Antipsychotics are associated with an assortment of side effects, many of which can seriously
affect a patient's physical health and quality of life. Side effects occur because neurotransmitters are
affected by drugs, drug half-life, P450 liver enzyme system metabolism, and percentage of the drug
bound to a given receptor. By understanding these concepts, clinicians can better understand why and
how side effects occur, and also predict to some degree in which patients side effects will occur. The
more factors involved in a given patient, the more likelihood side effects will occur. It is important to
appreciate that while not all side effects are serious, some can be fatal
In 1961, clozapine was developed as 1 of nearly 2000 tricyclic compounds. It was tested in 1966
in patients with schizophrenia and was noted to have good antipsychotic effects and an absence of the
typical tardive dyskinesia and Parkinsonian-like side effects of the phenothiazine-type drugs. It was
thus referred to as an "atypical" antipsychotic. Clozapine was originally known to affect the levels of
multiple neurotransmitters including epinephrine, norepinephrine, acetylcholine, and histamine, with a
minimal effect on the nigrostriatal dopamine tracts.[1] Clozapine was pulled from the market briefly
because of several deaths resulting from agranulocytosis, but it was released again to be used when all
other treatments had failed and with the caveat that patients have a complete white blood cell count
drawn monthly while taking the medication.
In the late 1950s, the development and study of lysergic acid led to the suggestion that serotonin
had a role in psychosis. After it was discovered that clozapine had a significant serotonin blocking
action (antagonism) and much less blocking of dopamine, federal and industry research into brain
function and pharmacologic therapies exploded. By 2000, the list of approved atypical or second-
generation antipsychotics, also referred to as serotonin/dopamine antagonists (blockers), grew to
include risperidone, olanzapine, quetiapine, and ziprasidone. Their effects on multiple
neurotransmitters, however, produced a distinct set of side effects, including weight gain, diabetes
mellitus, dyslipidemias, and sexual dysfunction. In 2002, the first antipsychotic to not fully block
dopamine, aripiprazole, was approved by the US Food and Drug Administration. In addition to
selective antagonism of various neurotransmitters, it has a partial agonist effect on dopamine 2
receptors. In May 2009, iloperidone, with a pharmacologic profile similar to that of risperidone, was
approved.
Because each atypical antipsychotic exerts various antagonist or reuptake blocking actions on
multiple neurotransmitters, an understanding of the functions of the major neurotransmitters is helpful
in teaching patients about both the desired therapeutic and side effect potentials of a given drug (Table
2).
Table 2. Selected Neurotransmitters
Adapted from Stahl S. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical
Applications. 3rd ed. New York: Cambridge University Press; 2008
Adapted from: Moller M. Psychopharmacology. In: Mohr W, ed. Psychiatric-Mental Health Nursing:
Evidenced Based Concepts, Skills, and Practices. 7th ed. Philadelphia: Wolters Kluwer, Lippincott
Williams & Wilkins; 2009:Chapter 16
Table 7 gives some approximations of Ki values, although there is tremendous variability in ranges
reported for each. The National Institute of Mental Health's Psychoactive Drug Screening Program
provides an online database of receptor values at http://pdsp.med.unc/edu/index.htm.
Table 7. Binding of Antipsychotic Medications to Specific Receptors
Sources: Preskorn S. Classification of neuropsychiatric medications by principal mechanism of action:
a meaningful way to anticipate pharmacodynamically mediated drug interactions. J Psychiatr Pract.
2003;9: 376-384 (chart adapted and used with permission); Farah A. Atypicality of antipsychotics.
Primary Care Companion. J Clin Psychiatry. 2005;7:268-274; Goldstein JM. The new generation of
antipsychotic drugs: how atypical are they? Int J Neuropsychopharmacol. 2003;3:339-349; Kalkman
HO, Subramanian N, Hoyer D. Extended radioligand binding profile of iloperidone: a broad spectrum
dopamine/serotonin/norepinephrine receptor antagonist for the management of psychotic disorders.
Neuropsychopharmacology. 2001;25:904-914
Variations in Metabolism
CYP2C19 and CYP2D6 are bimodally distributed in the population allowing classification of
individuals as either extensive or poor metabolizers. This is referred to as genetic polymorphism.
Tremendous research is going on to develop quick office-based tests to determine who may be at risk
for these significant metabolic variations.[5,6] Adverse effects and/or toxicity from high levels of
unmetabolized drugs are more likely to develop in poor metabolizers. Approximately 7% of whites and
upward of 33% of Asians and African Americans are poor metabolizers.[7] Extensive metabolizers are
more likely to be nonresponders at the usual therapeutic dose range. It is now possible through
genotyping to predict up to 90% of individuals who will be poor metabolizers for CYP2C19 and
CYP2D6.
Summary
The purpose of this article was to acquaint and alert the clinician to the complexities and often-
subtle nuances behind drug side effects. The prevention and early detection of antipsychotic side effects
requires both art and science. The art of predicting, detecting, and managing side effects includes a
thorough assessment of lifestyle including the use of alcohol and smoking, dietary and beverage
choices, use of herbal supplements, and exercise and sleep patterns. The science of predicting,
detecting, and managing side effects requires knowledge of the pharmacokinetic and pharmacologic
action of prescribed drugs in combination with a thorough understanding of comorbid medical
conditions and the medications used to treat them. Clinicians are encouraged to consult with a
pharmacist whenever a question of a potential drug-drug, drug-disease, and/or drug-diet interaction is
suspected. By using the charts and tables in this article, clinicians will be better informed to educate the
patient in a variety of interventions that will diminish the potential for medication side effects, promote
better pharmacologic efficacy from prescribed medications, and improve the overall quality of life.