Antipsychotics

INDICATIONS

FDA

Schizophrenia
Bipolar affective disorder
Major depressive disorder (adjunctive therapy)
Agitation associated with schizophrenia or bipolar mania
Autism
Tourette’s syndrome
Psychosis
See Table Table 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-HT_2A, 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®)	TABLET ACUTE IM	75	200-600	2000	NO	Tab: 10, 25, 50, 100, 200mg IM: 25mg/mL	10mg (100): $20.79; 25mg (100): $27.03; 50mg (100): $38.24; 100mg (100): $43.52; 200mg (100): $56.77
Fluphenazine (Prolixin®)	TABLET ACUTE IM LIQUID	2.5-10	1-5	40	YES	Tab: 1, 2.5, 5, 10mg IM: 2.5mg/mL Liq: 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®)	TABLET ACUTE IM LIQUID	1.5-15	1-30	30	YES	Tab: 0.5, 1, 2, 5, 10, 20mg IM: 5mg/mL Liq: 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®)	TABLET ODT* ACUTE IM LIQUID	10-15	10-15	30	NO	Tab: 2, 5, 10, 15, 20, 30mg ODT*: 10, 15mg IM:7.5mg/mL Liq: 1mg/mL	2mg (30): $570.01; 5mg (30): $558.02; 10mg (30): $584.00; 15mg (30): $560.01; 20mg (30): $793.98; 30mg (30): $815.98 ODT* --> 10mg (30): $631.30
Asenapine (Saphris®)	SUBLINGUAL	10	10-20	20	NO	SL: 5, 10mg	5mg (6 boxes, 10 ea): $676.02
Clozapine (Clozaril®)	TABLET ODT*	12.5-25	300-450	900	NO	Tab: 25, 50, 100, 200mg ODT*: 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®)	TABLET ODT* ACUTE IM	5-10	10-20	20	YES	Tab: 2.5, 5, 7.5, 10, 15, 20mg ODT*: 5, 10, 15, 20mg IM: 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
Pimavanser in (Nuplazid®)
Quetiapine (Seroquel®)	TABLET	50	300-800	800	NO	Tab: 25, 50, 100, 200, 300, 400mg XR 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): $575.97 XR --> 50mg (60): $337.99; 150mg (60): $597.99; 200mg (60): $673.96; 300mg (60): $880.02; 400mg (60): $1022.95
Risperidone (Risperdal®)	TABLET ODT* LIQUID	2	2-8	16	YES	Tab: 0.25, 0.5, 1, 2, 3, 4mg ODT*: 0.25, 0.5, 1, 2, 3, 4mg Liq: 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): $542.99 Liquid -->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®)	CAPSULE ACUTE IM	40	40-160	200	NO	Tab: 20, 40, 60, 80mg IM: 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 Cl_Cr < 50mL/min initial 20mg, maximum 80mg
- Paliperidone if Cl_Cr 50-79mL/min initial 3mg, maximum 6mg; if Cl_Cr 10-49 initial 1.5mg, maximum 3mg; if Cl_Cr < 10 don’t use
- Risperidone if Cl_Cr < 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 QT_C 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®)	Schizophrenia Bipolar - Mania Nausea/Vomiting Acute Intermittent Porphyria Tetanus Intractable hiccups Pre-surgical apprehension Problem Behavior (pediatric)	METABOLISM: liver extensively, intestinal wall to variable extent; CYP2D6; active metabolites EXCRETION: renal (23%), bile, feces T_1/2: 6 hours (parent), 10-40 hours (active metabolite)
Fluphenazine (Prolixin®)	Schizophrenia	METABOLISM: liver extensively; CYP2D6; active metabolites EXCRETION: urine, bile, feces T_1/2: 33 hours; 14-26 days (decanoate)
Haloperidol (Haldol®)	Schizophrenia Tourette’s Hyperactive Behavior (pediatric)	METABOLISM: liver extensively, evidence of partial extrahepatic metabolism; CYP1A2, CYP2D6, CYP3A4; active metabolites EXCRETION: renal (33-40%), feces (15%) T_1/2: 21-24 hours; 21 days (decanoate)
Loxapine (Loxitane®)	Schizophrenia	METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4; active metabolites EXCRETION: renal, feces T_1/2: 7 hours
Perphenazine (Trilafon®)	Schizophrenia Nausea/Vomiting	METABOLISM: liver extensively, some intestinal wall, possible enterohepatic cycling; CYP1A2, CYP2D6, CYP3A4 EXCRETION: urine primarily, some bile and feces T_1/2: 8.4-12.3 hours
Pimozide (Orap™)	Tourette’s	METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4 EXCRETION: renal (40%), feces (15%) T_1/2: 55-66 hours
Thioridazine (Mellaril®)	Schizophrenia	METABOLISM: liver extensively, GI tract; CYP2D6; active metabolites EXCRETION: renal primarily, bile, feces T_1/2: 21-24 hours
Thiothixene (Navane®)	Schizophrenia	METABOLISM: liver extensively; CYP1A2, CYP2D6 EXCRETION: bile, feces T_1/2: initially 3.4 hours, later 34 hours
Trifluoperazine (Stelazine®)	Schizophrenia Anxiety	METABOLISM: liver extensively, some GI tract; CYP1A2; active metabolites EXCRETION: urine, bile, feces T_1/2: 24 hours
SECOND-GENERATION ANTIPSYCHOTICS ("ATYPICALS")
Aripiprazole (Abilify®)	Schizophrenia Bipolar - Mania Depression (adjunct) Autism	METABOLISM: liver, extent unknown; CYP2D6, CYP3A4 (poor CYP2D6 metabolizers have 60% increased active drug); active metabolites EXCRETION: feces (55%), renal (25%) T_1/2: 75 hours (parent drug), 94 hours (metabolite), 146 hours (CYP2D6 poor metabolizers)
Asenapine (Saphris®)	Schizophrenia Bipolar	METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4; active metabolites EXCRETION: renal (50%), feces (40%) T_1/2: 24 hours
Clozapine (Clozaril®)	Schizophrenia Refractory Suicidality	METABOLISM: extensive extra-hepatic presystemic routes; CYP1A2, CYP2D6, CYP3A4; active metabolites EXCRETION: renal (50%), feces (30%) T_1/2: 4-66 hours
Iloperidone (Fanapt®)	Schizophrenia	METABOLISM: liver extensively; CYP2D6, CYP3A4; active metabolites EXCRETION: renal (45-58%), feces (20-22%) T_1/2: 18-33 hours, 37 hours (poor metabolizers)
Lurasidone (Latuda®)	Schizophrenia	METABOLISM: liver extensively; CYP3A4; active metabolites EXCRETION: feces (80%), renal (9%) T_1/2: 18 hours
Olanzapine (Zyprexa®)	Schizophrenia Mania Depression	METABOLISM: liver extensively; CYP1A2, CYP2D6, CYP3A4 EXCRETION: renal (57%), feces (30%) T_1/2: 21-54 hours; 30 days (Zyprexa® Relprevv™)
Paliperidone (Invega®)	Schizophrenia	METABOLISM: liver minimal; minimal CYP450 EXCRETION: renal (59%), feces T_1/2: 23 hours; 25-49 days (Invega® Sustenna®)
Quetiapine (Seroquel®)	Schizophrenia Bipolar - Mania Bipolar - Depression Major Depression (Adjunct)	METABOLISM: liver extensively; CYP2D6, CYP3A4 EXCRETION: renal (70-73%), feces (20%) T_1/2: 6 hours, 7 hours (ER)
Risperidone (Risperdal®)	Schizophrenia Bipolar - Mania Bipolar - Maintenance	METABOLISM: liver extensively; CYP2D6; active metabolite EXCRETION: renal (70%), feces (14%) T_1/2: 3-20 hours (parent), 21-30 hours (metabolite); 3-6 days (Consta®)
(Geodon®) (Ziprasidone)	Schizophrenia Bipolar - Mania Bipolar - Maintenance	METABOLISM: liver extensively; CYP1A2, CYP3A4; active metabolites EXCRETION: feces (66%), renal (20%) T_1/2: 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].

References

Hartling L, Abou-Setta AM, Dursun S, et al. Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis. Ann Intern Med. 2012;157(7):498-511. [PMID:22893011]
Hasnain M, W Victor RV, Hollett B. Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians. Postgrad Med. 2012;124(4):154-67. [PMID:22913904]
Miller LJ. Management of atypical antipsychotic drug-induced weight gain: focus on metformin. Pharmacotherapy. 2009;29(6):725-35. [PMID:19476423]
Komossa K, Rummel-Kluge C, Hunger H, et al. Ziprasidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2009. [PMID:19821380]
Wu RR, Zhao JP, Guo XF, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry. 2008;165(3):352-8. [PMID:18245179]
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-23. [PMID:16172203]
American Diabetes Association. American Psychiatric Association,American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity; Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes; Diabetes Care, 2004; Vol. 27: 596-601.
Abilify (aripiprazole) US prescribing information. Otsuka America Pharmaceutical, Inc. February, 2012.

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