General Factors That Contribute to Breakthrough Psychosis and/or Symptom Worsening

Breakthrough psychosis and/or symptom worsening may occur for a variety of reasons, including psychotic relapse, concurrent medical illness, substance abuse or misuse, other psychiatric comorbidity, psychosocial stressors, suboptimal drug administration, incorrect dosage, ineffective medication, use of other drugs leading to pharmacodynamic (PD) or PK interactions, poor adherence, and AEs leading to refusal or discontinuation of treatment.Reference Brissos, Veguilla, Taylor and Balanza-Martinez^1, Reference Correll, Citrome and Haddad^2, Reference Porcelli, Bianchini and De¹⁶ Low plasma therapeutic levels may also contribute to breakthrough psychosis. Therapeutic plasma reference ranges are now available in the new AGNP guidelines,Reference Hiemke, Bergemann and Clement¹⁵ and while these are preliminary, together with therapeutic dose monitoring they may be of some use toward medication and dosing decision making, as exemplified in Table 2.Reference Saklad¹⁷ Idiopathic symptomatic worsening and exacerbation of the illness for unknown, disease-related reasons despite continued antipsychotic treatment can also occur. It is critical to understand that breakthrough symptoms are not always an indication of treatment failure. Therefore, as a first step, HCPs should identify all potential factors that could contribute to specific symptoms or symptom clusters and devise patient-specific mitigation strategies to optimize outcomes (Figure 1).

Table 2 Medication and dosing decision table for therapeutic dose monitoringReference Saklad¹⁷

Δ = change to different medication; ↑ = increase the dose; ↓ = decrease the dose.

Figure 1 Management of breakthrough psychotic symptoms in a patient receiving long-acting injectable (LAI) antipsychotic in whom the LAI antipsychotic dose has been optimized. LAI = long-acting injectable; OAP = oral antipsychotic. *Off-label; based on PK modeling (no supporting clinical trial data available).Reference Saklad^{17 †}Caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and oral antipsychotics are limited, especially over extended periods of time.

Relevance of Pharmacokinetic and Pharmacodynamic Aspects of Long-acting Injectable Antipsychotics

The PK and PD profiles of LAIs may contribute to patients experiencing psychotic breakthrough symptoms and should be considered when evaluating a patient. The slow, gradual dose titration inherent with the use of many LAIsReference Knox and Stimmel^18, Reference Remington and Adams¹⁹ may mean that a patient will experience residual symptoms or require oral supplementation until the LAI dosage is optimized and the steady state of therapeutic blood concentration is achieved.Reference Citrome^10, Reference Knox and Stimmel¹⁸ Both aripiprazole lauroxil (Aristada^®) and risperidone LAI (Risperdal Consta^®) require 3 weeks of oral supplementation, whereas aripiprazole monohydrate (Abilify Maintena^®) requires 2 weeks. A shorter, 1-week course of oral supplementation is needed with flupenthixol decanoate (Fluanxol^®; Table 1). The proper administration of LAI antipsychotics is essential for establishing effective plasma concentrations. This includes sufficient shaking of atypical LAIs before injection (if required); Z-track injections for first-generation sesame oil preparations; choosing the appropriate needle size and administration site; injecting the LAI antipsychotic into the muscle, not fat tissue; and in some cases, administering the injection rapidly and without hesitation (because aripiprazole lauroxil is thixotropic, it may block the syringe if it is not injected rapidly; Table 1).Reference Citrome^{10, 20} If these steps are not taken during LAI administration, effective plasma concentrations may not be reached or sustained. In addition, missed LAI doses and their effect on blood concentrations must be accounted for and may require potentially restarting the initiation doses or administering booster injections (Table 3). Drug–drug interactions must also be taken into consideration as a potential cause of symptom breakthrough or psychotic symptom worsening.Reference Citrome¹⁰ Carbamazepine, a potent inducer of several drug-elimination pathways, can decrease plasma concentrations of risperidone or aripiprazole LAI, whereas the selective serotonin-reuptake inhibitors fluoxetine and paroxetine can increase the plasma concentrations of risperidone or aripiprazole LAI.Reference Citrome^10, Reference Spina, Hiemke and de Leon^{21, 22} Furthermore, clozapine (serotonin dopamine-receptor antagonist) may impair clearance of risperidone, whereas the H₂-receptor inhibitors cimetidine and ranitidine can increase its bioavailability.Reference Citrome¹⁰

Table 3 Management of missed doses for long-acting injectable antipsychotics^{20, 22–24, 38, 43–46}

LAI = long-acting injectable; PP1M = paliperidone palmitate once monthly; PP3M = paliperidone palmitate once every 3 months.

Carbamazepine is also known to increase the clearance rates of olanzapine, whereas fluvoxamine has been shown to increase the concentrations of olanzapine.Reference Citrome¹⁰ Strong CYP3A4/P-glycoprotein inducers (e.g., carbamazepine, rifampin, St. John’s wort) given concomitantly with LAI formulations of paliperidone palmitate may decrease the exposure to paliperidone.^{23, 24} If administration of a strong CYP3A4/P-glycoprotein inducer during the dosing interval is necessary, it is recommended that the patient be managed with paliperidone extended-release tablets.^{23, 24} Renal function is an important factor for paliperidone, such that LAI paliperidone palmitate (Invega Sustenna^® and Invega Trinza^®) is not recommended for use in patients with moderate or severe renal impairment, and only lower doses should be administered in patients with mild impairment.²⁴ Dosage adjustments are recommended in patients who are treated concomitantly with aripiprazole and strong CYP3A4/CYP2D6 inducers and for those who are poor CYP2D6 metabolizers.Reference Citrome¹⁰ In poor CYP2D6 metabolizers, the dose of aripiprazole should be reduced. In patients who are CYP2D6 ultra-rapid metabolizers, it has been demonstrated that plasma levels of some LAIs (aripiprazole, haloperidol, risperidone, zuclopenthixol) are reducedReference Lisbeth, Vincent and Kristof²⁵; however, the need to increase LAI dosing in these patients has yet to be established. In one small study of 85 patients taking risperidone, there was no indication that the subtherapeutic levels of the drug found in three CYP3D6 ultra-rapid metabolizers affected either the efficacy or tolerability of the LAI in these patients.Reference Ganoci, Lovric and Zivkovic²⁶ Modeling of the interaction between CYP2D6 inhibitors and oral aripiprazole suggests that dose alteration is not required for courses of CYP2D6 inhibitors lasting ≤2 weeks.^{20, 22} Therefore, the dose of LAI should not be automatically adjusted if a patient is on a short course of enzyme inducer or inhibitor (Supplemental Table 1); rather, the patient should be monitored for adverse effects and the dose increased only after persistent problems arise. An overview of clinically relevant drug interactions for first- and second-generation LAIs is shown in Supplemental Table 2. A more detailed description of the PK/PD properties and interactions of LAIs is reviewed elsewhere.Reference Baldelli, Clementi and Cattaneo^14, Reference Meyer^27–Reference Schoretsanitis, Spina, Hiemke and de Leon²⁹

Management of Symptomatic/Breakthrough Illness: Practical Considerations

Clinical scenario: LAI antipsychotic-treated patient presenting with exacerbation of symptoms

Patients receiving LAI antipsychotics who experience acute exacerbation of psychotic symptoms may present at a psychiatrist’s office or the emergency department. Upon presentation, it is imperative to determine whether a medical illness, substance use, psychiatric comorbidity, relevant stressors, or nonadherence to treatment could explain the exacerbation. It is also crucial to assess which LAI the patient was given and, if possible, why the patient was started on an LAI (e.g., patient choice, poor adherence, prevention of poor adherence, court order). Determining when the LAI was last administered is essential, as this information will indicate whether the patient had sufficient time to reach therapeutic plasma concentrations. The timing of LAI administration will also reveal whether the patient had sufficient time to stabilize on the LAI before the current exacerbation or relapse. Ascertaining whether the patient missed a dose or received doses with a relevant delay is crucial, because strategies for managing missed doses vary depending on the specific LAI (see Table 3 for specific instructions). To help alleviate psychotic symptoms, it may be possible to give the next LAI dose early (off-label) or to increase the dose, depending on the release properties and dosing windows of the LAI. The HCP should determine whether acute oral supplementation is necessary based on the severity of the acute symptoms. Additional components of the evaluation should include relevant medical history, such as whether the patient presents episodically (exacerbations) or if the patient is always symptomatic (i.e., has residual symptoms), and whether any key medical or psychiatric comorbidities require attention. Identifying current symptoms (e.g., anxiety, depressive, psychotic, self-harm, suicidality), their duration, and whether there has been a significant increase in psychopathology will also help guide management. Certain lifestyle factors may also be relevant, such as (in the case of olanzapine LAI) smoking.Reference Heres, Kraemer, Bergstrom and Detke³⁰ A list of pertinent questions that could be posed to the patient, caregiver, or HCP is summarized in Table 4.

Table 4 Key questions asked by health-care providers to ascertain the etiology of breakthrough symptoms

AE = adverse event; LAI = long-acting injectable; OAP = oral antipsychotic; PP1M = paliperidone palmitate once monthly; PP3M = paliperidone palmitate once every 3 months.

Table 4 also summarizes actions that the clinician should consider based on the response to these questions and whether the corresponding features may be related to breakthrough psychotic symptoms. Figure 1 shows a decision tree regarding adaptation of management strategies for symptom breakthrough in patients receiving an LAI. For example, potential causes of breakthrough psychotic symptoms that may need to be addressed can include treatment nonadherence to LAIs, OAPs, non-antipsychotic comedications, and inappropriate or inadequate dosing, including initiating treatment incorrectly and other medication errors. Other causes of breakthrough psychotic symptoms can include AEs; treatment resistance or failure; alcohol or drug abuse or misuse; possible stressors present in the patient’s life, including legal issues; and/or psychosocial issues unrelated to relapse, including unstable living conditions, financial pressures, and stressors induced by the family environment, caregivers, or workplace. Difficulties accessing treatments or care would further complicate the management of breakthrough psychotic symptoms and should be improved or resolved if possible. In cases where substance abuse is a contributing factor to breakthrough symptoms, symptomatic management with either OAPs or benzodiazepines can be implemented until concentrations of the offending drug decrease. Psychoeducation and referral for substance abuse treatment can also be considered. If the symptom exacerbation is not caused by pharmacologic issues, then nonpharmacologic resolutions should be evaluated and sought. For example, therapy and family treatment sessions, lifestyle coaching, cognitive behavior therapy and rehabilitation, and acute pharmacologic support may still be necessary. If the etiology of the breakthrough symptoms is pharmacologic, the clinician should work to determine the efficacy of the patient’s treatment. The clinician should also consider whether the optimal dosage is being used and whether the efficacy outcome is sufficient (and in which domains). Some patients may require higher or lower doses to obtain optimal benefit, or they may require shorter intervals between doses (off-label). However, caution should be exercised to avoid overdosing and underdosing. Because higher doses may increase the incidence of AEs, regular and continuous supervision and reassessment is considered essential to identify and maintain the lowest dose level that is compatible with adequate symptom control. It is important to consult the prescribing information for LAIs for their recommended dosing; drug manufacturers can also be contacted for additional information on file, if needed (Table 1).

If causal factors for symptom exacerbation cannot be identified quickly enough, the addition of an OAP—ideally the same agent given in the LAI formulation—may be needed as an acute measure (Figure 1). The benefit of adding a different antipsychotic, although done frequently in clinical care, is not supported by high-level evidence based on randomized controlled trials.Reference Correll, Rubio and Inczedy-Farkas^31–Reference Correll, Rummel-Kluge and Corves³³ This even seems to apply to clozapine, for which there is limited and inconsistent evidence of benefit when included as part of a polypharmacy regimen.Reference Galling, Roldan and Hagi^32, Reference Fleischhacker and Uchida³⁴ The coadministration of an OAP with an LAI formulation of the same antipsychotic should be intended as a transient measure (off-label), and the efficacy and safety of this strategy should be assessed within 1 to 2 weeks. However, caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and OAPs are limited, especially over extended periods of time. If addition of the OAP is successful, the time of regained stability can be used to adjust the LAI administration, dose, or dosing interval (off-label) to optimize LAI treatment; to adjust pharmacologic or nonpharmacologic treatments for the core disorder or comorbidities; or to address any other identified reason for symptom exacerbation. If the patient is sufficiently stable, a slow taper of the OAP can be attempted. If addition of the OAP and concurrent optimization of the LAI antipsychotic treatment do not sufficiently stabilize the patient, if symptoms reappear after stopping the OAP, or if other potential causes cannot be identified or addressed adequately, the patient may not be responding to treatment, and a switch of the adjunctive OAP or switch of the LAI may need to be considered.

During this entire process, it is critical that there be appropriate communication among treatment providers, the patient, the patient’s family or partner, and HCPs in different treatment settings (if the patient requires stabilization in an inpatient setting). Furthermore, the multidisciplinary nature of treating patients with schizophrenia highlights the importance of organizations and disciplines working as a team. For example, a patient with schizophrenia often receive care from multiple psychiatric teams (i.e., inpatient setting, community mental health, and crisis home treatment teams) as well as a general practitioner. Therefore, information pertaining to a patient’s condition and treatment should be readily communicated among these HCPs.Reference Haddad, Brain and Scott³⁵ The treatment plan and details about LAI administration with or without OAP supplementation, the goals and steps of further management of the OAP, and any other aspect of the management should be clearly communicated with the patient and everyone involved in his or her care.

If the patient was stabilized in an inpatient setting, a discharge checklist could be used to facilitate communication and minimize the risk of future breakthrough psychosis or symptomatic worsening (Figure 2). Details regarding the stabilization, including the source of the problem, intervention, and follow-up, should be noted in the patient’s medical record and communicated to the patient and to his or her caregivers and HCPs. Medication reconciliation and discussion of, and agreement with, a recovery plan with all HCPs should be carried out. The patient and caregiver(s) should be provided with clear, detailed outpatient discharge instruction. Importantly, continuity of care should be facilitated by sharing the recovery plan with the patient’s current HCPs. Counseling and reflection with the patient and caregivers on the cause and consequences of this exacerbation would be advantageous to the patient’s outcome. Furthermore, combining nonpharmacologic with pharmacologic interventions, such as discussing the patient’s goals and how to prevent a future episode of breakthrough symptoms, can benefit the patient by helping him or her to achieve goals and improve overall prognosis.

Figure 2 Hospital discharge checklist for patients with schizophrenia.

Future Directions and Limitations

It should be noted that the recommendations provided in this article are based on available clinical, PK, and dosing data that are supplemented with clinical experience. The recommendations do not represent a formal consensus statement and therefore were not subjected to the explicit methodology commonly used to identify areas of agreement and disagreement among experts. The paucity of data regarding management strategies in response to patients experiencing breakthrough symptoms while undergoing LAI treatment underscores the need for future research, and in particular well-designed studies that examine the outcome of increasing LAI dose, switching LAIs, or supplementing the LAI with a low dose of the corresponding oral formulation in patients with symptom exacerbation. As such data become available, it is hoped that a formal guideline-consensus process based on a broader evidence base that may change or sharpen the currently made recommendations will be possible.

Summary

This article provides a framework and action plan for HCPs who manage patients treated with LAI antipsychotics who present with breakthrough psychosis and symptomatic worsening. Management options aimed at optimizing the disease prognosis and patient outcome include first ruling out or addressing medical or substance use as a contributing factor, identifying and addressing potential stressors, optimizing nonpharmacologic treatments, treating medical and psychiatric comorbidities, ensuring proper LAI administration technique, addressing missed LAI doses or lack of steady state, and increasing the dose of LAIs or shortening their injection intervals (off-label). If these strategies do not work sufficiently with frequent monitoring for efficacy and safety, supplementing the LAI with a low dose of the corresponding OAP formulation for fast symptom control may need to be considered (off-label). Caution should be exercised with this strategy, because data on the safety of concomitant use of LAI and OAPs are limited, especially over extended periods of time. If symptoms abate, optimizing the LAI therapy and addressing any other factors potentially related to the symptomatic exacerbation should be continued, and slowly discontinuing the OAP can be attempted. If symptoms continue or worsen despite addition of the OAP, if symptoms recur after stopping the OAP, and/or if addressing other factors potentially related to the breakthrough symptoms is insufficient, it may be necessary to switch the OAP or the LAI. However, regardless of the management plan, it must be documented and communicated clearly so that continuity of care is assured. Any strategies that are successful in restabilizing patients receiving LAI antipsychotic therapy who presented with breakthrough psychosis or symptomatic worsening should be retained and repeated in the event of future destabilization.