Clinicians recognize that monitoring psychotropic levels provides invaluable information to optimize therapy and track treatment adherence, but they lack formal training specifically focused on the use of plasma antipsychotic levels for these purposes. As new technologies emerge to rapidly provide these results, the opportunity to integrate this information into clinical care will grow. This practical handbook clarifies confusing concepts in the literature on use of antipsychotic levels, providing clear explanations for the logic underlying clinically relevant concepts such as the therapeutic threshold and the point of futility, and how these apply to individual antipsychotics.
Amisulpride, Asenapine, Lurasidone, Brexpiprazole, Cariprazine
Amisulpride is available in most countries except the US and Canada, but exists only in an oral formulation. Like olanzapine, amisulpride may be slightly more effective for schizophrenia than other antipsychotics, although it is not effective in treatment-resistant patients. Amisulpride also has antidepressant properties and low risk for drug–drug interactions, but is among the highest-risk agents for hyperprolactinemia.
Asenapine is the only antipsychotic available in a sublingual form that relies completely on buccal absorption due to > 99% first pass metabolism if swallowed. To avoid the unique kinetic issues posed by the sublingual tablet, asenapine was developed as a transdermal patch, with much lower peak–trough plasma level variation, and a higher mean trough value. Due to the unique delivery methods, both forms of asenapine have a low risk for drug–drug interactions. While asenapine has binding properties that suggest antidepressant activity, this has not been extensively studied. Asenapine plasma levels are slowly becoming more available from laboratories.
Lurasidone is extensively used due to its low risk for metabolic adverse effects and indications for schizophrenia and for bipolar I depression (as monotherapy, or adjunctive to lithium or valproate). Like ziprasidone, lurasidone drug exposure is doubled with food intake, but lurasidone only needs to be taken once daily. Lurasidone tolerability is greatly increased by dosing with an evening meal, so prescription orders should be very clear: take within 30 minutes of dinner. Lurasidone plasma levels are slowly becoming more available from laboratories.
Brexpiprazole and cariprazine are the latest dopamine partial agonist antipsychotics to be approved, but with different indications and kinetic properties. Brexpiprazole is indicated for schizophrenia and adjunctively for unipolar major depression, while cariprazine is indicated for schizophrenia, acute manic or mixed episodes (as monotherapy), and bipolar I depression (as monotherapy). Cariprazine has a half-life of 31.6–68.4 hours and reaches steady state in 1–2 weeks, but it has an active metabolite with a half-life of 13–18 days, so steady state for the active moiety may not be achieved for 60–90 days. Very few laboratories run brexpiprazole or cariprazine assays, but over time this is likely to change.
|Oral dose correlation (bedtime dosing, 12h trough)*||Level of evidence||Therapeutic threshold||Level of evidence||Point of futility||Level of evidence|
||High||100 ng/ml||Moderate||550–700 ng/ml||Low|
||High||1.0 ng/ml||Moderate||(Based on maximal licensed dose of 10 mg sublingual BID)||Low|
||High||1.0 ng/mlb||Moderate||(Based on maximal licensed dose of 7.8 mg/24 hours)||Low|
||High||36 ng/ml||Low||(Based on maximal licensed dose of 4 mg QHS)||Low|
||High||5.6 ng/ml||High||(Based on maximal licensed dose of 6 mg QHS)||Low|
||High||7.2 ng/ml||Moderate||(Based on maximal licensed dose of 160 mg with an evening meal)||Low|
* See Table 17.1 for effects of CYP inhibitors/inducers on this relationship.
AUC0-24 = the area under the curve over 24 hours
a Although the lowest transdermal formulation dose of 3.8 mg/24 hours provides equivalent asenapine exposure over 24 hours to the sublingual dose of 5 mg BID (by AUC0-24), trough levels for the sublingual dose are lower due to higher peak–trough variation (see Figure 17.8). The conversion factor of 0.53 is for the transdermal dose per 24 hours.
b The expected mean asenapine trough level for the lowest dose of the transdermal patch (3.8 mg/24 hours) is 2.0 ng/ml (see Figure 17.8).
c The values for cariprazine represent the parent compound only. At steady state on 6 mg/d the active moiety is: cariprazine 28%, DCAR 9%, and DDCAR 63% . Very few laboratories have cariprazine assays, and none reports the metabolites at present. Should this change, the values represented will be nearly four-fold higher. For example, the steady state cariprazine level on 6 mg/d is 11.2 ng/ml, but the active moiety level will be approximately 40 ng/ml .
d The concentration–dose relationships for lurasidone are based on 12h trough values obtained at steady state (day 9 or later) and with lurasidone administered within 30 minutes of an evening meal of at least 350 kcal. This does not include the active metabolite ID-14283 (exohydroxylurasidone), which comprises 25% of the active moiety, but whose levels are not reported by commercial laboratories presently .
|Basic facts||Inhibition effects||Induction effects|
||No impact of cytochrome (CYP) inhibitors. Reports of increased dose corrected plasma levels in patients on lithium or clozapine . As a PGP substrate, increased brain amisulpride levels may possibly be seen during concurrent use with strong PGP inhibitors (e.g. amiodarone, cyclosporine, nifedipine, verapamil) [7, 8]. This is best monitored by clinical observation and not plasma levels||No impact of smoking or CYP inducers|
||There is no impact from the strong CYP 3A4 inducer carbamazepine |
||There is no impact from the strong CYP 3A4 inducer carbamazepine |
||Strong 3A4 inducers reduce exposure AUC0-24H by ~70%. Double the dose with strong CYP 3A4 inducers |
||The strong CYP 3A4 inhibitor ketoconazole at the dose of 400 mg/d increased cariprazine Cmax and AUC0-24H by 3.5- and 4.0-fold, respectively. Ketoconazole also increased DDCAR Cmax and AUC0-24H by 1.5-fold, and decreased DCAR Cmax and AUC0-24H by about one-third. Reduce the dose by 50% with strong 3A4 inhibitors. There is no impact from 2D6 inhibitors ||Not studied with inducers, and impact unknown. Not recommended with 3A4 inducers |
||Rifampin, a strong CYP 3A4 inducer, decreased AUC by 80%. Lurasidone cannot be used with strong CYP 3A4 inducers (e.g. rifampin, carbamazepine, phenytoin)|
The psychopharmacology field is moving toward a mechanism-based nomenclature to replace outmoded descriptors of molecules with multiple pharmacological properties. In addition to publications covering these efforts [15–17], a Neuroscience-Based Nomenclature website was created (https://nbn2r.com) where one can download a free smartphone app, and which posts twice-yearly glossary updates in May and September. For the sake of simplicity, the term second-generation antipsychotic (SGA) will be used in this chapter, but the antipsychotics described herein have a range of pharmacologic properties, and a wide variety of kinetic profiles. Moreover, with the exception of transdermal asenapine and cariprazine, the SGAs presented in this chapter represent a group that are generally available worldwide. As of this writing, plasma levels for each antipsychotic may not be available in certain countries, and none have a long-acting injectable (LAI) formulation. These important issues may limit use of specific agents as maintenance treatments for schizophrenia. (Though many antipsychotics are indicated for acute mania, it should be noted that lurasidone and cariprazine have indications for bipolar depression, and brexpiprazole for adjunctive use with antidepressants for unipolar major depression.) While cariprazine does not exist as an LAI, it has an active metabolite didesmethylcariprazine (DDCAR) that comprises over 60% of the active moiety at steady state and which has a half-life of 13–18 days; this extraordinarily long half-life has been shown to reduce relapse risk compared to other oral antipsychotics, all of which have much shorter half-lives [13, 18].
A number of other SGAs exist that are not covered here, as each has issues that result in low utilization for schizophrenia: iloperidone – prolonged titration to minimize orthostasis ; zotepine – regionally limited; sertindole – QT prolongation ; ziprasidone – multiple daily dosing and significant food kinetic effects [21, 22]; quetiapine – sedation, metabolic adverse effects, and efficacy concerns that preclude routine use as monotherapy for schizophrenia [23, 24]. Lumateperone is an SGA approved in the US in December 2019 with an interesting constellation of mechanisms; very low risk for metabolic, neurological, and endocrine adverse effects; and only one approved dosage form for schizophrenia (42 mg capsules) . The approval of this one dose is due to the lack of separation of lower dosages (14 mg, 28 mg) and a higher dose (84 mg) from placebo, but this also limits the possibility of dose increases for those with lower than expected levels, since the licensed maximum dose is 42 mg/d [26, 27]. A lumateperone plasma level assay is not obtainable through commercial laboratories, but may be useful to track adherence once available.