Mechanism of Action of Antipsychotic Medications

Christoph U. Correll, MD

Recognition and Prevention Program (RAP), The Zucker Hillside Hospital, Glen Oaks; the Department of Psychiatry and Molecular Medicine, Hofstra-North Shore-Long Island Jewish School of Medicine, Hempstead; and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York

Clinicians have a variety of pharmacologic options for treating patients with schizophrenia, and antipsychotic medications are recommended first-line treatments.1 However, clinicians must balance each medication’s efficacy and adverse effects to optimize outcomes, and knowledge of the pharmacology and mechanism of action of antipsychotics can help accomplish this goal.

Pharmacologic Variables

Two main variables must be considered for any medication: the pharmacokinetics, or what the body does to the drug, and the pharmacodynamics, or what the drug does to the body. Although no foolproof way exists to predict the response a patient will have to a medication, some pharmacokinetic and pharmacodynamic parameters can be used to achieve the best response while minimizing side effects.

AV 1. Pharmacokinetic Phases and Parameters (00:36)

 

Pharmacokinetics. Anticipating the onset of a drug’s therapeutic effect and adverse effects requires knowledge of pharmacokinetics.2 Pharmacokinetics involves 4 phases: absorption, distribution, metabolism, and elimination.3 The absorption phase includes the time from ingestion to the time when the maximum plasma concentration of the medication reaches the site of action (SOA) or systemic circulation (AV 1) . The peak concentration, called the Cmax, is related to most side effects. Formulations with a slower release over time or long-acting injectable medications are generally related to fewer side effects. The type of formulation (eg, oral liquids, tablets) also affects the rate at which drugs are absorbed into the body.4 The volume of distribution is the measure that links the amount of drug in the body to the measured plasma concentration.4

Drugs are metabolized by various enzymes. The patient’s genetic profile can affect drug metabolism. For example, cytochrome P450 enzymes in the liver determine the metabolism of antipsychotics, but genetic variations can lead patients to be either slow or rapid metabolizers.2,5 Age, sex, other medications, medical conditions, and smoking status are also factors that affect drug metabolism and must be considered when clinicians assess the therapeutic effect of a drug.2,4,6

Elimination of medication can occur through processes in the liver, kidney, or other organs.3 The medication’s half-life is the time required for 50% of the medication to be eliminated from the blood.4 The area under the curve (AUC) is the measure of medication concentration that has entered the blood between first ingestion and total washout.4 Knowing the half-life and AUC can help clinicians determine how long to wait until a steady state concentration has been reached, then they can assess the medication’s efficacy and side effects and make dose adjustments. As a general rule, 5 half-lives are required until steady state is attained.2 The steady state concentration will be maintained only if the drug input rate matches the output rate.4

Because antipsychotics can have a large variety in their half-lives, clinicians must be aware of the differences. For example, quetiapine immediate release and ziprasidone have a half-life of about 7 hours, meaning that after about 1 to 2 days, the steady state is reached and a dose adjustment can be made.7,8 Most atypical antipsychotics (such as asenapine, clozapine, olanzapine, and risperidone) have a half-life between 17 and 30 hours, meaning that the steady state takes between 4 to 7 days to achieve; however, some antipsychotics (like aripiprazole that has a half-life of about 3 days) take even longer to achieve a steady state.2,9

Pharmacodynamics. Several factors influence the effect of the drug on the body. The first pharmacodynamic factor to consider is the affinity of the drug for the target, which for antipsychotics means how well the medication binds to a receptor or SOA. Both beneficial effects and side effects are the result of activity at any SOA.5 More potent drugs require less concentration to affect an SOA.5 Affinity, termed Kd or Ki, is measured as the concentration of drug that is needed to occupy half of the total receptor population.10 The lower the Ki value, the higher the affinity and the resulting occupancy.10 An exception to this rule can occur if other mechanisms interfere with the ability of the drug to reach the target. For example, if a high-affinity drug has poor blood-brain penetration, then the resultant receptor occupancy would be low despite high affinity.

The second factor is the relative binding affinity, which describes the drug’s affinity for a secondary receptor divided by the affinity for the primary receptor. The primary efficacy receptor for antipsychotics used for psychotic disorders is the D2 receptor,10 where they have an overall blocking or antagonizing effect. If the affinity for a secondary receptor is stronger than for dopamine receptors, the effect on the secondary receptor will be an important component of the clinical effect of the medication.

The third factor relates to intrinsic activity, or what the drug does at the receptor. A drug can act as a full agonist, which stimulates the receptor; an antagonist, which decreases the transmission in certain areas of the brain to a neutral position; a partial agonist, which binds to the receptor site so the endogenous neurotransmitter cannot reach it but also stimulates the receptor less than 100%; or an inverse agonist, which reduces the transmission below the neutral point.

Antipsychotic Mechanism of Action

Functional dopamine D2 receptor antagonism remains the core feature of all available antipsychotics (AV 2), contributing to their therapeutic effect for psychosis and mania, but excessive blockade can cause adverse effects.2 The differences in receptor binding affinity and relative binding affinity are important determinants of antipsychotics’ predicted efficacy and adverse effects.2

AV 2. Antipsychotic Mechanism of Action

 

Dopamine receptor binding affinity. When the same dose of a medication is given to 2 patients, the same amount of medication does not necessarily get absorbed and reach the receptor target at the same concentration. In a study by Frankle and colleagues,11 the percentage of D2 receptor occupancy in patients taking risperidone 6 mg/d generally fell within the 60% to 80% range, which is the therapeutic window for most patients. However, 8% of patients exceeded 80% occupancy, increasing the risk for EPS. This study shows why doses that generally help large groups of patients may be too high or too low for a subgroup of patients.

Another study12 found that patients who have less than 65% striatal dopamine occupancy were mostly nonresponders, whereas patients who had at least 65% striatal dopamine occupancy were mostly responders. However, this was not a 100% division, meaning that some patients may respond at lower D2 occupancy or not respond even with sufficient dopamine receptor occupancy.12 This finding indicates that dopamine may be only one neurotransmitter system involved in the treatment of psychosis, and some people with schizophrenia may require modulation of additional neurotransmitter systems or second messenger systems to improve their symptoms. However, to date insufficient knowledge exists to modulate these nondopaminergic targets to enhance efficacy in schizophrenia.13

Dopamine occupancy is equivalent to functional dopamine blockade only for medications that are pure antagonists. For example, the partial agonist aripiprazole already occupies 57% and 72% of striatal D2 receptors at doses as low as 1 mg/d and 2 mg/d, respectively. However, despite >65% D2 occupancy, these doses are not effective to treat psychosis. Rather, the dose must be increased to at least 10 mg/d where already 85% of D2 receptors are occupied because 20% to 30% of the binding results in an agonist-like effect.14 Thus, the “functional” D2 blockade only reaches 85% occupancy minus 20% to 30% agonism (which equals 55% to 65%). Typically, clinicians want to keep patients below the 80% threshold of striatal D2 blockade to avoid side effects like EPS.12

Relative binding affinity. Effective D2 blockade is attained at different dose levels and occurs before, around, or after the antipsychotic concentration is potent enough to block other receptor systems.2 This means that when a drug has stronger affinity for another receptor system than for the dopaminergic receptor, side effects or therapeutic effects linked to the blockade of this receptor system are likely to occur.2

AV 3. Approximate Relative Ki Values for Receptor Binding Profiles of Selected Antipsychotics (00:56)

Adapted with permission from Correll2
Ki = nanomolar concentration of the antipsychotic required to block 50% of the receptors in vitro
Ki value for dopamine D2 receptor affinity for each drug set as 1
Aripiprazole is a partial agonist at D2 receptors
©Elsevier Editeur

When examining the relative binding affinity of antipsychotics, 3 main groups emerge (AV 3).2 The first group contains the first-generation antipsychotics like haloperidol and perphenazine, which have the strongest affinity for dopamine D2 receptors relative to other receptor types. However, in this group are also aripiprazole and amisulpride, which seem to balance their selectively high D2 affinity by possessing partial D2 agonism or selectively bind less to striatal D2 receptors.2 The second group includes most atypical antipsychotics, such as ziprasidone and risperidone, which are both 5-HT2A and D2 antagonists. These medications bind more tightly to 5-HT2A than to D2, which allows for antipsychotic efficacy at lower D2 blockade,15 resulting in a lower risk of EPS. The third group consists of chlorpromazine, clozapine, olanzapine, and quetiapine, which all bind more tightly to 5-HT2A receptors as well as histamine receptors than to D2 and also block cholinergic receptors or α1 receptors as much or more than dopamine receptors. These medications are associated with more weight gain and sedation than the other agents but also have relatively little EPS.2 Atypical antipsychotics that dissociate quickly from the D2 receptor (ie, clozapine and quetiapine) are associated with less motor side effects because they do not antagonize dopamine transmission for extended periods of time.16 These drugs also have low D2 occupancy, lower than the EPS threshold, which by itself can explain their lower propensity for motor side effects.

More

Disruption and therapeutic modulation of dopamine pathways: benefits and adverse effects. A number of dopamine pathways originating in the midbrain exist, and dysfunction of each one is associated with specific effects (see AV 2).16–18 For example, hyperactivity of dopaminergic transmission in the medial part of the striatum including the dorsal anterior striatum (associative striatum) is related to the positive symptoms of psychosis. Thus, antipsychotic-mediated blockade in this pathway can help treat delusions and hallucinations. Dysregulation in or blockade of the dopaminergic mesolimbic pathway projecting from the ventral tegmental area of the midbrain to the ventral striatum including the nucleus accumbens (limbic striatum) has been associated with primary or secondary negative symptoms and may also be related to depression. Dysregulation in or blockade of the dopamine pathway with projections from the ventral tegmental area of the midbrain to the cortex (mesocortical pathway) has been associated with primary or secondary cognitive, negative, and depressive symptoms. Dopamine blockade in the nigrostriatal pathway, consisting of projections from the substantia nigra part of the midbrain to the dorsal posterior striatum (sensorimotor striatum) that projects via the pallidum and thalamus to the motor cortex, is associated with EPS. Finally, blockade in the dopamine pathway in the hypothalamus (tuberoinfundibular pathway) disinhibits prolactin secretion in the anterior pituitary gland, leading to side effects such as galactorrhea, amenorrhea, and sexual dysfunction.16,17 Unfortunately, antipsychotics are unable to affect only one dopamine pathway, but atypical antipsychotics have additional mechanisms that can counter otherwise potentially overshooting dopamine antagonistic effects.

Mechanisms that can help counter unopposed dopamine blockade and allow antipsychotic efficacy while limiting antidopaminergic side effects include a low D2 occupancy over the full dose range, partial D2 agonism, and indirect augmentation of dopamine activity by muscarinic and histaminic blockade or manipulation of serotonin.2,16 Importantly, dopaminergic transmission is also regulated by inhibitory GABAergic and excitatory glutamatergic activity (See “Schizophrenia: The Role of Dopamine and Glutamate”),19 which require further elucidation to provide clinically applicable drug targets in schizophrenia.

A network meta-analysis20 of the overall efficacy and side effects of current antidopaminergic schizophrenia treatments found that all 15 antipsychotics studied were superior to placebo for overall change in symptoms (effect sizes ranged from –0.33 to –0.88), but their side effect profiles varied greatly. For EPS, odds ratios compared with placebo ranged from 0.3 with clozapine and 1.0 with olanzapine and quetiapine to 2.7 with chlorpromazine and 4.76 with haloperidol. Haloperidol and lurasidone were associated with the least weight gain (0.09 and 0.10) while clozapine and olanzapine had the highest (0.65 and 0.74). Clozapine, zotepine, and chlorpromazine were associated with more sedation than most drugs, while amisulpride, paliperidone, and sertindole caused less. For prolactin effects, aripiprazole had the lowest (–0.22) and paliperidone had the highest increase (1.30).20

Although study design and time effects influence these results, antidopaminergic agents are effective for patients with schizophrenia, but they are only or mostly helpful for positive symptoms. Thus, a treatment need remains for resolving negative symptoms and cognitive impairments, which do not appear to be predominantly dopamine-related.

Conclusion

Knowledge of the pharmacology of antipsychotics can help physicians predict response and side effects. The drug’s effect on the body (pharmacodynamics) and the body’s effect on the drug (pharmacokinetics) as well as individual patient factors all play a role in response to treatment. With current antipsychotics, D2 blockade may alleviate positive symptoms but also cause adverse effects. Efficacy and adverse effects need to be balanced to optimize outcomes. Because all antipsychotics have antidopaminergic effects, which treat mainly positive symptoms of schizophrenia, medications targeting additional pharmacologic mechanisms need to be developed that can address negative and cognitive symptoms.

Clinical Points

  • Use the pharmacology of antipsychotics to help predict their clinical activity
  • Know the half-life and affinity to relevant brain receptors for antipsychotics, which can help determine how long to wait until a steady state concentration is reached, when efficacy and side effects can be assessed and which ones to expect, and when dose adjustments can be made
  • Understand that the current antipsychotic mechanism of action (D2 blockade) is useful for treating positive symptoms but may not be effective treatment for negative symptoms or cognitive impairment

Abbreviations

5-HT = serotonin, α = alpha-adrenergic receptor, AUC = area under the curve, D2 = dopamine D2 receptor, EPS = extrapyramidal symptoms, H = histaminic receptor, M = muscarinic receptor, SOA = site of action

Drug Names

asenapine (Saphris), aripiprazole (Abilify), clozapine (Clozaril, FazaClo, and others), haloperidol (Haldol and others), iloperidone (Fanapt), lurasidone (Latuda), olanzapine (Zyprexa and others), paliperidone (Invega), quetiapine (Seroquel and others), risperidone (Risperdal and others), ziprasidone (Geodon and others)

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