10 Factors to Consider When Cross-Titrating Antipsychotics

Psychiatric Times, Vol 39, Issue 2,

In this CME article, familiarize yourself with various pharmacokinetic, pharmacodynamic, and patient-specific factors to review to develop a successful cross-titration plan from one antipsychotic to another.

CATEGORY 1 CME

Premiere Date: November 20, 2021

Expiration Date: May 20, 2023

ACTIVITY GOAL

The goal of this activity is to familiarize the prescriber of antipsychotic medication with the various pharmacokinetic, pharmacodynamic, and patient-specific factors to review to develop a successful cross-titration plan from one antipsychotic to another.

LEARNING OBJECTIVES

At the end of this CE activity, participants should be able to:

• Develop an understanding of the many pharmacokinetic, pharmacodynamic, patient drug exposure, and patient-specific factors that a prescriber should consider when creating a cross-titration plan from one antipsychotic to another.

• Appreciate the importance of obtaining an antipsychotic plasma level when evaluating reasons for lack of efficacy of an antipsychotic, and prior to beginning a cross titration from one antipsychotic to another.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

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This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

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A daily occurrence in the practice of most psychiatrists is designing a cross-titration schedule to change a patient’s medication regimen from one antipsychotic to another. The possible reasons for this cross-titration are many and are listed in Table 1. Since the US Food and Drug Administration (FDA) approval of chlorpromazine in 1954, our armamentarium of antipsychotic medications has grown significantly, and each antipsychotic has unique properties that should be considered once the decision has been made to change antipsychotic medications.

There is no single correct way to perform this cross-titration, and the approaches used in clinical practice vary considerably. This article will review 10 important factors to consider when cross-titrating from one antipsychotic (drug A: the drug that is being tapered and discontinued) to another antipsychotic (drug B: the drug that is being initiated and titrated upward as the new antipsychotic) to maximize success and minimize complications. The ultimate goal is to provide the patient with the experience of a smooth transition to increase the likelihood of a successful cross-titration and maximize the patient’s compliance with this change in antipsychotic.

Ten factors stand out as meriting serious consideration when cross-titrating antipsychotics, and each will be explored in detail. These are listed in Table 2. Historically, 3 general approaches have been used to cross-titrate from 1 antipsychotic to another: abrupt, brief overlapping, and gradual overlapping.1

1. Baseline Antipsychotic Plasma Level

The published recommendations of these approaches over the decades are confounded by 1 important missing detail: What was the antipsychotic plasma level of drug A on day 1 of this cross-titration? Over the past 5 years, significant attention has been directed at the importance of obtaining a baseline antipsychotic plasma level before any treatment modifications are made.2-4

The current standard is to obtain a 12-hour postdose plasma level, once at steady state (5 half-lives [t ½s]) for oral antipsychotics, and a long-acting injectable antipsychotic serum level 1 to 72 hours before an injection once at steady state.5

Although for most antipsychotics there is no well-defined therapeutic range, a great deal of information can be gleaned from the resulting level obtained. Interpretation of the level depends on a range of clinical factors as well as the drug delivery system of the antipsychotic. The interested reader is directed to the recently published comprehensive handbook entitled “The Clinical Use of Antipsychotic Plasma Levels.”5

If the antipsychotic plasma level of drug A is undetectable, it is reasonable in many circumstances to begin drug B in the same manner as a new start. However, there are exceptions to this, such as antipsychotics with very short t½s, which may be technically absent from the plasma, but could still result in specific withdrawal symptoms depending on the pharmacodynamics of the drug (for example, antihistamine and anticholinergic withdrawal, as well as withdrawal dyskinesia). If the antipsychotic plasma level of drug A is in the low range and there is a high confidence of patient drug compliance, increasing drug A’s dose and allowing for an adequate trial should be the next step. Many variables can result in a subtherapeutic drug level in the context of patient compliance. If the antipsychotic plasma level is in an accepted therapeutic range for an adequate duration, drug A can be considered a failed trial, and cross-titrating to a new antipsychotic is recommended.

2. Pharmacodynamic Differences

Chlorpromazine revolutionized the treatment of psychotic disorders in the United States in 1954, resulting in the first massive wave of deinstitutionalization of patients from numerous psychiatric hospitals. Remarkably, it was 3 years later, in 1957, that Katharine Montagu became the first scientist to confirm the presence of dopamine in the human brain. The activity of dopamine as a neurotransmitter was demonstrated the next year by Arvid Carlsson, MD, PhD. Following the completion of the sequencing of the 3 billion base pairs in the human genome in 2003, all 5 dopamine receptors have been identified and characterized. Elegant research in neuropsychiatry, including PET scans on live human brains in the presence of various concentrations of an antipsychotic along with the dopamine-2 receptor (D2R) antagonist radioisotope C-11 raclopride, have consistently demonstrated that a functional antagonism of 65% to 75% of D2Rs seems to be the sweet spot of antagonism to treat psychosis and mania.6,7

Similar progress has simultaneously led to the classification and understanding of other neurotransmitter systems that are involved in drug-receptor activity by chlorpromazine and all the subsequent antipsychotics. Significantly, each antipsychotic has a unique receptor binding profile at the many subreceptors that are in play with the various antipsychotics. The common neurotransmitter systems that can be impacted include dopamine, norepinephrine (α and β subreceptors), serotonin, histamine, and muscarinic cholinergic, just to name the most significant.

Knowing the binding affinities at these different receptors by drug A and drug B, along with the functional effect (ie, antagonist, agonist, inverse agonist, partial agonist, antagonist/partial agonist, positive or negative allosteric modulator) of this binding, the clinician can create a cross-titration strategy to maximize success and minimize adverse effects. Table 3 gives some examples of important pharmacodynamic differences.

When cross-titrating antipsychotics, the D2R is the most important receptor to compare drug A with drug B in regard to the receptor binding affinity (the inhibition constant, also known as the Ki) and the functional type of binding. Not coincidentally, the only 3 antipsychotics that are antagonist/partial agonists—aripiprazole, brexpiprazole, and cariprazine—have the most potent binding affinity to D2Rs. This makes clinical sense, because in order to saturate the D2R as antagonists, which then allows the partial agonism (intrinsic activity) to achieve the ideal functional D2R antagonism, these 3 drugs need to bind strongly enough to displace dopamine and other antipsychotics that would otherwise interfere with their function at D2Rs. Research from the laboratories of Elliot Richelson, MD, and Bryan Roth, MD, PhD, has provided a wealth of information defining the various receptor inhibition constants for antipsychotic drugs.8,9

3. Half-Life Differences

Antipsychotics have a wide range of t½s; these predict how long it will take for drug A to leave the body once discontinued, and how long it will take for drug B to achieve steady state once at its target dose. Table 4 lists the t½s for many of the antipsychotic drugs, including their active metabolites when relevant. In general, after 5 t½s at the target dose, a drug has reached 97% of its steady-state level. Similarly, once a drug is discontinued, in 5 t½s, 97% of the drug will have been eliminated from the patient’s body. Exceptions to this include long-acting injectable antipsychotics, as well as drugs that have active metabolites that build up over time and contribute significantly to the pharmacological activity of that drug.

An extreme example would be cross-titrating from quetiapine to cariprazine, or vice versa. Both drugs have active metabolites, which need to be factored into the cross-titration. Excluding pharmacodynamic differences, which are significant, the t½ characteristics of quetiapine and cariprazine—including their active metabolites—are dramatically different. Quetiapine is metabolized immediately to the active metabolite N-desalkyl quetiapine, and both molecules contribute to its putative mechanism of action. Once at steady state, the mean area under the curve (AUC) and mean maximum concentration (Cmax) of N-desalkyl quetiapine are approximately 21% to 27% and 46% to 56%, respectively, of quetiapine itself. Quetiapine’s t½ is 6 hours, while N-desalkyl quetiapine’s t½is 12 hours. Hence, steady state of both molecules will be reached by 60 hours.10

Cariprazine, on the other hand, has 2 active metabolites, of which the second—didesmethyl cariprazine—gradually increases its plasma level over the first 4 to 6 weeks once cariprazine is begun, or after a dosage increase. At steady state, didesmethyl cariprazine becomes the predominant active molecule, with a t½ of 12 to 14 days.

If drug A is quetiapine, cariprazine can be added and titrated to the target dosage quickly, as it is significantly more potent at the D2R than quetiapine and lacks effects at the histaminergic and cholinergic receptors. Quetiapine should then be slowly tapered to minimize any antihistaminergic and/or anticholinergic withdrawal.

If drug A is cariprazine, it theoretically could be discontinued as early as day 1 of the titration onto quetiapine. Due to the very long t½ of didesmethyl cariprazine, once it is discontinued, it will slowly leave the body over the following 60 to 70 days. Quetiapine can be titrated up without having to consider the presence of cariprazine.

4. Metabolic Pathways Involved

First-pass metabolism occurs primarily in the liver, but with some drugs, it begins while crossing the intestines into the portal vein on its way to the liver. In humans, approximately 60 different cytochrome P450 (CYP) metabolic enzymes have been identified and characterized. Of these, the 3 most important in the metabolism of antipsychotics are CYP1A2, CYP2D6, and CYP3A4. Antipsychotics themselves have minimal effects on inhibiting or inducing CYP enzymes, but they can be significantly affected by other medications.

When planning a cross-titration, it is important to review with the patient all the prescription medications, over-the-counter medications, vitamins, food supplements, exposure to smoke, and ingestion of certain food items (such as grapefruit) before planning your medication choice and titration strategy. Information gleaned from this history can inform decisions on which drugs are the best options to be drug B, and potential changes in pharmacokinetics to be mindful of in drug A.

Clozapine and olanzapine are both primarily metabolized by CYP1A2. In addition to potential drug-drug interactions, CYP1A2 is significantly induced by smoke of any type, including smoke from cigarettes (nicotine is not involved in CYP1A2 induction). When starting either of these medications in an in-patient setting where smoking is not allowed (patients are often offered a nicotine patch), once stabilized and prior to discharge, it is useful to obtain a 12-hour postdose plasma level. Upon discharge, the patient will likely resume smoking, which will slowly induce CYP1A2 over the next several weeks. A repeat 12-hour postdose antipsychotic plasma level 2 weeks after discharge can be compared with the predischarge level when the patient was stable, and the appropriate dose adjustment can be made. This may very well prevent a psychotic relapse.

CYP2D6 is a common metabolic pathway for several antipsychotics, and it has the largest number of genetic polymorphisms of any CYP enzyme (approximately 100 different alleles). Significantly, 3 antidepressants that are commonly coprescribed in patients on antipsychotics are fluoxetine, paroxetine, and bupropion—all 3 of which are potent inhibitors of CYP2D6. It is well established that these 3 antidepressants can convert a CYP2D6 extensive metabolizer to a poor metabolizer, which would result in prolonging the t½ of the antipsychotic and increasing its serum level. This example demonstrates the value of obtaining an antipsychotic plasma level to determine the patient’s actual plasma level, rather than guessing from a pharmacogenomic test that will provide only the patient’s genotype, not their functional phenotype.

The most common CYP pathway for all prescription drugs is CYP3A4. Such is the case for many antipsychotics. There are numerous inhibitors and inducers of CYP3A4, including grapefruit juice (depending on the concentration of furanocoumarins in a particular grapefruit strain) as a potentially potent inhibitor, and St. John’s wort as a potent inducer (similar to carbamazepine). Numerous prescription drugs have varying inhibitory and inducing effects on CYP3A4, which can be found in a good drug-interaction program.

Hence, knowing the metabolic pathway of drug A and drug B, along with all of the potential molecules that can impact that pathway, can provide important information when designing a cross-titration strategy.

5. Dose of Drug A Compared With Usual Dose Range of Drug A

Although a drug’s FDA-approved product insert provides a range of dosages recommended for each drug in each indication, the rule in clinical practice is that the prescriber finds the ideal dose through trial and error. The goal is always maximal benefit with minimal adverse effects, and over time, an attempt should be made to find the lowest effective dose of all medications. As a result of numerous patient-specific factors—including, among others, pharmacokinetic and pharmacodynamic variables, genetic vulnerabilities, drug absorption, cardiac output, renal and biliary excretion, P-glycoprotein heterogeneity, age, gender, and body mass index—2 patients who look exactly the same in most of these factors may still require very different dosages to achieve efficacy from the same drug.

As a proxy of sorts, the dose of drug A that has stabilized the patient relative to the usual dose of drug A that it takes to stabilize an average patient on that same drug for that same indication should be considered when constructing a cross-titration to a new antipsychotic. If the dose is significantly lower or higher than that for similar patients, the prescriber should attempt to determine the factors that contributed to this unusual dose, and determine whether these same factors will apply to drug B.

6. Length of Time on Drug A

In a typical community mental health center practice, some long-term patients have been prescribed the same antipsychotic for years or longer. Other patients may have been on their current antipsychotic for several months. With our growing understanding of the brain’s neuroplasticity and constant rewiring through synaptogenesis, it intuitively makes sense that the longer a person has been on the same medication, the more that medication is integrated into the neurophysiology of the brain. Although speculative, it seems reasonable that, if clinically possible, the longer the patient has been taking a specific medication, the slower the cross-titration should be. This is a possible approach if the reason for antipsychotic cross-titration is due to a nonemergent factor. Possibilities include changing antipsychotics to decrease adverse events that impact quality of life and may be reversed by changing antipsychotics. Morbidities including weight gain, somnolence/sedation, hyperlipidemia, onset of prediabetes or frank diabetes, hyperprolactinemia, drug-induced movement disorders, cognitive impairment, residual psychotic symptoms, uncontrolled affective symptoms, or vague dysphoria may improve and possibly resolve with a change in antipsychotics. In this setting, a well-documented risk/benefit/adverse effect discussion with the patient/guardian should occur prior to the change.

7. Acuity of Target Symptoms

Often the clinical circumstances do not allow for a gradual and ideal cross-titration of antipsychotics. When a patient presents with severe acute symptoms and the prescriber determines that an immediate antipsychotic change is required, a more rapid antipsychotic cross-titration may be necessary. However, even in this situation, the 9 other factors should be reviewed. If drug A has receptor activity that drug B lacks, such as anticholinergic or antihistaminic properties, an attempt should still be made to taper drug A, albeit as fast as is clinically possible. Alternatively, if drug A must be discontinued and anticholinergic or antihistaminergic withdrawal symptoms occur, adding a non-antipsychotic such as diphenhydramine to prevent anticholinergic and antihistaminergic withdrawal can be considered.

The D2R Ki’s and doses of drugs A and B should be reviewed, and the dosage of each drug throughout the cross-titration should be determined to minimize the likelihood of too much D2R antagonism, which could lead to increased movement disorders, sedation, dysphoria, and increased risk for neuroleptic malignant syndrome acutely and tardive dyskinesia over the long term. On the other hand, if not enough D2R antagonism is present during the cross-titration, the patient can have a relapse of psychotic symptoms or experience withdrawal dyskinesia.

If the decision is made to add an antagonist/partial agonist to replace a current pure antagonist, ensure that the likely current D2R antagonism of drug A is equal to or less than what will result from the dose of drug B. If drug B is started at a dose to fully occupy the D2R and drug A produced more D2R antagonism than drug B can provide, the patient may experience an increase in psychosis or withdrawal dyskinesia. Additionally, all 3 of the antagonist/partial agonists have lengthy t½s that, along with the potent binding affinity at the D2Rs, will create a brain pharmacology that cannot be easily reversed.

8. Patient’s Motivation to Change From Drug A to Drug B

As clinicians, one of our biggest challenges is to motivate our patients to adhere to their medication regimen, to tolerate side effects—some transient and some chronic—and to acknowledge that they have a mental illness that may benefit from their treatment plan. In a world where instant gratification rules the roost, it is even more difficult to convince our patients to move on to a second trial of medication after they failed to improve with an adequate dose for an adequate time on the first.

Additionally, many adverse effects make socialization even more difficult and can erode self-esteem and self-confidence. These issues highlight the importance of a solid and mutually respectable therapeutic alliance. Drawing upon all members of the treatment team to support the patient and provide a consistent message regarding goals and expectations is critical. As the prescribing clinicians, we bear the responsibility to ensure to the best of our abilities that the trial of drug A is adequate. If we conclude that it is a failed trial, that adverse effects of drug A are unacceptable, or that the best choice for our patient moving forward is to cross-titrate to a different antipsychotic, transparent communication with the patient is important to motivate them to consider such a change, and to see it through.

9. Educating Patient/Guardian on Risks/Benefits of Cross-Titration

Once a decision has been made to cross-titrate to a different antipsychotic, it is important to include the patient/guardian and all relevant support systems in a detailed discussion explaining the risks and benefits of this medication change, and to provide ample time for questions and discussion. When the patient/guardian and their support system feel included and respected during this process, there is a greater likelihood of participation, cooperation, and ultimate success with the transition to the new medication.

10. Type of Delivery System of Drug A Vs Drug B

A variety of drug delivery systems exist for antipsychotics. Most antipsychotics are available in an oral formulation in tablet, capsule, and/or liquid forms. Quetiapine is also available in an extended-release form. Asenapine must be administered and absorbed sublingually because, if it is swallowed, it is inactivated by UGT-1A4, a metabolic enzyme in the gut. Asenapine is also available in a transdermal patch. Many antipsychotics are available for intramuscular injection. This allows for a more rapid onset of action and bypass of first pass metabolism in the liver.

Long-acting injectable antipsychotics (LAIA) are being used increasingly in the United States.11 There are currently formulations for haloperidol, fluphenazine, risperidone, paliperidone, aripiprazole, and olanzapine. Injection frequency varies dramatically, from every 2 weeks to every 6 months. When cross-titrating on to or off of a LAIA, the pharmacokinetic properties differ across drug formulations, and the clinician should carefully review the product insert of the particular LAIA(s) being used.

Novel Exception to Amount of D2R Antagonism

As often occurs in science, a finding is published that is inconsistent with established dogma, requiring us to refine our hypothesis. All antipsychotics that have been studied in live human brains for D2R occupancy at various doses have demonstrated that their antipsychotic activity correlates best when dosed so that their plasma level achieves between 60% and 80% of human brain D2R occupancy for at least 1 hour of every 24. The common protocol is to inject the radioisotope C-11 raclopride at Cmax of the antipsychotic and immediately perform a PET scan to look at percent binding of C-11 raclopride in contrast to its binding with no antipsychotic present. Clozapine and quetiapine, the 2 antipsychotics with the least potent inhibition constants at the D2R, have been shown to transiently occupy slightly more than 60% when dosed high enough (in the FDA-approved clinical dosage range). Some experts do opine that these 2 antipsychotics may provide efficacy below the usual 60% occupancy threshold.

Lumateperone, the newest FDA-approved antipsychotic for the treatment of schizophrenia, has demonstrated its clinical improvement in the Positive and Negative Syndrome Scale score by occupying only 39% of D2R at Cmax at the study dosage of 40 mg. Lumateperone is FDA approved only at the dose of 42 mg, which is its starting and treating dosage. The pharmacodynamics associated with this efficacy are not fully understood, but it has been hypothesized that lumateperone’s additional property of simultaneous partial agonism of the presynaptic D2R may contribute to its ability to provide an antipsychotic effect with low postsynaptic D2R antagonism. Theoretically, the partial agonism at the presynaptic D2R could decrease the release of presynaptic dopamine, hence creating less dopamine that needs to be blocked postsynaptically.12,13

Regardless of the pharmacodynamics, given lumateperone’s low D2R antagonism at its therapeutic and only dose of 42 mg, when cross-titrating to lumateperone, theoretically it should be able to be added on day 1 of the cross-titration, and then drug A will be slowly tapered off.

Concluding Thoughts

As is often the case in psychiatry, good clinical practice involves a solid understanding of the science of psychopharmacology as well as effective therapeutic skills and a healthy therapeutic alliance with the patient. The decision to cross-titrate from one antipsychotic to another should not be made lightly, as it will conclude a lengthy trial of drug A, with all the time, effort, and clinical acumen invested. Despite this, antipsychotic cross-titrations are a daily occurrence in all clinical psychiatric settings. The 10 factors presented in this article that should be considered before designing the cross-titration may increase the likelihood of a successful cross-titration.

References

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