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Side Effects of Antipsychotic Medications: Understanding the Variables

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

Neurotransmitter Involvement in Side Effects


The tranquilizing effects of antipsychotic agents were originally discovered in the late 1940s
when potent antihistamines were developed to alleviate postoperative shock. The initial antipsychotic
effect was thought to be attributed to antihistaminic qualities. However, the high doses of
chlorpromazine initially used to prevent postoperative shock caused numerous severe and sometimes
permanently disabling multisystem side effects when used repeatedly.[1] Patients given doses in the
range of 2000 mg daily started experiencing severe endocrine and neuromuscular side effects similar to
those of Parkinson's disease as well as acute and tardive dystonic reactions and emotional flattening.
The discovery in the 1960s of L-dopa, used to treat the dopamine deficits of Parkinson's disease, led to
the serendipitous understanding of the relationships between dopamine blockade and the creation of
antipsychotic effects, and provided the first window into understanding side effects. As a deductive
conclusion, the role of dopamine excess as etiologic in psychosis symptoms led to an explosion of
available phenothiazine-related antipsychotic drugs over the next 30 years. These original
phenothiazine-type drugs are referred to as typical or first-generation antipsychotics. Drugs in this
category typically have side effects related to excessive blocking of 1 or more of the 4 major dopamine
tracts in the brain, resulting in primarily neuromuscular and neuroendocrine side effects (Table 1).
Eventually 2 major dopamine subsystems were identified: D1 and D2. The D2 system is the primary
system involved in treating psychosis.

Table 1. Dopamine Receptor Families


GABA = gamma aminobutyric acid
Sources: Kandel ER, Schwartz JH, Jessell T M. Principles of Neural Science.4th ed. New York:
McGraw-Hill; 2000
Stahl S. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. New
York: Cambridge University Press; 2008

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

Currently Available Antipsychotic Drugs


A complete listing of currently available antipsychotic medications is found in Table 3. As a
class, these drugs are effective in helping manage the many troublesome symptoms of psychosis, yet
there is a great variation in the response and side effect profile that individual patients experience.
Additionally, with the exception of indications for the use of risperidone and aripiprazole, this category
of drugs is not yet approved for children and adolescents by the US Food and Drug Administration.
There is also a black box warning for the entire category of drugs for use in the elderly.
Table 3. Antipsychotic Medications
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

What Are Antipsychotic Medication Side Effects?


Side effects are problems that occur when treatment goes beyond the desired effect, such as the
patient sleeping for 24 hours when only mild sedation is desired, or problems that occur in addition to
the desired therapeutic effect such as blocking dopamine transmission to stabilize acute psychosis that
culminates in creating a Parkinsonian-type tremor.
Unfortunately, antipsychotic medications are not site-specific like an antibiotic developed to
combat a specific bacterium. Because of the miniscule size and nature of the structure of the neuron
and the fact that neural networks are multifunctional, each neurotransmission can affect many different
neurons in a process referred to as a "chemical puff".[2] The resulting effect is a "dusting" and thereby
unintentional interruption of normal functioning of adjacent neurons, creating side effects. To further
complicate the situation, there is a reciprocal relationship between dopamine and acetylcholine in the
sympathetic and parasympathetic (cholinergic) nervous systems. When dopamine is blocked,
acetylcholine levels increase and cause very uncomfortable potentially widespread parasympathetic
side effects such as dry mouth, blurred vision, constipation, urinary retention, tachycardia, mydriasis,
and even paralytic ileus.
Additionally, there is an inverse relationship in the sympathetic (adrenergic) nervous system
between dopamine and serotonin. If dopamine is blocked, serotonin increases, resulting in both
therapeutic effects and side effects. Increasing serotonin can block dopamine in selected brain regions
-- again with both therapeutic and side effects. Some antipsychotic medications block serotonin in
certain brain regions with the net result of increasing dopamine where there are few dopamine
transporter neurons. The net result of these actions on dopamine and serotonin, however, is to decrease
psychosis. This is a very delicate balancing act, one that is often difficult to predict.
The prescriber and the patient have to discuss the risk/benefit ratio of therapeutic and side effect
consequences and arrive at a mutual decision. The possibility of the occurrence of widespread effects
on multiple body systems must be discussed with patients (Table 4). The following side effects must be
reported immediately: shuffling walk; stiffness of arms and/or legs; twitching or jerky movements
especially of the head, face, mouth, or neck; restlessness or inability to sit still; trembling and/or
shaking of hands and fingers; difficulty swallowing; vision problems; muscle spasms; lack of
coordination; weakness; difficulty urinating; menstrual changes; rash, fever, yellow skin, sore throat, or
hives; unusual bleeding or bruising; face or mouth movements that occur after a few months; drooling;
and involuntary movements of the tongue. There are, however, distinct differences between the
individual drugs ( Table 5 ). The Glasgow antipsychotic side effect scale is a useful tool for helping
patients track their symptoms over time.[3]
Table 4. Possible Systemic Side Effects of Antipsychotic Medications
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.

The Role of Receptor Binding in Antipsychotic Side Effects


Because major neurotransmitter systems parallel each other in the same circuits, histamine,
acetylcholine, alpha- and beta-adrenergic, and muscarinic receptors are also often recipients of
unwanted blockade and side effects are created (Table 6). Side effects occur based on the specific
receptors affected by the various drugs. However, the degree of blockade (receptor occupancy) and
length of time a drug is on the receptor are what actually determine the degree of the side effect. There
is also a close correlation to the half-life of a drug and the length of drug occupancy on a given
receptor.[4] The level of receptor occupancy is called Ki binding. The closer the Ki is to 1, the higher
the affinity of the drug for a given receptor (Table 7). For example, a patient on haloperidol with a
Dopamine 2 receptor Ki value of 0.7 would be much more likely to experience extrapyramidal side
effects than a patient on quetiapine that has a 160 Ki value. In looking at weight gain, it is predictable
that olanzapine will have the highest likelihood because of a muscarinic Ki value of 2 when compared
to > 1000 for both aripiprazole and ziprasidone and > 10,000 for risperidone. It is important to realize
that tremendous variations can occur in individual patients.
Table 6. Effects of Receptor Blockade

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

The Role of the P450 System in Antipsychotic Medication Side Effects


The general rule is that any person can experience any side effect at any time from any
medication, but the likelihood varies tremendously. Patients who have no general health problems, are
not overweight, eat a healthy diet, get plenty of exercise, and are not elderly face fewer risks. The fewer
medications a person takes, the lower the likelihood of side effects. The level of liver metabolic
enzymes plays a strong part in this aspect of evaluating the potential for side effects.
Most medications require metabolism by specific liver enzymes, referred to as the cytochrome
P450 enzyme system. If a patient takes several drugs and drug A blocks a given liver enzyme system
and drug B requires that enzyme for metabolism, then drug B will continue to exert its effect,
sometimes for days. Conversely, if drug A induces a given liver enzyme system and drug B requires
that enzyme for metabolism the effect of drug B will be greatly diminished. More than 90% of human
drug oxidation is controlled by 6 CYP isoenzymes: 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. The 2D6
system metabolizes at least 30% of common medications including selective serotonin reuptake
inhibitors, pain relievers, beta-blockers, and many of the antipsychotic drugs. However, the 3A4 system
metabolizes at least 50% of all other common medications including antihistamines, antibiotics, lipid
lower medications, protease inhibitors, antifungals, and antipsychotics. The 3A4 also often serves as
the second isoenzyme system or "safety net" involved in drug metabolism. Except for trazodone, the
following psychotropics are metabolized by another isoenzyme in addition to CYP3A4:
• Antidepressants: imipramine, paroxetine, sertraline;
• Antipsychotics: aripiprazole, clozapine, haloperidol, iloperidone, olanzapine, pimozide,
risperidone; and
• Benzodiazepines: most except for lorazepam, oxazepam, and temazepam.
Many antidepressants and antipsychotic medications are metabolized by either CYP2C19 or CYP2D6.
This often results in clinically significant drug-drug interactions when treating an individual (eg,
psychotic depression) with both an antidepressant and an antipsychotic. Likewise, concerns about
toxicity arise when co-prescribing both a tricyclic antidepressant and a selective serotonin reuptake
inhibitor (an accepted practice for treatment-resistant depression). Table 8 depicts the metabolic
pathways for the atypical antipsychotics. Most antipsychotics actually inhibit their own metabolism,
which also makes it difficult to predict response and the actual number of milligrams a given patient
will require. The identification of cruciferous vegetables, arial hydrocarbons, caffeine, and St. John's
Wort as enzyme inducers and grapefruit juice as an enzyme inhibitor adds to the complexity of both
patient assessment and education related to watching for side effects created by foods, smoke, caffeine,
and herbal supplements.
Table 8. Metabolic Pathways for Atypical Antipsychotics

TCAs = tricyclic antidepressants


Sources: Cozza KL, Armstrong SC, Osterheld JR. Concise Guide to Drug Interaction Principles for
Medical Practice. 2nd ed. Washington DC: American Psychiatric Publishing, Inc; 2003; Hansten PD,
Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management. Freeland, Washington:
H&H Publications; 2008;
Indiana University School of Medicine Division of Clinical Pharmacy. Drug-drug interactions.
Available at: http://www.medicine.iupui.edu/clinpharm/DDIs/table.asp Accessed May 17, 2009

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.

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