History and Overview of Long-acting Injectable Antipsychotics

Long-acting injectable (LAI) antipsychotics are commonly indicated for schizophrenia. Schizophrenia is characterized by positive, negative, and cognitive symptoms.¹

Schizophrenia Symptoms
Positive Symptoms	Negative Symptoms	Cognitive Symptoms
Hallucinations, Delusions, Disorganized thinking	Anhedonia, Alogia, Affect flattening, Avolition	Attention and memory impairment, Diminished executive functioning

The first LAI was introduced in 1966 with proven applicability and convenience for patients and healthcare providers alike.² Before the turn of the century, many healthcare professionals such as psychiatrists and psychologists directly treated patients with schizophrenia and other similar mental illnesses in hospital settings.²

It wasn’t until the latter part of the 20^th century where outpatient services vastly grew. With expansions in psychiatric healthcare, there was strong acknowledgement of the problem of nonadherence of antipsychotic medications prescribed in the long term. The recognition of the use and need of LAIs definitely demonstrated good patient outcomes despite early side effect profiles with first-generation antipsychotics (e.g., tardive dyskinesia, extrapyramidal symptoms). Subsequently, second-generation LAIs were then introduced in 2003, but also presented with its own side effect profiles in direct comparison to oral agents (e.g., QTc prolongation, sedation, weight gain).³ Choosing the right LAI for the right patient can be challenging when there are many factors to consider, but it is always important to have your patient’s best interest in mind.

The Issue of Adherence

Long-acting injectable antipsychotics are largely prescribed for combating the issue nonadherence. LAIs are highly effective in preventing relapse of schizophrenia; however, there are numerous barriers that often prevent patients from staying on their appropriate LAI regimens. The common reasons for nonadherence of LAIs can be attributed to⁴:

• stigma
• serious adverse events
• patient mistrust with healthcare professionals
• lack of medical resources
• patient denial of diagnosis
• regimen issues

Most often than not, patients are nonadherent because their symptoms might simply “resolve” or “go away.” While on oral medication, patients might take their pills when their symptoms come back and these gaps in therapy might not be the best course of treatment patients. LAIs, however, fix this issue as patients are more likely to be adherent. This is mostly in part to longer dosing intervals and the elimination of oral overlap in some LAIs. Since the medication is slowly delivered over the course of weeks to months, it is likely that the patient will be more willing to continue therapy in the convenient setting of an outpatient clinic.

As always, it is important to discuss with patents the risks and benefits of LAIs. An informed patient will have the tools for better decision making in the long run. A summary of long-acting injectable antipsychotics is outlined below.^5,6

Medication	LAI Generation	Injection Schedule
Haloperidol Decanoate Haldol	First generation	Every monthNo PO overlap if loading dose is given
Fluphenazine Decanoate Prolixin	First generation	Every 2 to 3 weeksNo PO overlap
Risperidone Risperdal Consta	Second generation	Every 2 weeksPO overlap given 3 weeks after first injection
Paliperidone Palmitate Invega Hafyera	Second generation	Every 6 months; No PO overlap*
Paliperidone Palmitate Invega Sustenna	Second generation	Every month; No PO overlap
Paliperidone Palmitate Invega Trinza	Second generation	Every 3 months; No PO overlap
Olanzapine Pamoate Zyprexa Relprevv	Second generation	Every 2 weeks or every 4 weeks; No PO overlap
Aripiprazole Monohydrate Abilify Maintena	Second generation	Every month; PO overlap given 2 weeks
Aripiprazole Lauroxil Aristada	Second generation	Every 1 to 2 months; PO overlap given 21 days after first injection

Long-acting Injectable Antipsychotics: First Generation vs Second Generation

The side effect profiles of first and second generation LAIs are unique to their respective classes. For example, First generation LAIs can cause more extrapyramidal symptoms (e.g., akathisia) than second generation LAIs. In addition, second generation antipsychotics can cause undesirable side effects such as metabolic issues (weight gain and hyperlipidemia), sedation, and hyperprolactinemia.⁵

Selection is everything. Second generation LAIs such as paliperidone and risperidone are known to have higher incidences of hyperprolactinemia than aripiprazole.³ With all things considered, depending on the patient’s comorbid conditions and specific risk factors (heart disease, sleep disturbances), certain LAIs may be given priority over others.

Clinical research has shown that even though second-generation LAIs are fairly tolerable given their side effect profiles, differences in patient relapse outcomes are pretty much favorable just like their first generation counterparts.³ The ACLAIMS trial was a pivotal randomized controlled trial that examined the relapse differences in patients with schizophrenia who were administered either haloperidol decanoate or paliperidone palmitate. The primary outcome of efficacy failure in both groups was not statistically significant (HR = 0.98; 95% CI = 0.65-1.47).⁷ Given these clinical outcomes, LAI therapy is guided by patient factors rather than a certain medication.

Other Considerations for Long-acting Injectable Antipsychotics

Some patients may have other conditions or diagnoses that might be a cause for concern. In any case, a comprehensive medication history is needed for the appropriate LAI treatment. The following considerations may be evaluated on a case-by-case basis^8,9:

Patient Considerations for Long-acting Injectable Antipsychotics
Pregnancy	Pregnant patients may safely take an LAI unless:   There is a known contraindication There is a rational reason for discontinuation   Pregnant patients may benefit from taking an LAI if:   There is a history of nonadherence There is a history of many hospitalizations There is a history illicit drug use There are unresolved symptoms during postpartum term
Differential Diagnosis	Patients are candidates for LAIs if they also have these diagnoses:   Bipolar disorder* Schizoaffective disorder†

After selecting the right treatment for the right patient, long-acting injectable antipsychotics can be quite effective in treating patients with schizophrenia. The data out there is consistent with positive results with both LAI generation formulations. Despite these outcomes, adherence remains a widespread problem.³ Healthcare professionals should always advocate for their patients while reinforcing the advantages of therapy. With collaborative efforts, we will eventually see a step in the right direction.

Dr. Joseph Suarez, Pharm.D. is a Medical Writer at RxPharmacist, LLC who resides in San Antonio, Texas. His interests are in psychopharmacology, psychotherapy, and reconciling healthcare disparities. Dr. Suarez is seeking opportunities to utilize his incredible medical writing talents. If you are looking to hire, you may contact Dr. Suarez via LinkedIn.

References:

1. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5). Washington, DC: APA, 2013.
2. Johnson DAW. Historical perspective on antipsychotic long-acting injections. The British Journal of Psychiatry . 2009;195:s7-s12. doi: 10.1192/bjp.195.52.s7 
3. Jann MW. Understanding long-acting injectable antipsychotics for better treatment adherence. Psychiatric Times. https://www.psychiatrictimes.com/view/understanding-long-acting-injectable-antipsychotics-better-treatment-adherence. Published March 19, 2020. Accessed February 7, 2022. 
4. Correll CU, Lauriello J. Using long-acting injectable antipsychotics to enhance the potential for recovery in Schizophrenia. The Journal of Clinical Psychiatry. 2020;81(4):1-8. doi:10.4088/jcp.ms19053ah5c 
5. Crimson ML, Smith T, Buckley PF. Schizophrenia. In: Pharmacotherapy: A Pathophysiologic Approach. 11th ed. New York: McGraw Hill Medical; 2020. 
6. Invega Hafyera. [package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ. 2021.
7. McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia. JAMA. 2014;311(19):1978. doi:10.1001/jama.2014.4310 
8. Reinstein SA, Cosgrove J, Malekshahi T, Deligiannidis KM. Long-acting injectable antipsychotic use during pregnancy. The Journal of Clinical Psychiatry. 2020;81(6):1-3. doi:10.4088/jcp.20ac13597 
9. Pacchiarotti I, Tiihonen J, Kotzalidis GD, et al. Long-acting injectable antipsychotics (LAIS) for maintenance treatment of bipolar and schizoaffective disorders: A systematic review. European Neuropsychopharmacology. 2019;29(4):457-470. doi:10.1016/j.euroneuro.2019.02.003