Side Effects of Antipsychotic Medications

Side Effects of Antipsychotic Medications: Understanding the Variables CME


Mary D. Moller, DNP, MSN

Published: 06/10/2009



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 (Figure 1).



Click to zoom Figure 1.


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

D1 family
   D1: substantia nigra, striatum, basal ganglia, nucleus accumbens, olfactory, amygdala
   D5: hippocampus, hypothalamus
D2 family
   D2 subtype: striatum, nucleus accumbens, substantia nigra, olfactory bulb
   D3: tuberoinfundibular-hypothalamus, nucleus accumbens, olfactory bulb
   D4: frontal cortex, midbrain, medulla
Major dopamine tracts in the brain
   1. Mesolimbic: originates in the ventral tegmental area of the brainstem and extends to the nucleus accumbens and limbic system, thalamus, brainstem, and reticular-activating system
      a. Influences control of autonomic and endocrine functions
      b. Influences perception, thinking, emotion
      c. Neurotransmitters involved
         i. Agonistic: dopamine, norepinephrine, acetylcholine
         ii. Antagonistic: serotonin, GABA
      d. Antagonism has antipsychotic effects
   2. Mesocortical: also projects from the ventral tegmental area and sends axons to prefrontal cortex and involves the corpus and ventral striatums
      a. Receives stimuli from the external environment (what can be evoked as memory and what can be discarded)
      b. Codes incoming information for distribution and intensity
      c. Sends and receives information from memory storage areas in temporal and frontal lobes
      d. Influences interpretation of incoming information by coding it for storage
      e. Antagonism has antipsychotic effects.
   3. Nigrostriatal: originates in the substantia nigra area of brainstem and involves both upper and lower motor neurons and corpus striatum including the extrapyramidal nervous system
      a. Modulates and coordinates motor outflow to skeletal muscles
      b. Controls "associated" movements (ie, movements encoded in memory)
      c. Neurotransmitters involved
         i. Agonist: acetylcholine
         ii. Antagonist: dopamine
      d. Antagonism creates potentially serious side effects, including parkinsonism
   4. Tuberoinfundibular: originates in the hypothalamus
      a. Inhibits the release of prolactin and melanocyte-stimulating hormone from the pituitary gland
      b. Stimulates vagus nerve
      c. Antagonism creates potentially serious side effects such as prolactin elevation

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

Neurotransmitter Physiologic Action Effect of Excess Effect of Deficit
-Precursor is the amino acid tyrosine
-Four major tracts in the brain: mesocortical, mesolimbic, nigrostriatal, tuberoinfundibular
-Two major receptor groups: D1-D5 and D2, 3, 4
• Thinking
• Decision-making
• Respond with reward-seeking behaviors; ie, the "gusto" neurotransmitter
• Fine muscle movements
• Integration of thoughts and emotions
• Stimulates the hypothalamus to release hormones affecting thyroid, adrenal, and sex hormones
Mild: • Helps with creativity
• Assist with problem-solving
• Able to generalize situations
• Good spatial ability Severe: • Disorganized thoughts
• Loose associations
• Disabling compulsions
• Tics
• Stereotypic behaviors
Mild: • Poor impulse control
• Poor spatial ability
• Inability to have abstract thinking Severe: • Parkinson's disease
• Endocrine changes
• Movement disorders
- Only 1% of all brain neurotransmitter volume
- Precursor is dopamine
- Measured in the urine as MHPG
-Major receptor groups are α-1, α-2, and β-1, β-2
• Alertness
• Ability to focus attention
• Ability to be oriented
• Primes nervous system for "fight or flight"
• Arouses senses
• Ability to learn
• Increases memory
• Awareness
• Stimulates sympathetic nervous system
• Anxious
• Hyperalert
• Paranoid
• Loss of appetite
• Dull
• Low energy
• Depression
-Precursor is norepinephrine
-Released by the adrenal medulla in response to stress
-Overrides inhibitory and other neurotransmitters to provide immediate strength and single-focused concentration
• Released by the lower brainstem and directly stimulates the hypothalamus to release hormones
• Inhibits firing in the locus ceruleus
• Acts on α-1, α-2, β-1, and β-2 receptors predominate in the brain with β-1 the most dominant in the cortex and β-2 in the cerebellum to provide rapid response to perceived threats
• Overstimulation of all mental and physical functions
• Cardiac arrest
• Manic behaviors
• Paranoia
• Dull
• Low energy
• Depression
• Muscle weakness
-Helps to balance norepinephrine/dopamine through inverse relationship in adrenergic nervous system
-Precursor is the amino acid tryptophan
-Measured in urine as 5-HIAA
-24 major receptor groups include 1, 2, 3, 4, 5, 6 with subgroups under each major group
• Inhibits activity and behavior
• Increases sleep time
• Reduces aggression, play, sexual, and eating activity
• Temperature regulation
• Sleep cycle
• Pain perception
• Regulates mood states
• Precursor to melatonin, which plays a role in circadian rhythms, some depressions, light-dark cycles, jet lag, female reproductive cycle, seasonal skin pigment changes
• Sedation
• If greatly increased, the metabolites may lead to hallucinations
• Irritability
• Hostility
• Depression
• Sleep disturbance
-Precursor is the amino acid choline
• Promotes preparation for action
• Conserves energy
• Attention
• Memory
• Defense and/or aggression
• Thirst
• Sexual behavior
• Mood regulation
• Ability to "play"
• Rapid eye movement sleep
• Stimulates cholinergic nervous system
• Controls muscle tone by a balance with dopamine in the basal ganglia
• Self-consciousness
• Overinhibition
• Anxious depression
• Depression
• Lack of inhibition
• Poor recent memory
• Alzheimer's disease
• Euphoria
• Parkinson's disease
• Antisocial
• Manic behavior
• Speech blockage
-Synthesized from glutamic acid
-Transmitter glutamate is different from metabolic glutamate
• Glutamate occurs naturally in protein-containing foods such as cheese, milk, mushrooms, meat, fish, and many vegetables
• Glutamate is also produced by the human body and is vital for metabolism and brain function
• One of the most important components of protein
• Generalized activator of interneural transmission
• Elevated levels of extracellular glutamate are responsible for neuronal damage and degeneration in brain disorders
• Rage reactions, including assault
• Delusions
• Hallucinations
• Migraine headaches
• Hyperirritability
• Decreased protein synthesis
• Lack of overall "sharpness" in mental functions
• Inability to synthesize GABA
• Lack of ability to calm oneself
-(gamma-aminobutyric acid)
-Precursor is glutamate, which is synthesized from the amino acid glutamic acid
• Reduces aroused aggression, anxiety, and excitation
• Generalized inhibitor of interneural transmission
• Anticonvulsant
• Sedation
• Impaired recent memory
• Irritability
• Seizures
• Huntington's disease
• Epilepsy
(endogenous opioid peptides)
-Counteracts the impact of physical and psychologic stress and
reestablishes homeostasis
• Alters the emotional implications of a painful experience
• Involved in brain reward center
• Involved in feeding behaviors
• Involved in growth
• Involved in memory consolidation
• Insensitive to pain
• Movement disorder similar to catatonia
• Auditory hallucinations
• Impaired memory
• Hypersensitivity to pain and stress
• Inability to experience pleasure

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

First-Generation Medications (listed alphabetically by brand name)
Brand Name Generic Name Daily 
Dosage Range 
Subgroup Peak (hr) Half-life 
Compazine® Prochlorperazine 15-20 Piperazine 1-3 6-8
Haldol® Haloperidol 2-100 Butyrophenone 1-3 12-38
Loxapine 20-400 Dibenzoxazepine 1½-3 4
Mellaril® Thioridazine 30-800 Piperidine 1-4 7-13
Moban® Molindone 15-400 Dihydroindolone ½-1 2
Navane® Thiothixene 6-60 Thioxanthene 1-3 10-20
Prolixin® Fluphenazine 1-20 Piperazine 1-3 15-30
Serentil® Mesoridazine 100-400 Piperidine 1-3 24-48
Stelazine® Trifluoperazine 2-20 Piperazine 2-4 10-20
Thorazine® Chlorpromazine 30-1200 Aliphatic 2-4 16-30
Trilafon® Perphenazine 6-64 Piperazine 2-4 8-20
Second-Generation Medications (listed chronologically, oral forms only)
Clozaril® Clozapine 250-600 Dibenzodiazepine 2.5 4-66
Risperdal® RisperidonePaliperidone 1-16 3-9 BenzisoxazoleActive metabolite of risperidone 3-1724 3-2023
Zyprexa® Olanzapine 5-20 Thienobenzodiazepine 6 21-54
Seroquel® Quetiapine 150-800 Dibenzothiazepine 2 6-7
Geodon® Ziprasidone 80-160 Benzisothiazole 3 4-6
Abilify® Aripiprazole 2.5-30 Dichlorophenylpiperazinyl 3-5 75
Fanapt™ Iloperidone 12-24 Benzisoxazole Rapid 14

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

I. Neurologic: This refers primarily to effects of drugs on the motor aspects of central (brain) and peripheral (nerves coming off the spinal cord) nervous systems and includes the following extrapyramidal side effects
   A. Dystonias: Severe muscle spasms that can be life-threatening if not treated immediately
      1. Torticollis: Severe twisting of the neck and back
      2. Opisthotonus: Severe arching of the back
      3. Oculogyric crisis: Severe rolling back of the eyes into the head
      4. Laryngospasms: Spasms of the throat in which breathing and swallowing become severely impaired and emergency tracheotomy may be required
      5. Spasms of the face, lips and tongue, making it very difficult to talk, chew, and eat
   B. Dyskinesias: Abnormal muscle movements, not as severe as spasms
      1. Facial tics and twitches
      2. Chewing movements
      3. Lip smacking
      4. Blinking
      5. Aimless movements of tongue
      6. Shoulder shrugging
      7. Pedaling movements of legs
      8. Flailing arms
   C. Tardive dyskinesia: Late onset (after a minimum of 3 months in adults and 1 month in the elderly) of dyskinesias. Tardive dyskinesia can become permanent and must be treated at the first symptom
   D. Akathisia: Psychomotor restlessness, less intense than dystonias or dyskinesias
      1. Intolerance of inactivity
      2. Continuous agitation and restlessness
      3. Pacing
      4. Constant leg and finger movements
      5. Rocking and shifting of weight while standing
      6. Shifting of legs and tapping of feet while sitting
   E. Pseudoparkinsonism: Muscle movements that mimic Parkinson's disease
      1. Stiffness and slowness of voluntary movement
      2. Masklike immobility of facial muscles
      3. Stooped posture
      4. Slow, monotonous speech
      5. Shuffling gate that speeds up on its own
      6. Immobility
II. Central nervous system -- effects on alertness
   A. Sedation
   B. Psychomotor retardation
   C. Lowered seizure threshold
   D. Drug-induced depression
III. Autonomic nervous system
   A. Anticholinergic (parasympathetic nervous system)
      1. Dry mouth
      2. Blurred vision
      3. Constipation
      4. Urinary retention
      5. Tachycardia (heart beats more than 80 beats per minute)
      6. Mydriasis (pupils dilate)
      7. Paralytic ileus (bloating due to absence of movement in the small bowel)
      8. Urinary hesitancy (difficulty starting the stream of urine)
      9. Dental cavities
   B. Alpha-adrenergic blocking
      1. Postural hypotension
      2. Inhibition of ejaculation
      3. Diarrhea
      4. Miosis
      5. Rhinitis
      6. Bradycardia
      7. Drooling
IV. Cardiovascular
   A. Lengthening of the Q-R interval that could lead to Torsades de Point
V. Hematopoietic
   A. Leukopenia
   B. Agranulocytosis
VI. Dermatologic/ophthalmologic
   A. Generalized skin rash
   B. Photosensitivity
   C. Oculocutaneous pigmentation -- a purple or gray color to the skin. May also occur on the cornea and lens of the eye
   D. Retinal pigmentation
VII. Liver and allergic responses
Generalized symptoms of virus infections, such as weakness and abdominal pain, followed by itching and yellowing of the skin about 4 weeks after starting the medication
VIII. Endocrine system
   A. Weight gain
   B. Females: breast engorgement with milk production. Amenorrhea may occur
   C. Males: enlarged breasts
   D. Decreased libido
   E. Hyper/hypothermia
   F. Malignant hyperthermia
IX. Metabolic
   A. Lipid abnormalities
   B. Glucose dysregulation

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

Specific Receptor/Source Location Effects of Blockade
Alpha adrenergic 1: sympathetic/motor Dizziness, postural hypotension, tachycardia
Alpha adrenergic 2: sympathetic/motor Anxiety, tachycardia, dilated pupils, tremor, sweating
Beta adrenergic 1: sympathetic neurons Orthostatic hypotension, sedation, sexual dysfunction
Muscarinic: hippocampus and cortex; activates K+ channels, postsynaptic parasympathetic sites Constipation, blurred vision, dry mouth, memory dysfunction, urinary retention, tachycardia
Histaminic: hypothalamus converts histadine Weight gain, drowsiness, hypotension, sedation
Nicotinic: spinal autonomic ganglia; preganglion Muscle irritability, restlessness, insomnia
Dopaminergic 1: substantia nigra, striatum, basal ganglia, nucleus accumbens, olfactory, amygdala Extrapyramidal side effects: dystonias, dyskinesia, akathisias
Dopaminergic 2: striatum, olfactory, nucleus accumbens, substantia nigra Extrapyramidal side effects: dystonias, dyskinesia, akathisias
Dopaminergic 3: pituitary, nucleus accumbens, olfactory, hypothalamus Endocrine problems, weight gain, sexual dysfunction
Dopaminergic 4: frontal cortex, midbrain, medulla Psychosis
Serotonergic 1: hippocampusraphe, cortex 1a -- anxiety (buspirone is agonist)1d -- cerebral arteries constrict (sumatriptan is antagonist)
Serotonergic 2: Cortex, olfactory system, claustrum Psychotic symptoms, anxiety, and appetite
Serotonergic 3: Area postrema, cortex, "leaky" blood brain barrier around posterior pituitary and supraventricular areas This receptor can counter the activity of excessive dopamine

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


Table 7. Binding of Antipsychotic Medications to Specific Receptors

Drug D1 D2 D3 D4 5HT1a 5HT1d 5HT2a 5HT2c A1 A2 H1 M1
Clozapine 85 126 473 35 875 980 16 16 7 50 6 1.9
Risperidone 430 4 10 9 490 100 .5 25 .7 .81 20 > 10,000
Olanzapine 31 11 49 27 > 1000 800 4 23 19 500 7 1.9
Quetiapine 1268 160 340 1600 717 -- 295 0 7 500 11 > 10,000
Ziprasidone 525 5 7 32 3 2 .4 1 11 > 1000 50 > 1000
Aripiprazole 265 .34 .80 44 1.7 -- 3.4 15 57 200 61 > 10,000
Iloperidone 216 21.4 7.1 -- 92.1 -- 5.6 42.8 .4 162 -- 4898
Haloperidol 210 .7 2 3 1,100 -- 45 > 10,000 6 20 440 > 1500

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

CYP 1A2 
CYP 2D6 
CYP 3A4 
Inducer Inhibitor Inducer Inhibitor Inducer Inhibitor
Broccoli (cruciferous vegetables)
Brussels sprouts
Charbroiled meats (arial hydrocarbons)
St. John's Wort
Tobacco smoke (arial hydrocarbons)
bupropion (low)
Fluvoxamine (high)
Fluoxetine (mod)
Grapefruit juice
mirtazapine (low)
nefazodone (low)
paroxetine (mod)
sertraline (low)
tertiary TCAs (mod)
venlafaxine (low)
bupropion (low)
fluoxetine (high)
fluvoxamine (low)
mirtazapine (low)
nefazodone (low)
paroxetine (high)
secondary TCAs 
sertraline (low)
venlafaxine (low)
charbroiled meats (arial hydrocarbons)
St. John's Wort
Tobacco smoke (arial hydrocarbons
astemizole (high)
erythromycin (mod.)
clarithromycin fluvoxamine
grapefruit juice 
mirtazapine (low)
nefazodone (high)
paroxetine (low)
protease inhibitors
sertraline (mod.)
TCAs (mod.)
venlafaxine (low)

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: 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.



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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