Antipsychotics Antipsychotics ReviewReview

CaseCase

40 year old man with long hx of paranoid 40 year old man with long hx of paranoid schizophrenia.schizophrenia.

On perphenazine (Trilafon) 12 mg qhs, On perphenazine (Trilafon) 12 mg qhs, benztropine (Cogentin) 2 mg qhs x 15 benztropine (Cogentin) 2 mg qhs x 15 years. years.

PMH notable for DM II on metformin, PMH notable for DM II on metformin, glyburide, accupril, last HgA1c of 7.9glyburide, accupril, last HgA1c of 7.9

Lives at B&C, smokes 2 packs per day, Lives at B&C, smokes 2 packs per day, occ ETOH, remote hx of occ ETOH, remote hx of methamphetamines.methamphetamines.

CaseCase

On MSE, overweight man with BMI 33, On MSE, overweight man with BMI 33, plain dress, adequate grooming, plain dress, adequate grooming, diminished spont movements, eye diminished spont movements, eye contact fixed, occ resting tremor in R contact fixed, occ resting tremor in R hand noted and occ grimacing. Speech hand noted and occ grimacing. Speech has slight delay with diminished tone has slight delay with diminished tone but o/w fluent. Mood is “fine” Affect is but o/w fluent. Mood is “fine” Affect is constricted to blunted. TP generally constricted to blunted. TP generally linear, bit concrete, sparse details. TC linear, bit concrete, sparse details. TC of:of:

CaseCase

A) “I like what I’m taking.” Some A) “I like what I’m taking.” Some mild paranoia of police but without mild paranoia of police but without evidence of overt delusionsevidence of overt delusions

B) “I know the B&C is poisoning B) “I know the B&C is poisoning me.”me.”

AntipsychoticsAntipsychotics

First antipsychotic was a First antipsychotic was a phenothiazine (chlorpromazine) phenothiazine (chlorpromazine) synthesized in 1950. synthesized in 1950.

First Generation, also called “typical”First Generation, also called “typical” ““Me too D2”Me too D2”

Second Generation, also called Second Generation, also called “atypical”“atypical” Starting in early 90’sStarting in early 90’s

How do Typical Antipsychotics How do Typical Antipsychotics

work?work? Dopamine HypothesisDopamine Hypothesis

Targets for DTargets for D22 blockade blockade Mesolimbic area: antipsychotic effectMesolimbic area: antipsychotic effect Nigrostriatal tract: EPSNigrostriatal tract: EPS Tuberinfundibular area: prolactin elevationTuberinfundibular area: prolactin elevation

76-80% D76-80% D22 occupancy needed for effect occupancy needed for effect for conventional antipsychotics for conventional antipsychotics

Problem:Problem: Atypicals have varying occupancy Atypicals have varying occupancy

requirementsrequirements

How do Atypical How do Atypical Antipsychotics work?Antipsychotics work?

Leading TheoriesLeading Theories May relate to DA receptors having May relate to DA receptors having

subtypes Dsubtypes D1-51-5 as well as other receptors as well as other receptors playing a part to playing a part to modulatemodulate dopamine dopamine receptors (such as 5-HTreceptors (such as 5-HT2A 2A .).)

Hypofunctional Hypofunctional NN-methyl-D-aspartate -methyl-D-aspartate (NMDA) receptors in VTA leads to(NMDA) receptors in VTA leads to hyperactive mesolimibic DA activity (via hyperactive mesolimibic DA activity (via

GABA interneuron)GABA interneuron) hypoactive mesocortical DA activityhypoactive mesocortical DA activity

First Generation Classified by First Generation Classified by PotencyPotency

Equivalent Dose (mg)

Sedation Autonomic (anti andrenergic and anticholineric)

SE’s

EPS

haloperidol (Haldol)

2 + + +++

trifluoperazine (Stelazine)

5 ++ + +++

perphenazine (Trilafon)

10 ++ ++ ++

mesoridazine (Serentil)

50 +++ ++ +

chlorpromazine (Thorazine)

100 +++ +++ +

Acute EPS esp with Acute EPS esp with high high potencypotency agents agents

Related to decreased DA activity in the Related to decreased DA activity in the basal ganglia basal ganglia

AkathisiaAkathisia: occurs in 2/3 of patients to : occurs in 2/3 of patients to some degreesome degree Treat with beta blockersTreat with beta blockers

DystoniaDystonia: occurs in 1/3 of patients: occurs in 1/3 of patients Treat with anticholinergicsTreat with anticholinergics

ParkinsonismParkinsonism: occurs in 1/3 of patients : occurs in 1/3 of patients treated long termtreated long term Treat with anticholinergicsTreat with anticholinergics

Neuroleptic Malignant SyndromeNeuroleptic Malignant Syndrome

Esp with high potency antipsychotics Esp with high potency antipsychotics escalated quickly to high dosesescalated quickly to high doses

Features are hyperthermia, severe Features are hyperthermia, severe muscular rigidity, autonomic muscular rigidity, autonomic instability, changing levels of instability, changing levels of consciousness.consciousness.

Psychiatric emergency = emergency Psychiatric emergency = emergency roomroom

Tardive DyskinesiaTardive Dyskinesia

Increased sensitivity of DA receptors Increased sensitivity of DA receptors in basal ganglia. in basal ganglia.

10-20% in one year, risk increases 4-10-20% in one year, risk increases 4-5% per year.5% per year.

Higher risk: include elderly women Higher risk: include elderly women and schizoaffective disorder.and schizoaffective disorder.

Typical Antipsychotics Typical Antipsychotics Bottom LineBottom Line

All work by blocking D2 receptorAll work by blocking D2 receptor High potency (haloperidol) = More High potency (haloperidol) = More

EPS, TD, NMSEPS, TD, NMS Low potency (chlorpromazine) = Low potency (chlorpromazine) =

more sedation, anticholinergic side more sedation, anticholinergic side effectseffects

All equally efficaciousAll equally efficacious High potency preferred by patientsHigh potency preferred by patients

Atypical vs Typical Atypical vs Typical AntipsychoticsAntipsychotics

Atypical antipsychotics Atypical antipsychotics advantagesadvantages greatly reduced to no propensity for EPS or TDgreatly reduced to no propensity for EPS or TD minimal elevation of prolactin (except minimal elevation of prolactin (except

risperidone)risperidone) Less impact on negative symptoms, cognitionLess impact on negative symptoms, cognition broader spectrum of actionbroader spectrum of action

Typical antipsychotic Typical antipsychotic advantagesadvantages depot formulations (except Consta)depot formulations (except Consta) costcost less severe metabolic impactless severe metabolic impact

How do Atypical How do Atypical Antipsychotics work?Antipsychotics work?

Leading TheoriesLeading Theories May relate to DA receptors having May relate to DA receptors having

subtypes Dsubtypes D1-51-5 as well as other receptors as well as other receptors playing a part to playing a part to modulatemodulate dopamine dopamine receptors (such as 5-HTreceptors (such as 5-HT2A 2A .).)

Hypofunctional Hypofunctional NN-methyl-D-aspartate -methyl-D-aspartate (NMDA) receptors in VTA leads to(NMDA) receptors in VTA leads to hyperactive mesolimibic DA activity (via hyperactive mesolimibic DA activity (via

GABA interneuron)GABA interneuron) hypoactive mesocortical DA activityhypoactive mesocortical DA activity

Are atypicals “better?”Are atypicals “better?”

Efficacy and effectivenessEfficacy and effectiveness MaybeMaybe

Side effectsSide effects DifferentDifferent

Cost effectivenessCost effectiveness UnknownUnknown

Are atypicals “better?”Are atypicals “better?” Improved efficacy based on short-term Improved efficacy based on short-term

structured studies, mostly industry structured studies, mostly industry sponsored.sponsored.

Meta-analyses have shown mixed results Meta-analyses have shown mixed results with risperidone and olanzapine edging with risperidone and olanzapine edging typicals slightly.typicals slightly.

NIMH sponsored Clinical Antipsychotic NIMH sponsored Clinical Antipsychotic Trials of Intervention Effectiveness Trials of Intervention Effectiveness (CATIE) was a r(CATIE) was a randomized DB, flexible dose andomized DB, flexible dose study with olanzapine, risperidone, study with olanzapine, risperidone, quetiapine, ziprasidone, perphenazine, 18 quetiapine, ziprasidone, perphenazine, 18 monthsmonths

CATIE Points to PonderCATIE Points to Ponder CATIE focused on “effectiveness” rather CATIE focused on “effectiveness” rather

than “efficacy.” than “efficacy.” Chronic schizophrenics have a high rate Chronic schizophrenics have a high rate

(>70%) of antipsychotic discontinuation (>70%) of antipsychotic discontinuation over time.over time.

Risperidone and especially olanzapine has Risperidone and especially olanzapine has comparatively better effectiveness comparatively better effectiveness compared to quetiapine and ziprasidonecompared to quetiapine and ziprasidone

Confirmed superior efficacy of clozapineConfirmed superior efficacy of clozapine Typical antipsychotics (perphenazine) can Typical antipsychotics (perphenazine) can

be as effective as atypicals (except be as effective as atypicals (except olanzapine)olanzapine)

However…However…

Atypical Antipsychotics Atypical Antipsychotics olanzapine and clozapine: most cases of olanzapine and clozapine: most cases of

new onset DM, DKA, death, elevated new onset DM, DKA, death, elevated triglyceride and LDLtriglyceride and LDL

ziprasidone and aripiprazole: fewest ziprasidone and aripiprazole: fewest cases of new onset DM, DKA, death, cases of new onset DM, DKA, death, elevated triglyceride and LDLelevated triglyceride and LDL

Weight gain over 1 year (pooled data Weight gain over 1 year (pooled data from multiple trials)from multiple trials) olanzapine: > 13.2 lb, >22 lb with doses > olanzapine: > 13.2 lb, >22 lb with doses >

12.5 mg 12.5 mg quetiapine and risperidone: 4.4 - 6.6 lbquetiapine and risperidone: 4.4 - 6.6 lb aripiprazole and ziprasidone: 2.2 lbaripiprazole and ziprasidone: 2.2 lb

Metabolic Impact (cont)Metabolic Impact (cont)

CATIE confirmed findingsCATIE confirmed findings Metabolic syndrome at baseline 42.7% Metabolic syndrome at baseline 42.7%

(twice general population. (twice general population. Olanzapine treatment:Olanzapine treatment:

30% gained > 7% weight compared to 7% 30% gained > 7% weight compared to 7% (ziprasidone), 13% (risperidone, quetiapine)(ziprasidone), 13% (risperidone, quetiapine)

Consistent increase in blood glucose (13.8 Consistent increase in blood glucose (13.8 mg/dL), Hg A1c (0.97%), cholesterol (17.5 mg/dL), Hg A1c (0.97%), cholesterol (17.5 mg/dL), triglyceride (94.1mg/dL)mg/dL), triglyceride (94.1mg/dL)

ADA Consensus Position on ADA Consensus Position on Antipsychotics and Obesity, Antipsychotics and Obesity,

Diabetes, DyslipidemiaDiabetes, Dyslipidemia

DrugDrug Weight Weight GainGain

DM RiskDM Risk DyslipidemDyslipidemiaia

clozapineclozapine ++++++ ++ ++

olanzapinolanzapinee

++++++ ++ ++

risperidorisperidonene

++ DiscrepantDiscrepant DiscrepantDiscrepant

quetiapinquetiapinee

++ DiscrepantDiscrepant DiscrepantDiscrepant

aripiprazaripiprazoleole

+/-+/- No effectNo effect No effectNo effect

ziprasidoziprasidonene

+/-+/- No effectNo effect No effectNo effect

Diabetes Care 2004; 27:596-601

MonitoringMonitoring At baseline, 1 month, 3 monthsAt baseline, 1 month, 3 months

weight, BP, fasting glucose, fasting lipid panelweight, BP, fasting glucose, fasting lipid panel YearlyYearly

weight, BP, fasting glucoseweight, BP, fasting glucose Every three yearsEvery three years

fasting lipid panelfasting lipid panel

Looking for:Looking for: > 5-7% increase from initial weight or BMI > > 5-7% increase from initial weight or BMI >

2525 Fasting glucose > 126Fasting glucose > 126 BP > 140/90BP > 140/90 Cholesterol thresholds depends on risk factorsCholesterol thresholds depends on risk factors

clozapine (Clozaril)clozapine (Clozaril) Relatively low D2 blocker, significant 5-Relatively low D2 blocker, significant 5-

HT2A, H1, alpha1, alpha2, muscarinic HT2A, H1, alpha1, alpha2, muscarinic receptor blocker.receptor blocker.

Indications: treatment resistant Indications: treatment resistant schizophrenia, severe TD (may improve)schizophrenia, severe TD (may improve)

Dosage: titrated over weeks to 250-450 Dosage: titrated over weeks to 250-450 mg qd. If more than a 2-3 days of doses mg qd. If more than a 2-3 days of doses missed, should restart titration.missed, should restart titration.

Common side effects: sialorrhea, Common side effects: sialorrhea, orthostatic hypotension (can be severe, orthostatic hypotension (can be severe, titration dependent), tachycardia, titration dependent), tachycardia, constipation, weight gain, sedation.constipation, weight gain, sedation.

clozapine (Clozaril)clozapine (Clozaril)

AgranulocytosisAgranulocytosis Overall risk < 1% with highest risk at week Overall risk < 1% with highest risk at week

6-186-18 Weekly CBC required for first 6 months Weekly CBC required for first 6 months

then every other weekthen every other week Discontinue if WBC < 3000 or granulocyte Discontinue if WBC < 3000 or granulocyte

count < 1500count < 1500 Bottom Line: most effective Bottom Line: most effective

antipsychotic period but limited by side antipsychotic period but limited by side effects. Watch for metabolic side effects. Watch for metabolic side effects. You won’t be starting it.effects. You won’t be starting it.

olanzapine (Zyprexa)olanzapine (Zyprexa)

Antagonism at the 5-HTAntagonism at the 5-HT2A2A, DA, muscarinic, , DA, muscarinic, HH11, alpha, alpha11 receptors receptors

FDA approved for schizophrenia, acute FDA approved for schizophrenia, acute bipolar mania and bipolar disorder bipolar mania and bipolar disorder maintenance. maintenance.

Dosing: (PO) start at 5-10 mg qhs and Dosing: (PO) start at 5-10 mg qhs and increase by 5 mg qweek to target dose of 10-increase by 5 mg qweek to target dose of 10-30 mg qhs. Max dose 40 mg qd. 30 mg qhs. Max dose 40 mg qd.

Common side effects: weight gain, sedation, Common side effects: weight gain, sedation, dry mouth, constipation,. May start seeing dry mouth, constipation,. May start seeing EPS at doses > 30 mg qd.EPS at doses > 30 mg qd.

Bottom Line: Probably most effective (except Bottom Line: Probably most effective (except clozapine) but metabolic effects limits use.clozapine) but metabolic effects limits use.

risperidone (Risperdal)risperidone (Risperdal)

Antagonism at 5-HT2A, D2, alpha1 and 2, H1 Antagonism at 5-HT2A, D2, alpha1 and 2, H1 receptorsreceptors

FDA approved for schizophrenia, acute bipolar FDA approved for schizophrenia, acute bipolar maniamania

Dosing: start 1-2 mg qd, increase by 1-2 mg Dosing: start 1-2 mg qd, increase by 1-2 mg every 3-6 days with usual therapeutic dose of 4-every 3-6 days with usual therapeutic dose of 4-6 mg qd. Max dose16 mg qd. Available in M-6 mg qd. Max dose16 mg qd. Available in M-Tab and IM Consta.Tab and IM Consta.

Precautions: orthostatic hypotension, Precautions: orthostatic hypotension, hyperprolactinemiahyperprolactinemia

Common side effects: somnolence, dizziness, Common side effects: somnolence, dizziness, constipation, weight gain and dose dependent constipation, weight gain and dose dependent EPS (> 6 mg qd).EPS (> 6 mg qd).

Bottom line: Popular first line agent, watch for Bottom line: Popular first line agent, watch for EPS at > 6 mg and hyperprolactinemia in EPS at > 6 mg and hyperprolactinemia in women.women.

quetiapine (Seroquel)quetiapine (Seroquel)

Antagonist at 5-HTAntagonist at 5-HT2A2A, D, D11, D, D22, H, H11, alpha, alpha11, , alphaalpha22 receptors receptors

FDA approved for schizophrenia, bipolar FDA approved for schizophrenia, bipolar mania and depression.mania and depression.

Dosing: start 25-50 mg bid, increase by Dosing: start 25-50 mg bid, increase by 100-200 mg every few days to at least 200 100-200 mg every few days to at least 200 mg bid. Max dose 400 mg bidmg bid. Max dose 400 mg bid

Common side effects: somnolence, Common side effects: somnolence, dizziness, dry mouth, constipation, weight dizziness, dry mouth, constipation, weight gain gain

Bottom Line: Sedating with no EPS Bottom Line: Sedating with no EPS liability at any dose,. Initially marketed liability at any dose,. Initially marketed with target dose too low, need to get to at with target dose too low, need to get to at least 200 mg bid. Don’t waste time at the least 200 mg bid. Don’t waste time at the low doseslow doses

ziprasidone (Geodon)ziprasidone (Geodon)

Antagonist at DAntagonist at D22, 5-HT, 5-HT2A2A, H, H11, agonist at 5-, agonist at 5-HTHT1A1A

Half life about 7 hours, metabolized by Half life about 7 hours, metabolized by aldehyde oxidase and less so by 3A4. aldehyde oxidase and less so by 3A4. Absorption increased two fold in the Absorption increased two fold in the presence of food.presence of food.

FDA approved for schizophrenia and FDA approved for schizophrenia and bipolar maniabipolar mania

Dosage: Dosage: Dose with foodDose with food usually bid. Start usually bid. Start 40-60 mg bid, target dose 60-80 mg bid.40-60 mg bid, target dose 60-80 mg bid.

Common side effects: mild somnolence, Common side effects: mild somnolence, dizziness, akathesia, nausea, agitationdizziness, akathesia, nausea, agitation

ziprasidone (Geodon)ziprasidone (Geodon)

Warnings: QTc prolongation (> 500 msec Warnings: QTc prolongation (> 500 msec significant)significant) No documented cases of torsade although this No documented cases of torsade although this

is the presumed riskis the presumed risk Avoid with other QTc prolonging drugs, Avoid with other QTc prolonging drugs,

preexisting bradycardia, hypokalemia / preexisting bradycardia, hypokalemia / hypomagnesemia, screen for congenital hypomagnesemia, screen for congenital prolonged QTc syndrome. (hx of sudden death prolonged QTc syndrome. (hx of sudden death in family)in family)

Bottom Line: Relatively nonsedating, but Bottom Line: Relatively nonsedating, but watch for agitation. QTc concern largely watch for agitation. QTc concern largely overblown but do screen above as overblown but do screen above as indicated. Dose adequately.indicated. Dose adequately.

aripiprazole (Abilify)aripiprazole (Abilify)

““Modulates” DA: acts as DAModulates” DA: acts as DA22 agonist/antagonist, 5-HTagonist/antagonist, 5-HT1A1A agonist, 5-HT agonist, 5-HT2A2A antagonist. FDA approved for schizophrenia antagonist. FDA approved for schizophrenia and bipolar mania.and bipolar mania.

Dosing: start 10-15 mg qd. Most patients on Dosing: start 10-15 mg qd. Most patients on 15-20 mg qd. For bipolar mania 30 mg qd15-20 mg qd. For bipolar mania 30 mg qd

Common side effects: anxiety, insomnia, mild Common side effects: anxiety, insomnia, mild somnolence, akathesia, constipation, tremor.somnolence, akathesia, constipation, tremor.

Bottom Line: Like Geodon, not very sedating Bottom Line: Like Geodon, not very sedating and a generally positive side effect profile. and a generally positive side effect profile. Some patient will complain of Some patient will complain of anxiety/akathesia initially.anxiety/akathesia initially.

Which Antipsychotic?Which Antipsychotic?

With exception of clozapine, all With exception of clozapine, all considered first line.considered first line. Weight concern/DM: consider starting Weight concern/DM: consider starting

with something other than olanzapine.with something other than olanzapine. Insomnia: consider olanzapine, Insomnia: consider olanzapine,

risperidone, quetiapine.risperidone, quetiapine. EPS sensitivity or TD: consider EPS sensitivity or TD: consider

quetiapine.quetiapine.

Which Antipsychotic?Which Antipsychotic?

If you see an atypical antipsychotic on a If you see an atypical antipsychotic on a clinic note.clinic note. Ask if the psychiatrist is checking lipids, Ask if the psychiatrist is checking lipids,

glucose periodically. If they are not, get a glucose periodically. If they are not, get a fasting lipid panel and glucose. If the fasting lipid panel and glucose. If the medication is new, check again in three medication is new, check again in three months, then the glucose yearly, lipids q3-5 months, then the glucose yearly, lipids q3-5 years.years.

Don’t forget monitoring increased weight > Don’t forget monitoring increased weight > 7% from baseline while on antipsychotic.7% from baseline while on antipsychotic.

Typical antipsychotic cause weight gain too Typical antipsychotic cause weight gain too although there is no mandatory monitoring although there is no mandatory monitoring of lipids or glucose. Do watch for TD.of lipids or glucose. Do watch for TD.