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Medications> Glucose-raising>
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Antipsychotics

Paul A. Pham, Pharm.D.
07-20-2010

INDICATIONS

FDA

  • See table for specific FDA indications for each antipsychotic.
  • Schizophrenia
  • Bipolar disorder
  • Psychotic depression
  • Agitation
  • Anxiety
NON-FDA APPROVED USES

  • Hiccups
  • ICU delirium

MECHANISM

  • Block postsynaptic dopamine receptors in the mesolimbic system resulting in depolarization blockade of dopamine tracts which has been correlated with antipsychotic effect.
  • Atypical antipsychotics (aripiprazole, clozapine, olanzapine, risperidone, quetiapine, ziprasidone) also block serotonin receptors.

USUAL ADULT DOSING

Elderly patients, patients with renal or hepatic disease should initiate antipsychotics at the lowest dose with slow titration.

  • Atypical antipsychotics: Aripiprazole: Starting dose: 10-15 mg/day PO; Maintenance dose: 30 mg/day PO (greater efficacy has not been established for doses exceeding 15mg/day) Max dose: 30 mg/day PO
  • Clozapine: Starting dose: 25-50 mg/day PO; Maintenance dose: 300-450 mg/day PO;Max dose: 600-900 mg/day PO
  • Olanzapine: Starting dose: 5-10 mg/day PO; 210-300 mg IM q2wk OR 405 mg q4wk IM; Maintenance dose: 10-20mg/day PO; 150-300 mg IM q2wk OR 300-405 mg IM q4wk; Max dose: 20 mg/day PO
  • Quetiapine: Starting dose: 50 mg/day PO; Maintenance dose: 300-400 mg/day PO; Max dose: 800 mg/day PO
  • Risperidone: Starting dose: 1-3 mg/day PO; Maintenance dose: 1-6 mg/day PO; 6 mg/day IM; Max dose: 16 mg/day PO;
  • Ziprasidone: Starting dose: 40 mg/day PO; Maintenance dose: 20-80 mg/day PO; Max dose: 200 mg/day PO
  • Typical antipsychotics:
  • Fluphenazine: Starting dose: 2.5-10 mg/day; 12.5-25 mg/dose IM or SC Maintenance dose: 20 mg/day; 50 mg/dose IM or SC Max dose: 40 mg/day PO; 100 mg/dose IM or SC of decanoate or enanthate depot injections/// Perphenazine: Starting dose: 20-100 mg/day PO Maintenance dose: 200-400 mg/day PO Max dose: 24 mg/day PO /// Thioridazine: Starting dose: 30-150 mg/day PO Maintenance dose: 300 mg/day PO Max dose: 300 mg/day/// Trifluoperazine: Starting dose: 4-10 mg/day PO Maintenance dose: 15-20 mg/day PO Max dose: 40 mg/day PO
  • Haloperidol: Starting dose: 1-6 mg/day PO; Maintenance dose: 6-15 mg/day PO; Max dose: 30 mg/day PO
  • Loxapine: Starting dose: 10-25 mg/day PO Maintenance dose: 60-100 mg/day PO Max dose: 250 mg/day PO/// Molindone: Starting dose: 50-75 mg/day PO Maintenance dose: 15-100 mg/day POMax dose: 225 mg/day PO/// Thiothixene: Starting dose: 15 mg/day PO Maintenance dose: 20-30 mg/day PO. Max dose: 60 mg/day PO

DOSING IN SPECIAL POPULATIONS

RENAL

  • With severe renal impairment, initiate with risperidone 0.5 mg twice daily with slower titration.
  • No dose adjustment needed for other antipsychotics, but should be initiated at the lowest dose (especially in patients with concurrent hepatic impairment).
HEPATIC

  • Initiate with the lowest dose and slow dose titration.
PREGNANCY

  • Antipsychotics are pregnancy category C (except clozapine category B). Limited human clinical data; use only if benefit outweigh risk.
BREASTFEEDING

  • Not recommended for use in lactating women due to excretion into breast milk.

ADVERSE DRUG REACTIONS

GENERAL

  • Newer atypical antipsychotics are generally better tolerated compared to phenothiazines, but have been associated with weight gain and development of diabetes.
  • All antipsychotics should be avoided or use caution in patients with acute altered mental status.
COMMON

  • Weight gain: at 10 weeks of therapy, estimated average weight gain with drug treatment compared with placebo varies from 0.5 to 5.0 kg. Olanzapine and clozapine are associated with greater weight gain and lipid elevation.
  • Anticholinergic side effects (e.g dry mouth, constipation, urinary retention). More frequently observed with thioridazine>chlorpromazine>loxapine compared to other agents. Risperidone associated with the lowest rate of anticholinergic side effects.
  • Dose related sedation with initial treatment, but improves over time.
  • Dose related extrapyramidal syndrome (e.g dystonia and akathisia, tardive dyskinesia). More common with high potency (e.g phenothiazines, haloperidol, and thiothixene) compared to low potency phenothiazines (e.g. chlorpromazine and thioridazine) and the atypical "second generation" antipsychotics (e.g aripiprazole, quetiapine, olanzapine, risperidone, ziprasidone).
OCCASIONAL

  • New onset diabetes: associated more commonly with olanzapine compared to quetiapine, risperidone, and haloperidol.
  • Increase prolactin levels
  • Orthostatic hypotension (secondary to alpha-1 blockade) +/- reflex tachycardia. More common with chlorpromazine and thioridazine compared to haloperidol
  • Sexual dysfunction including loss of libido and anorgasmia
  • Impaired cognition
  • LFT elevations and hepatitis
RARE

  • Neuroleptic malignant syndrome (NMS) presenting as confusion, fever, tachycardia, muscle rigidity, and labile blood pressure.
  • QTc and PR interval prolongation. Associated more frequently with ziprasidone, thioridazine, and clozapine.
  • Benign pigmentary deposits on the retina associated with thioridazine and chlorpromazine.
  • Agranulocytosis reported in 0.8% (1-year risk) of patients treated with clozapine during the first 4-6 month of therapy. Monitor weekly CBC for the first 6 months in clozapine treated patients. Transient leukopenia also reported with phenothiazines.
  • Hyperpyrexia (more commonly reported in hot weather or during exercise)
  • Seizure: use with caution in patients with a seizure history.

DRUG INTERACTIONS

Phenothiazines and haloperidol are primarily metabolized via CYP2D6. Atypical antipsychotics are metabolized primarily via CYP2D6, CYP3A4, and CYP1A2. Potent inducers and inhibitors of these isoenzymes may decrease and increase atypical antipsychotic serum concentrations, respectively. Dose may need to be adjusted based on toxicity and therapeutic response.

  • CYP 450 inducers (e.g carbamazepine, phenobarbital, phenobarbital, primidone, and rifampin) may decrease serum concentrations of atypical antipsychotics, phenothiazines, and haloperidol.
  • Cimetidine may increase serum concentrations of clozapine, risperidal, olanzapine, quetiapine, and ziprasidone.
  • CYP 1A2 inhibitor (e.g ciprofloxacin, cimetidine, fluvoxamine, fluoxetine) may increase serum concentration of clozapine and olanzapine. May increase risk of seizure with clozapine co-administration. Use with caution.
  • CYP 3A4 inhibitors (e.g erythromycin, clarithromycin, azole antifungal (e.g ketoconazole, itraconazole, voriconazole, posaconazole), HIV-protease inhibitors) may increase serum concentrations of clozapine, quetiapine, and ziprasidone.
  • CYP 2D6 inhibitors (e.g bupropion, fluoxetine, paroxetine, duloxetine, quinidine, ritonavir) may increase thioridazine, risperidone, and haloperidol.
  • Antihypertensive agents: may increase risk of orthostatic hypotension with antipsychotics co-administration. Co-administer with close monitoring.
  • Benzodiazepines: may increase risk of over sedation (esp. with clozapine). Co-administer with close monitoring.
  • Agents with anticholinergic side effects (e.g tricyclic antidepressants, antihistamines): may increase risk of anticholinergic side effects and impair cognition with antipsychotic co-administration.
  • Agents known to increase QTc (e.g high dose methadone, clarithromycin, erythromycin, tricyclic antidepressants): may increase risk of QTc prolongation (esp. with ziprasidone). Avoid co-administration with baseline QTc prolongation.
  • Metoclopramide: may increase risk of akathisia and other extrapyramidal side effects with antipsychotic co-administration.

PHARMACOKINETIC

COMMENTS

  • Atypical antipsychotics are now considered first line due to lower rates of extrapyramidal symptoms and tardive dyskinesia but are associated with weight gain, lipid abnormalities, and incident diabetes.
  • Olanzapine and clozapine are associated with greater weight gain and increased risk of type 2 diabetes (Lambert).
  • Weight gain, diabetes, and lipid abnormalities: clozapine, olanzapine>>risperidone, quetiapine>ziprasidone and aripiprazole (Lieberman).
  • In obese patients with diabetes, ziprasidone may be considered since it is associated with less weight gain compared to the other atypical antipsychotics (Komossa).
  • 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 atypical antipsychotic therapy and quarterly thereafter at the time of routine visits is recommended (Consensus Statement).
  • Typical antipsychotics (e.g haloperidal) are less likely to cause weight gain and diabetes compared to atypical antipsychotics (e.g olanzapine).
  • Although patients who gain weight during antipsychotic therapy are at higher risk of developing diabetes, hyperglycemia has also been reported in patients without significant weight gain (Lindenmayer)
  • Evidence is lacking as to whether these drugs worsen diabetic control in people with pre-existing diabetes, but diabetic patients newly started on atypical antipsychotics (e.g olanzapine) should have their blood sugar monitored closely.

REFERENCES


 
 
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