Updates on Second-Generation Antipsychotics

Antipsychotics developed after 1990 are referred to as second-generation agents because they act on different neuroreceptor sites compared to their first-generation (Thorazine, Haldol, Stelazine, Navane, Mellaril, etc.) counterparts. Specifically, the SGAs block both dopamine and serotonin receptors and are more different from each other than they are alike. SGAs have fewer movement-related side effects. They also seem to have mood stabilizing effects that the FGAs do not possess. The main reason for using these newer antipsychotics is that patients tolerate them better, although adherence to treatment is not necessarily improved.  SGA’s do have less risk of tardive dyskinesia, but unfortunately some of them, Clozaril and Zyprexa in particular, can cause major weight gain, problems with glucose and lipid metabolism  and elevated cholesterol levels – side effects collectively referred to as metabolic syndrome.

There are now 10 second-generation antipsychotics on the U. S. drug market. Bulleted below are the latest updates on the advantages and disadvantages of each:

Clozaril (clozapine)

  • Truly a miracle agent for some
  • Not a first-line treatment – can cause potentially serious agranulocytosis
  • FDA approved for the management of recurrent suicidal behavior in schizophrenics
  • Because of the agranulocytosis risk, blood count monitoring is necessary – weekly for 6 months, followed by every 2 weeks for 6 months, then monthly.
  • Significant weight gain and very sedating
  • High risk for the development of metabolic syndrome

Risperdal (risperidone)

  • Well accepted for the treatment of agitation and aggression in dementia, in spite of carrying a black-box warning
  • Few side effects at low dose
  • Above 6mg/day – extrapyramidal symptoms – dystonia, parkinsons, akathisia
  • Available in a long-acting Consta® formulation

Zyprexa (olanzapine)

  • Rapid calming action for agitation
  • Sedating, and produces the most weight gain among the SGAs
  • Like Clozaril, significant risk for the development of metabolic syndrome
  • Lowest discontinuation rate among the SGAs
  • Available in a long-acting injection – Relprevv

Seroquel (quetiapine)

  • Some efficacy in bipolar depression
  • Seroquel XR is FDA approved as an augmenting agent to traditional antidepressants in the management of treatment-resistant unipolar depression
  • Has taken off in the U.S as the new sleeping pill
  • Don’t count on its antipsychotic efficacy as a monotherapy treatment

Geodon (ziprasidone)

  • Least likely of the SGAs to cause weight gain
  • Cardiac safety is a concern, though not as serious as previously thought
  • Available as an IM injection

Abilify (aripiprazole)

  • Like Seroquel XR, Abilify is approved as an augmenting agent to traditional antidepressants in the management of treatment-resistant unipolar depression
  • Few side effects
  • Not sedating enough in acute agitation
  • Stand-alone antipsychotic efficacy questionable

Invega (paliperidone)

  • Active metabolite of risperidone, extended-release action
  • Kidney metabolized, fewer drug interactions compared to risperidone
  • Available as a long-acting IM preparation: Sustenna®
  • More expensive than risperidone for too little benefit

Saphris (asenapine)

  • Available only as a sublingual tablet
  • Elevated level of EPS – comparable to that of some FGAs
  • Associated with weight gain, oral numbness, and it’s sedating

Fanapt (iloperidone)

  • Twice-a-day dosing a disadvantage
  • The rights to the drug were handed off among several companies
  • Took at least 15 years to gain FDA approval
  • Linked to possible heart rhythm problems
  • No distinct advantages

Latuda (lurasidone)

  • No distinct advantages or disadvantages, a “me-too” SGA
Joseph Wegmann, R.Ph., LCSW is a licensed clinical pharmacist and a clinical social worker with more than thirty years of experience in the field of psychopharmacology. His diverse professional background in psychopharmacology and counseling affords him a unique perspective on medication management issues. In addition to consulting with numerous psychiatric facilities, he has presented psychopharmacology seminars to thousands of clinicians in 46 states.

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