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.
Chlorpromazine, Loxapine, Thiothixene, Trifluoperazine
These antipsychotics provide an inexpensive method of delivering D2 antagonism, with varying degrees of plasma level data to define a therapeutic threshold or point of futility. Use is limited because there are no comparable long-acting injectable versions, and due to the paucity of kinetic information on drug–drug interactions for certain agents. Other first-generation antipsychotic options should be sought for maintenance treatment.
Chlorpromazine has poor tolerability for long-term treatment, in part due to the high risk for anticholinergic adverse effects. Moreover, this anticholinergic burden also exacerbates the cognitive dysfunction of schizophrenia.
Chlorpromazine is occasionally used for short-term management of agitation or aggression, and has a short-acting intramuscular formulation (25 mg/ml). Intramuscular doses should be 1/3 of the comparable oral dose to account for the low bioavailability of oral chlorpromazine.
|Oral dose correlation (bedtime dosing, 12h trough)*||Level of evidence||Therapeutic threshold||Level of evidence||Point of futility||Level of evidence|
||Moderate||3.0–30.0 ng/ml [2, 4, 5]||Low||100 ng/ml [2, 4, 5]||Moderate|
||High||3.8 ng/ml [7, 8]||Moderate||18.4 ng/ml [7, 8]||Low|
||High||1.0 ng/ml ||Low||12 ng/ml ||Low|
|Trifluoperazine||Unknown||–||1.0 ng/ml ||Moderate||2.3 ng/ml ||Low|
* See Table 11.1 for effects of CYP inhibitors/inducers on this relationship
As discussed in Chapter 6, first-generation antipsychotics (FGAs) are therapeutically as effective as newer antipsychotics, and their utility derives from low cost and the availability of long-acting injectable (LAI) preparations for certain agents. While there are close to 3 dozen FGAs available worldwide, many have very limited or regional use (e.g. melperone, chlorprothixene, perazine), some are rarely used (thioridazine, pimozide) due to disproportionate effects on the rate-corrected QT interval (QTc) of the EKG, and some are so poorly characterized that plasma level data is virtually nonexistent (molindone). (For many years pimozide had a niche use for delusional parasitosis based on a small number of poorly designed studies; recent data indicate no unique efficacy benefit compared to the much safer antipsychotic risperidone, so there is no reason to use pimozide in modern psychiatric practice .) As discussed in Chapter 12, FGAs are not therapeutically inferior to second-generation antipsychotics (SGAs) when treating patients who do not have treatment-resistant schizophrenia, but have a higher risk of neurological adverse effects. When used in equipotent dosages, the risk for D2-related adverse effects is roughly equal among all FGAs unless the specific molecule has an inherent mechanism (e.g. potent muscarinic antagonism for chlorpromazine) that helps to lessen this risk. The tolerability issues seen with low-potency FGAs such as chlorpromazine (sedation, anticholinergic adverse effects, orthostasis) are markedly diminished in medium- and higher-potency FGAs.
The four FGAs presented in this chapter represent a group that are generally available worldwide, but none has a comparable LAI formulation, so there is no reason to initiate these antipsychotics as maintenance treatments for schizophrenia or other serious mental illnesses. Nonetheless, there are a small number of patients who remain on oral therapy, so the kinetic information is summarized, and levels provided for the therapeutic threshold and point of futility where there is sufficient information to generate an estimate. All of these molecules are more than 45 years old, so in some instances there is virtually no imaging data, or there are no fixed-dose studies from which to estimate plasma level cutpoints. The absence of this data is a compelling reason to opt for other FGAs that are better characterized for maintenance treatment, especially when there might be an LAI option. Among these four antipsychotics, some are distinguished by unique tolerability profiles (e.g. sedation from chlorpromazine can be useful in acute situations), or unusual aspects of the molecule that have engendered debate. As will be discussed below, a mythos emerged around loxapine that it might be an SGA based on in vitro binding assays showing higher affinity for serotonin 5HT2A than for dopamine D2 receptors [36, 37]. Imaging data disproved this hypothesis in 1997 , but there are other interesting features of loxapine, including an inhaled aerosolized powder for acute treatment of agitation in adults with schizophrenia or bipolar I , and antidepressant activity from the metabolite amoxapine (see Section B) . Clinicians should understand the appropriate dosing for intramuscular (IM) chlorpromazine, and realize that concepts around loxapine’s unique efficacy or tolerability have been discredited. A passing familiarity is sufficient for the two other FGAs mentioned in this chapter so that one can effectively manage existing patients, or convert those patients to other FGAs when the older drug is removed from the market.