Are Injectable Antipsychotics Effective in Managing Schizophrenia?

When treating schizophrenia, acute flare-ups are inevitable, but their severity and frequency can be better controlled through maintenance interventions.¹ Continuity of treatment is essential for preventing relapse, therefore any therapeutic interventions that enhance treatment adherence are preferred.² Long-acting injectable (LAI) antipsychotics can decrease the risk of relapse in both first-episode and chronic schizophrenia, making them an attractive option for patients of most ages.¹

Research has shown that adherence to therapy is an issue for at least 50% of all patients with schizophrenia.¹ Further, data reveals a 1-year relapse rate of 77% in patients with a first episode of schizophrenia who discontinue antipsychotic therapy, and that rate balloons to 90% at 2 years, compared with a mean relapse risk of 3% in those continuously treated with antipsychotics.² When relapse is impending or present, rates of substance abuse, suicide, and violent behavior rise, compounding the necessity of continuity of treatment.²

While LAI antipsychotics have been an important option for managing schizophrenia for years, up until recently, the longest dosing interval was 4 weeks between injections.¹ Now, new injectable formulations provide a wider range of dosing options for 6, 8, or 12 weeks.¹

The Benefits of Long-Acting Injectable Antipsychotics
For patients, the benefits of LAI antipsychotic include^1,2

• freedom from taking daily oral medications;
• improved medication adherence;
• more stable therapeutic blood levels between injections;
• decreased risk of relapse;
• decreased risk of rehospitalization;
• fewer emergency room visits;
• improved rehabilitation and re-entry into society;
• more discrete method of medication;
• decreased stress from caregivers asking about adherence to oral medications;
• decreased risk of accidental or deliberate overdose; and
• improved quality of life.

For clinicians, the benefits of next-generation LAI antipsychotics include¹

• eliminating the guesswork about adherence status;
• smoother transition for patients from inpatient to outpatient programs;
• more regular physician-patient contact and improved monitoring;
• greater dosing options;
• most can be injected with smaller needle bores;
• oral supplementation may not be required; and
• may be appropriate for schizoaffective disorder and bipolar disorder.

Antipsychotic pharmacological therapy should be accompanied by psychoeducational and psychosocial interventions appropriate for each patient.² These interventions can include occupational therapy, community-based treatment, family interventions, vocational rehabilitation, counseling, psychotherapy, behavior therapy, and cognitive behavioral therapy.² In fact, UK guidelines recommend cognitive behavioral therapy as first-line therapy for at-risk adults.²

Evaluating Long-Acting Injectable Antipsychotics

For physicians, selecting the optimal treatment that’s effective, well tolerated, and promotes adherence can be a challenge. Variability among both patients and antipsychotics often results in a series of medication changes to find the best fit.¹ While not all oral antipsychotics are available in LAI formulations, newer LAI antipsychotics can be useful once the antipsychotic molecule most effective for the patient has been identified.¹

Five second-generation, long-acting injectable antipsychotics are approved for the treatment of schizophrenia in the United States¹:

Risperidone microspheres: Administered every 2 weeks; requires 21 days of oral supplementation at the time of initiation; requires refrigeration; can also be used for bipolar maintenance as a monotherapy or adjunctive to lithium or valproate.

Paliperidone palmitate: Administered every 4 weeks (monthly version) or every 12 weeks (3-month version); prefilled syringes; can use a 23 gauge (G) needle for some patients; small injection volumes; can store at room temperature; no need for oral supplementation; patients can be transitioned to a 3-month formulation; 1-month formulation can be used to treat schizoaffective disorder either as a monotherapy or adjunctive to antidepressants or mood stabilizers.

Olanzapine pamoate: Administered either every 2 weeks or every 4 weeks; requires a 3-hour post-injection monitoring period due to the risk of post-injection delirium/sedation syndrome; gluteal injection; can use 19 G needle only; there is no need for oral supplementation.

Aripiprazole monohydrate: Administered every 4 weeks; lower tendency for prolactin elevation; can use a 23 G needle for some patients; requires 14 days of oral supplementation at the time of initiation; can be used for bipolar maintenance as a monotherapy.

Aripiprazole lauroxil: Administered every 4, 6, or 8 weeks; lower tendency for prolactin elevation; prefilled syringes; requires 21 days of oral supplementation at the time of initiation.

However, these medications have risks. Adverse effects might include¹

• headache;
• weight gain;
• restlessness
• common cold; and
• injection-site redness, pain, or swelling.

Another potential deterrent to prescribing these new formulations is that they are relatively expensive.¹

Reducing the Stigma

Research shows that most psychiatrists don’t currently offer their patients LAI antipsychotic treatment as an option, and many patients are unaware of this potential treatment.¹ Educating patients who are on oral antipsychotics about LAI antipsychotics is a key step in helping decrease the stigma that these formulations are a last resort measure instead of a safe, mainstream offering.¹

“If the patient is already on oral fluphenazine, haloperidol, risperidone, paliperidone, olanzapine, or aripiprazole and demonstrating reasonable efficacy and tolerability, then patients should be offered the corresponding LAI formulation,” wrote Leslie Citrome, MD, MPH, Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York.¹

A real-world cohort study of the use of oral and LAI antipsychotics after the first hospitalization of patients for schizophrenia found that less than half (45.7%) adhered to their discharge antipsychotic medication in the 60 days after discharge.² However, there was a significantly lower risk of all-cause antipsychotic discontinuation with LAIs.² In fact, LAIs significantly reduced the risk of rehospitalization compared with oral antipsychotics.² The Texas Medication Algorithm Program and French Association for Biological Psychiatry and Neuropsychopharmacology both recognize LAI antipsychotics as first-line treatment for schizophrenic patients requiring long-term therapy.²

However, Dr. Citrome cautions that LAI antipsychotics are not for everyone.¹ Because the LAI antipsychotics are usually administered once monthly, physicians lose the flexibility that oral dosing provides when the optimal dose for the individual isn’t known. Additionally, some patients are reluctant to accept injections, and this method of administration may play into their paranoid delusions or delusions of being controlled.

In the event of adverse reactions, slow distribution from the muscle may prolong side effects. Sesame oil-based products such as haloperidol decanoate can cause injection-site reactions, including pain, erythema, swelling, and discomfort.

“Reassuringly, people who are receiving LAI antipsychotics denote that this formulation is actually preferred and that they feel better supported in their illness,” Dr. Citrome concluded.¹

Future Research

New products in development include novel long-acting formulations of risperidone that don’t require oral supplementation.¹

Another area that may warrant more research is the role of ceramides in schizophrenia. As a class of lipid-signaling molecules, ceramide plays an important role in cell proliferation, apoptosis, differentiation, and growth inhibition.³

Studies show that the white matter of brain tissues autopsied from schizophrenic patients often has higher ceramide levels than control group samples.³ The underlying regulatory mechanism is unclear, but it has been suggested that ceramide is involved in regulating immunoinflammation in schizophrenia through the nuclear factor-κB/TNF-α pathway.³

References

1. Citrome L. Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications. Expert Rev Neurother. 2017;17(10):1029-1043.

2. Biagi E, Capuzzi E, Colmegna F, et al. Long-Acting Injectable Antipsychotics in Schizophrenia: Literature Review and Practical Perspective, with a Focus on Aripiprazole Once-Monthly. Adv Ther. 2017;34(5):1036-1048.

3. Ling WM, Chen MC, Zhang, YC, Ou MM, Gu LZ. Study on ceramide modulates EAAT-2 participation in the immunoinflammatory response in schizophrenia. Eur Rev Med Pharmacol Sci. 2019 Mar;23(5):2263-2272.