Exploring psychotherapeutic issues and agents in clinical practice
Fluphenazine (Prolixin®) was introduced in the 1960s as an oil-based depot intramuscular injection (fluphenazine decanoate) to treat patients with schizophrenia who had difficulty with medication adherence (Jann & Penzak, 2018). Eventually, haloperidol depot was added and, in 2003, second-generation long-acting injectables (LAIs) came on the market beginning with risperidone. First-generation LAIs use oil as a vehicle to hold the medication, whereas second- and third-generation LAIs use microcrystallization and water-based preparations resulting in reduced pain on administration. The current article focuses on a comparison of oral and injectable formulations in terms of tolerability, dosing, and kinetics, and discusses the advantages and disadvantages of both formulations. Recommendations about how to use LAIs effectively with adolescent and adult clients with psychosis (i.e., schizophrenia and bipolar disorders) are also presented.
Benefits of Long-Acting Injectables
Schizophrenia is a progressive neurogenerative disorder characterized by remissions and relapses. Relapses often result in hospitalizations, loss in function, increased burden of illness, and decreased quality of life (Huang, Amos, Joshi, Wang, & Nash, 2018). Relapse commonly occurs when clients reduce or discontinue taking medication for various reasons, including side effects and continuing psychotic cognitive processing. Maintaining consistency in medication plasma levels that have reduced symptoms predicts better outcomes and prognosis (Andrews et al., 2017; Catts & O'Toole, 2016; Nielsen, Hessellund, Valentin, & Licht, 2018). Meta-analyses of long-term neuroimaging studies showed enhanced neurogenesis and other neuroprotective effects with second-generation antipsychotics (Nasrallah, 2018; Taipale et al., 2018).
As convincing as it is that medication improves the course and prognosis of psychosis, the challenge to clinicians and family members is helping clients take their medications. At onset of illness, it may take several medication trials to find a medication regimen that is effective and tolerable to the client. Oral medications are most convenient and safer to adjust, yet they are also challenging for monitoring and maintenance. The client must be willing to take the medications regularly, refill the prescriptions, and afford the cost. Once the client is stable on a medication, the challenge persists and lapses in medication adherence are a risk. However, if the oral medication is replaced with a LAI, there is reduced risk of medication discontinuation and improved consistency in medication benefits. Oral formulations have similar mechanisms of action and pharmacodynamics as injectable formulations; therefore, replacement is feasible and even preferable (Ostuzzi, Bighelli, So, Furukawa, & Barbui, 2017). If the client abruptly stops receiving the LAI (i.e., fails to get subsequent injections), there are less rebound withdrawal symptoms because there is gradual discontinuation of the medication as it is absorbed in the muscle and distributed.
LAIs have been used with a variety of populations including adolescents, individuals with comorbid substance use disorders, and incarcerated clients. Lytle, McVoy, and Sajatovic (2017) reported improved outcomes with first-episode schizophrenia in teenagers with minimal side effects. LAIs have also been used in teenagers with psychotic disorders and disruptive behavior disorders, resulting in significant improvement in functioning and symptom reduction (Fortea et al., 2018). Because substance use frequently interferes with schizophrenia and bipolar pathology and invites nonadherence to prescribed medication, incorporation of LAIs early in treatment improves overall outcomes, reduces substance use, and improves medication adherence (Andrews et al., 2017; Green, 2012; Lynn Starr, Bermak, Mao, Rodriguez, & Alphs, 2018; Williams, McKinney, Martinez, & Benson, 2016).
The plasma half-life of LAIs is determined by the rate of drug release more than drug metabolism; this rate of release determines the persistence of the drug in the system rather than the elimination rate (National Council for Behavioral Health, Montefiore Medical Center, New York State Office of Mental Health, n.d.). For most LAIs, the half-life after repeated administration is between 14 and 27 days. When switching from the oral to LAI formulation, overlap may be needed depending on the drug. Paliperidone and olanzapine are exceptions in that they do not need oral loading to achieve steady state (Jann & Penzak, 2018). Table 1 shows the most common agents, the need for oral initiation/overlap, and the dose conversions. Paliperidone palmitate, which comes in a once per month or once every 3-month formulation, has the unique characteristic of loading by changing the dosage in the first three injections. The first injection of paliperidone palmitate (Invega Sustenna®) is 234 mg for 7 days followed by an injection of 156 mg for the next 21 days followed by the maintenance dosage of 117 mg on a monthly basis.
Long-Acting Injectable (LAI) Antipsychotic Agents and Related Pharmacokinetics
Barriers to Use of Long-Acting Injectables
The side effects of oral and LAI medications are similar except for pain or discomfort at the intramuscular injection site for LAIs. LAIs are all intramuscular; therefore, they require professional administration with associated logistics and costs. It is recommended to inject using the Z-track method (Jann & Penzak, 2018) in either the gluteal, vastus lateralis, or deltoid muscles, depending on the client's muscle mass in relation to the volume of drug.
Clients who are smokers usually need a higher dosage for any of the LAIs; however, a decrease in dosage will be necessary if the client stops smoking. Metabolic side effects continue with second-generation LAIs, and clients need guidance in managing their weight and exercise regimen.
Clinicians tend to consider LAI use for clients who have difficulty maintaining their oral medication regularity due to motivation, stigma, side effects, or residual cognitive reasoning symptoms. Because evidence indicates use in first episodes of psychosis (i.e., bipolar disorder and schizophrenia) reduces long-term morbidity, increases remission of symptoms, and returns functioning, it is especially advantageous to initiate LAIs immediately after achieving stability of symptoms. Explaining the long-term benefits to clients and family members and involving them in recovery treatment assures improved outcomes. Provider bias regarding depot medication use for only nonadherent clients may serve as a more significant barrier than client preference, especially if the benefits of neuroprotection and reduced relapses are presented. One setting incorporated the LEAP (Listen, Empathize, Agree, Partner) communication strategy in its program to gain client understanding and acceptance of LAIs (Lasser, Schooler, Kujawa, Docherty, & Weiden, 2009). Clinicians used motivational interviewing to partner with clients with chronic mental illness to achieve effective approaches to care (Lasser et al., 2009). Nystazaki et al. (2018) found that clients initially did not understand the information provided about their medication and benefited from LAIs with additional resources in managing side effects such as weigh gain.
Cost and logistics pose challenges to using LAIs. However, the overall cost of repeat hospitalization due to relapse outweighs the cost of medication. The logistics of injections can be incorporated into regular follow-up appointments and day treatment or other recovery activities. Some centers offer LAI clinics and group patient education sessions to consolidate services.
- Use the therapeutic relationship to introduce the option of LAIs in partnering with clients in treatment planning.
- Include LAIs in medication options when discussing treatment with clients, especially patients with new-onset psychosis after they are stabilized on a medication regimen.
- Explain the long-term benefits of LAIs with clients who are currently stable on medications, including their possible neuroprotective benefits.
- Provide LAI management within a recovery-oriented model that focuses on clients' understanding about their illness, medications, and treatment options.
- Include assessment of weight; eating, exercise, and smoking behaviors; and substance use in medication management appointments.
Given the recent literature, it is within best practice to offer LAI administration as a medication regimen option when a client is stabilized on oral antipsychotic medication. LAIs are not simply for nonadherent clients, but rather can be used to provide consistent, effective serum levels of medication to treat a progressive neurological disease. Provider attitudes regarding LAIs may be more significant barriers to their effective use than client preferences. By incorporating LAI medication administration into the full spectrum of recovery practice, the client has a greater probability of improved outcome.
- Andrews, C.E., Baker, K., Howell, C.J., Cuerdo, A., Roberts, J.A., Chaudhary, A. & Nucifora, F.C. Jr. . (2017). Risk of hospitalization due to medication nonadherence identified through EMRs of patients with psychosis. Psychiatric Services, 68, 847–850. doi:10.1176/appi.ps.201600334 [CrossRef]
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- Lasser, R.A., Schooler, N.R., Kujawa, M., Docherty, J. & Weiden, P. (2009). A new psychosocial tool for gaining patient understanding and acceptance of long-acting injectable antipsychotic therapy. Psychiatry, 6(4), 22–27.
- Lynn Starr, H., Bermak, J., Mao, L., Rodriguez, S. & Alphs, L. (2018). Comparison of long-acting and oral antipsychotic treatment effects in patients with schizophrenia, comorbid substance abuse, and a history of recent incarceration: An exploratory analysis of the PRIDE study. Schizophrenia Research, 194, 39–46. doi:10.1016/j.schres.2017.05.005 [CrossRef]
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- National Council for Behavioral Health, Montefiore Medical Center, New York State Office of Mental Health. (n.d.). LAI dosing & kinetics. Retrieved from https://www.thenationalcouncil.org/wp-content/uploads/2018/02/LAI-Dosing-and-Kinetics.pdf
- Nielsen, R.E., Hessellund, K.B., Valentin, J.B. & Licht, R.W. (2018). Second-generation LAI are associated to favorable outcome in cohort of incident patients diagnosed with schizophrenia. Schizophrenia Research, 202, 234–240. doi:10.1016/j.schres.2018.07.020 [CrossRef]
- Nystazaki, M., Pikouli, K., Tsapakis, E.M., Karanikola, M., Ploumpidis, D. & Alevizopoulos, G. (2018). Decision-making capacity for treatment of psychotic patients on long acting injectable antipsychotic treatment. Archives of Psychiatric Nursing, 32, 300–304. doi:10.1016/j.apnu.2017.11.019 [CrossRef]
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Long-Acting Injectable (LAI) Antipsychotic Agents and Related Pharmacokineticsa
|Agent||Formulation||Oral Initiation||Oral to LAI Dose Conversion/Administration Interval|
|Olanzapine (Relprevv®)||150 mg/mL
Pamoic acid crystal||None||10 mg/d = 210 mg every 2 weeks or 405 mg every 4 weeks
15 mg/d = 300 mg every 2 weeks or 210 mg every 2 weeks
20 mg/d = 300 mg every 2 weeks|
|Risperidone (Consta®)||12.5 mg/2 mL
25 mg/2 mL
37.5 mg/2 mL
50 mg/2 mL
Microspheres||21-day overlap||2 to 4 mg = 25 mg
4 to 6 mg = 37.5 mg
6 to 8 mg = 50 mg|
|Paliperidone palmitate (Invega Sustenna®)||39 mg/0.25 mL
78 mg/0.5 mL
117 mg/0.75 mL
156 mg/1.0 mL
234 mg/1.5 mL
Nanocrystals||None||3 mg = 39 to 78 mg
6 mg = 117 mg
12 mg = 234 mg
234 mg Day 1, 156 mg Day 8, 117 mg Day 21, and every 4 weeks thereafter|
|Paliperidone palmitate (Invega Trinza®)||273 mg/0.875 mL
410 mg/1.315 mL
546 mg/1.75 mL
819 mg/2.625 mL
Nanocrystals||None||78 mg = 273 mg
117 mg = 410 mg
156 mg = 546 mg
234 mg = 819 mg
Every 3 months|
|Aripiprazole monohydrate (Maintenna®)||300 mg/1.5 mL
400 mg/1.9 mL
Polymorphic||14-day overlap||10 to 15 mg = 400 mg
Every 2 to 4 weeks|
|Aripiprazole lauroxil (Aristada®)||441 mg/1.6 mL
662 mg/2.4 mL
882 mg/3.2 mL
Pro-drug, hydrolysis||21-day overlap||10 mg = 441 mg
15 mg = 662 mg
20 mg = 882 mg
Every 4 to 6 weeks|
|Haloperidol decanoate||50 mg/mL
Sesame oil based||21-day overlap||5 mg = 50 mg
10 mg = 100 mg
Every 2 to 4 weeks|