Long-Acting Injectable Antipsychotics for Schizophrenia: Why They Deserve Another Look

Despite the efficacy and safety of second-generation antipsychotic (SGA) long-acting injectables (LAIs) in treating schizophrenia, psychiatrists have not considered these agents as first-line therapy.1,2 To fully understand the hesitancy to adopt these injectables, a half-century retrospective is necessary.3 Originally designed to eliminate poor adherence in patients with schizophrenia, the first antipsychotic injectables were viewed with suspicion and coercion.4,5 This negative perception was due to delayed disappearance of side effects after discontinuation, patient reluctance to accept injections, and the patient’s feeling of being controlled. 3,6 Because clinicians prescribed LAIs when patients were nonadherent to treatment or perceived as a danger to others, they were primarily viewed as second- or third-line agents.1

“Previously, patients thought to be eligible for LAIs — also reflected in past guidelines — were chronically ill patients, those with multiple relapses, established nonadherence, or patients already on LAIs or asking for them,” explained Christoph U. Correll, MD, professor of psychiatry and molecular medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Hempstead, New York.

Benefits of LAI Antipsychotics for Schizophrenia

Now that LAIs are formulated with SGAs — including aripiprazole, olanzapine, paliperidone, and risperidone — which have fewer adverse effects than first-generation antipsychotics, emerging evidence has led psychiatrists to consider SGA LAIs for their patients with a first episode of schizophrenia.3 The introduction of the SGAs ushered in advantages beyond adherence, including:

  • Fewer emergencies and abrupt relapses;
  • Lower risk of overdose;
  • Improved patient and physician satisfaction;
  • No need for daily dosing, which reduces peak-trough plasma levels; and
  • Reduced gastrointestinal absorption problems.3

Treatment continuity is critical to avoid relapse and improve outcomes for those who are newly diagnosed with schizophrenia.9 In patients experiencing a first episode of schizophrenia, relapse rates can be as high as 77% during the first year after diagnosis and up to 90% during the second year.9

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Improving Care During a Pandemic

LAIs have been an important treatment modality for patients and caregivers concerned about making frequent visits to an office or a pharmacy for medication refills.2 Dosing every 2 or 3 months with aripiprazole lauroxil (Aristada Initio® 1064 mg) or paliperidone palmitate (Invega Trinza®) makes this possible.16

“Insight into illness fluctuates, and on some days, adherence is in jeopardy, even for some of our most adherent patients,” said Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla, New York. He notes that there has been an “uptake in requests for LAIs, as patients and caregivers want to avoid going to the local pharmacy.”16

Role of LAIs in Schizophrenia Treatment Adherence

LAIs can play a critical role in the treatment of schizophrenia by helping to preserve brain volume and cognitive function, which rapidly deteriorates within the first 5 years of an initial psychotic episode.3 By maintaining treatment adherence during this critical stage, patients may experience better functional outcomes.3

This evidence is convincing psychiatrists to reassess their LAI treatment to preserve the function and quality of life of patients with early stage schizophrenia by reducing the likelihood of nonadherence.3 In addition, suicide mortality risk is higher early in the course of schizophrenia than it is later in the disease.17

A 25-patient study of individuals who had been recently diagnosed with schizophrenia (≤5 years; n=10) vs those who had been diagnosed >5 years earlier (n=15) found that the patients who had been diagnosed while at an earlier stage tended to benefit more from treatment with an SGA LAI than did patients with longer-term illness.17 Assessments included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning (GAF), the Columbia Suicide Severity Rating Scale (C-SSRS), the Recovery Style Questionnaire (RSQ), and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) Managing Emotion branch. Compared with patients with longer-term schizophrenia, patients who had been recently diagnosed with schizophrenia demonstrated greater improvement in the GAF score, in the negative and depressive symptoms in the PANSS factor score, and in the severity and intensity for suicidal ideation.17

Safety and Tolerability of LAI Antipsychotics

Safety and tolerability of LAI antipsychotics were compared with those of oral antipsychotics in a 16-study meta-analysis.18 Discontinuation rates, adverse events, and all-cause death rates were comparable among the 2 groups.18 The meta-analysis also revealed no differences between LAIs and oral antipsychotics in extrapyramidal symptoms and weight gain, with the exceptions being akinesia and low-density lipoprotein cholesterol level.18  LAIs were associated with significantly lower prolactin levels compared with oral antipsychotics.6 Given the long elimination half-life of LAIs, however, onset and remission of adverse effects differ from those of oral antipsychotics.6

LAI Cost-Effectiveness

A study of 114 patients with schizophrenia demonstrated that LAI antipsychotics can reduce the number of inpatient days and associated costs.13 The study randomly assigned patients (65% men; mean age, 40 years) to either once-monthly aripiprazole (n=30) or once-monthly paliperidone (n=84). The 1-year mirror-image study found that both aripiprazole LAI and paliperidone LAI reduced hospitalizations as measured in mean bed days (63.0 before vs 6.3 after, P =.0001; 69.0 before vs 13.9 after, P =.001, respectively).19 Patients showed clinical improvement as measured with the Health of the Nation Outcome Scale (HoNOS) scores, a measurement established by the Royal College of Psychiatrists in the United Kingdom that measures behavior, impairment, symptoms, and social functioning. Except for the impairment scale, patients showed improvement in 3 of the 4 HoNOS subscales.19

Guideline Recommendations for Treating Schizophrenia With LAIs

Historically thought of as a last resort when oral antipsychotic agents have failed, LAIs are now being reconsidered as first-line treatments.9 As such, the Canadian guidelines for schizophrenia now recommend that patients be given an option of either oral or injectable antipsychotic, regardless of adherence history.20 Part of the rationale is that schizophrenia relapses can occur even with adequate doses of antipsychotic.20 Recognizing that SGA LAIs can prevent relapses, the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) guidelines for the use of LAIs for serious mental illnesses recommend SGA LAIs for first-episode schizophrenia.21

Following its international counterparts, the American Psychiatric Association has adopted a similar stance in its draft guidelines recommending that patients be offered an option of oral or injectable antipsychotic agents.22

“The paradigm has shifted — also reflected in past guidelines — to be more proactive, in that LAIs can be considered across the entire illness range, including early in the illness course, be given after a first relapse or even before nonadherence has evolved, which is likely to develop over time,” said Dr Correll.

Caveats for LAIs and Overcoming Stigma

Although the efficacy and safety of LAIs have been demonstrated to be better or comparable to their oral counterparts, there remain some aspects that may challenge clinicians.

  • Because some LAIs require supplementation with oral agents, it may take longer for patients to achieve steady state levels;
  • Adverse events may not dissipate quickly;
  • Dose flexibility is reduced;
  • Risperidone LAI must be refrigerated; and
  • The injection site may be painful.3

Still, though 94% of psychiatrists believe that LAIs can prevent relapse, 48% of clinicians thought of them as stigmatizing and 69% believed that patients would find LAIs unacceptable.23 A qualitative study of 24 Canadian psychiatrists in 4 provinces echoed this sentiment:  most clinicians viewed LAIs as a modality that would interfere with the therapeutic alliance.24

To overcome the stigma of LAIs, clinicians and their staff should consider learning as much as they can about the newer agents so that they can address their patients’ concerns in an informed manner.6 Both clinicians and patients should recognize that LAIs can be used after a first episode of schizophrenia.6

Paliperidone palmitate (every 4 weeks) side effects
Side effects most commonly reported include injection site reactions; sleepiness or drowsiness; dizziness; feeling of inner restlessness; and abnormal muscle movements, and abnormal movements of the eyes.
Paliperidone palmitate (every 12 weeks) side effects
Side effects most commonly reported include injection site reactions, weight gain, headache, upper respiratory tract infections, restlessness or difficulty sitting still, slow movements, tremors, stiffness, and shuffling walk.

Refer to the full Prescribing Information for additional details about Abilify Maintena®, Aristada Initio®, Zyprexa® Relprevv, Invega Sustenna®, Invega Trinza®, and Risperdal Consta®.


Christoph U. Correll, MD, declared affiliations with Alkermes, Forum, Bristol-Myers Squibb, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Otsuka, Pfizer, Sunovion, Supernus, Takeda, and Teva. Leslie Citrome, MD, MPH, declared affiliations with Acadia, Alkermes, Allergan, Avanir, BioXcel, Eisai, Impel, Indivior, Intra-Cellular Therapies, Janssen, Lundbeck, Luye, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Sage, Shire, Sunovion, Takeda, Teva, and Vanda; served as a speaker for Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Sage, Shire, Sunovion, Takeda, and Teva; and owns stock (small number of shares of common stock) in Bristol-Myers Squibb, Eli Lilly, J & J, Merck, and Pfizer purchased > 10 years ago.


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Reviewed September 2020