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Clinician’s Corner: 2nd Generation Antipsychotic Side Effects

Now that we are comfortable with the second-generation antipsychotics regarding their efficacy, let’s look at what separates them.  Most feel it is the side effect profiles that separate these drugs.  We’ll discuss the major parameters that separate this class of drugs. Side effect management is extremely important especially in the primary care physician’s office.

Black box warning: on all atypical antipsychotics concerning “sudden death” due to use of these drugs in elderly patients, when used for “behavior” problems.  Use with caution in debilitated or elderly patients. Black box warning below applies to ALL atypical antipsychotics.

Time of effective results:  Although many drugs may reach “steady state” in a matter of a few days, allow 4 to 6 weeks for drug to take effect.

FDA-Approved Adult Indications for Atypical Antipsychotics (cms.gov)

Bipolar-1 disorder aripiprazole, asenapine, olanzapine, quetiapine, quetiapine extended-release (XR), risperidone, ziprasidone
Bipolar depression lurasidone, olanzapine, quetiapine, quetiapine XR
Schizophrenia aripiprazole, asenapine, brexpiprazole, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, quetiapine XR, risperidone, ziprasidone
Schizoaffective disorder clozapine, paliperidone
Adjunct to Major Depressive Disorder aripiprazole, brexpiprazole, olanzapine, quetiapine XR

Tapering doses:  must be done gradually, watching for signs of re-occurrence. Reduce dose after acute episode, slowly and gradually reduce to lowest effective dose.   Abrupt withdrawal may precipitate relapse.

Monitoring of metabolic parameters:

Many psych clinics are aware of the metabolic effects of the second-generation antipsychotics.  Clinicians MUST be cognizant of the diabetes, obesity and dyslipidemias that these drugs can cause.

  • Clozaril and Zyprexa are the biggest offenders
  • Risperdal, Fanapt and Seroquel cause moderate weight gain
  • Abilify, Geodon, Saphris, Invega, Latuda are considered to be “weight neutral”

Monitoring recommendations.

    • Weight: check at baseline and then 1, 2, and 3 months after starting or changing therapy and then every 3 months.
    • Fasting glucose and blood pressure: check at baseline, 3 months, and then at least annually.
    • Lipids: check at baseline, 3 months, then every 5 years if normal. Because of risk factors, however it is wise to check lipid parameters annually. NOTE: diabetes and hyperlipidemia been noted in patients who have not had significant weight gain.
    • Waist measurement: check at baseline, then annually

Consider switch to different antipsychotic if glucose or lipids worsen or if patients have more than a 5% weight gain.


  • 60 to 70 percent of patients taking paliperidone and risperidone experienced sexual side effects. (no surprise-think prolactin)
  • 50 to 60 percent of those on olanzapine, quetiapine, and ziprasidone
  • Less than 50 percent on clozapine
  • 16 to 27 percent on aripiprazole

OTHER STUFF:  There is little clinical evidence to support the use of combination therapy of antipsychotic drugs within the same class.  The atypical antipsychotics may range in cost from $10 to $1200 per month.  Some studies have shown evidence that prescribing 2 or more atypical antipsychotics increases the occurrence of extrapyramidal symptoms.


  • Limited data available for 1st and 2nd generation antipsychotics in pregnancy
  • Chlorpromazine (Thorazine®) was at one time used for morning sickness, without causing reported teratogenesis
  • Only clozapine (Clozaril) and lurasidone (Latuda®) have received a Category-B rating from FDA
  • Risk of weight gain which may be problematic in pregnancy are greater with second generation anti-psychotics
Minimize weight gain Abilify, Latuda, Saphris, Geodon Clozaril (worst), Zyprexa (worst).  Seroquel
Minimize Extrapyramidal Symptoms Seroquel, Fanapt Risperidal, Invega
Minimize QT prolongation Abilify, Latuda, Zyprexa Geodon, Fanapt, Invega
Minimize Hyperprolactinemia   Risperdone, Invega
Minimize Sedation Abilify, Risperdal, Invega, Geodon  
Treatment of Agitation or Treat insomnia Zyprexa, Seroquel  

(for brevity brand names are listed)

Risperdal, Clozaril, Zyprexa, Seroquel, Abilify, Invega & Geodon are available generically Saphris, Fanapt, Latuda, Rexulti, Vraylar are still brand