EXCRETION: renal (50%), feces (40%)  
T1/2: 24 hours  
Clozapine(Clozaril®)| SchizophreniaRefractory Suicidality| METABOLISM: extensive extra-hepatic presystemic routes; CYP1A2, CYP2D6, CYP3A4; active metabolites  
EXCRETION: renal (50%), feces (30%)  
T1/2: 4-66 hours  
Iloperidone(Fanapt®)| Schizophrenia| METABOLISM: liver extensively; CYP2D6, CYP3A4; active metabolitesEXCRETION: renal (45-58%), feces (20-22%)  
T1/2: 18-33 hours, 37 hours (poor metabolizers)  
Lurasidone(Latuda®)| Schizophrenia| METABOLISM: liver extensively; CYP3A4; active metabolitesEXCRETION: feces (80%), renal (9%)  
T1/2: 18 hours  
Olanzapine(Zyprexa®)| SchizophreniaManiaDepression| METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4  
EXCRETION: renal (57%), feces (30%)  
T1/2: 21-54 hours; 30 days (Zyprexa® Relprevv™)  
Paliperidone(Invega®)| Schizophrenia| METABOLISM: liver minimal; minimal CYP450  
EXCRETION: renal (59%), feces  
T1/2: 23 hours; 25-49 days (Invega® Sustenna®)  
Quetiapine(Seroquel®)| SchizophreniaBipolar - ManiaBipolar - DepressionMajor Depression (Adjunct)| METABOLISM: liver extensively; CYP2D6, CYP3A4EXCRETION: renal (70-73%), feces (20%)  
T1/2: 6 hours, 7 hours (ER)  
Risperidone(Risperdal®)| SchizophreniaBipolar - ManiaBipolar - Maintenance| METABOLISM: liver extensively; CYP2D6; active metabolite  
EXCRETION: renal (70%), feces (14%)  
T1/2: 3-20 hours (parent), 21-30 hours (metabolite); 3-6 days (Consta®)  
(Geodon®)(Ziprasidone)| SchizophreniaBipolar - ManiaBipolar - Maintenance| METABOLISM: liver extensively; CYP1A2, CYP3A4; active metabolites  
EXCRETION: feces (66%), renal (20%)  
T1/2: 7 hours  
*_Data in above table from:_ Micromedix® 2.0 and Lexicomp Online™; _Data in above table reviewed by_ Sujin Lee, Pharm.D. BCPP  
  
## 

Distribution

  * Wide volume of distribution with tissue accumulation.



## 

COMMENTS

  * Second-generation antipsychotics are now considered first line due to lower rates of extrapyramidal symptoms (especially tardive dyskinesia), but are associated with more weight gain, lipid abnormalities, and incident diabetes.
  * Among second-generation antipsychotics the risk of causing weight gain/glucose dysregulation is as follows: Clozapine, Olanzapine, Quetiapine > Iloperidone, Paliperidone, Risperidone > Aripiprazole, Asenapine, Lurasidone, and Ziprasidone[2].


  * A recent review of first- vs. second-generation antipsychotics showed few differences of clinical importance for core illness symptoms of schizophrenia. There was some evidence for benefit of Haloperidol over Olanzapine for improving positive symptoms of schizophrenia. There was some evidence of Olanzapine over Haloperidol in improving negative symptoms of schizophrenia. There was low-strength evidence for increased incidence of the metabolic syndrome for Olanzapine and higher incidence of tardive dyskinesia for Chlorpromazine versus Clozapine. Evidence was insufficient to draw conclusions for diabetes mellitus[1].
  * The CATIE study compared Perphenazine (first generation antipsychotic) with several second generation antipsychotics in a double-blind study. The majority of patients in each group discontinued their assigned treatment due to lack of efficacy or intolerable side effects (74% by 18 months). Olanzapine showed the greatest weight gain and increases in measures of glucose and lipid metabolism. Perphenazine showed the greatest risk of extrapyramidal side effects[6].


  * In obese patients with diabetes, Ziprasidone may be considered since it is associated with less weight gain compared to the other atypical antipsychotics[4]. Aripirazole, Asenapine, and Lurasidone can also be considered.
  * Baseline diabetes screening should be obtained before, or as soon as clinically feasible after, the initiation of any antipsychotic medication. Reassessment at 4, 8, and 12 weeks after initiating or changing antipsychotic therapy and quarterly thereafter at the time of routine visits is recommended[7].
  * Growing evidence supports starting Metformin therapy in drug-naive first-episode schizophrenia patients in order to attenuate weight gain and insulin resistance[5]. This same evidence is not as strong for starting Metformin after the weight gain/insulin resistance has already formed[3].