INDICATIONS

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

• 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

ADVERSE DRUG REACTIONS

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

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

1. 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]
2. 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]
3. Miller LJ. Management of atypical antipsychotic drug-induced weight gain: focus on metformin. Pharmacotherapy. 2009;29(6):725-35.  [PMID:19476423]
4. Komossa K, Rummel-Kluge C, Hunger H, et al. Ziprasidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2009.  [PMID:19821380]
5. 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]
6. 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]
7. 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.
8. Abilify (aripiprazole) US prescribing information. Otsuka America Pharmaceutical, Inc. February, 2012.