LAIs for Schizophrenia: An Expert-Driven Psychiatry Case

Christoph Correll, MD reviews three case reports for patients with schizophrenia who may be candidates for switching to long acting injectable (LAI) antipsychotics from oral medication.

In this Expert-Driven Psychiatric Case, this renowned psychiatrist reviews the case reports of three patients–James, Joanna, and Tom–with schizophrenia who are candidates for switching from oral antipsychotic treatment to LAIs. “Long acting injectable antipsychotics, or LAIs, have the potential to reduce non-adherence, relapse, rehospitalization, and even mortality, even among patients with first episode schizophrenia and with comorbid substance use disorder,” explains Christoph Correll, MD. 

Through a series of eight brief episodes, Dr. Correll will:

  • Introduce the three patients: Two males, one female who range in age from 21-43
  • Share insights that highlights patient, clinician, and caregiver responses to LAIs
  • Present research data that supports the benefits of LAIs
  • Review the process for selecting a treatment path that includes LAIs, and why 
  • Show how to respond to breakthrough psychosis or continued relapse
  • Explain the role of LAIs with or without oral medication to avoid further psychosis 

This deep dive into the clinically relevant and impactful role of LAIs will explain why Dr. Correll calls long acting injectables a “seatbelt on the road to recovery and success” for a breadth of patients living with schizophrenia.

EPISODE 1: JAMES

[00:00:06] Dr. Christoph Correll The first patient case I will be discussing is James, a 33-year-old white male who was diagnosed with schizophrenia at the age of 22. James is unemployed and lives at home with his elderly parents. He has few social contacts and spends most of his time either gaming or intermittently using marijuana. James' mother is upset that her son is not leaving the house and not doing anything with his life. There have been frequent conflicts over her checking up on James taking this medication because she's worried about another psychotic episode. 

 

Recently, James required re-hospitalization for an acute psychotic episode after he was beaten up by strangers in the park. He stabilized on the unit and is currently taking oral risperidone. He tolerates it well, except for an asymptomatic, mild prolactin increase. As part of the discharge planning, which different maintenance treatment options would you discuss?

EPISODE 2: JOANNA

[00:00:05] Dr. Christoph Correll The second patient case for today is Joanna, a 43-year-old black female who has had schizophrenia since the age of 28. She lives in supported housing. She has comorbid social anxiety and gained more than 40 pounds on her past and current antipsychotic regime combined. Her weight gain has plateaued and her current BMI is 29, but except for mild elevated triglycerides, her glucose and lipid parameters are still currently within high normal limits. She also complains of mild daytime sedation. Joanna's psychotic symptoms are generally well controlled, and her social anxiety is more of a concern for the patient. Although, it is sometimes difficult for her to distinguish social anxiety from paranoia. 

Joanna's coming to the outpatient appointment accompanied by her guidance counselor who relates this concern that Joanna has been telling him that she wasn't sure that the medication was necessary for her anymore. She says that she feels fine and wants to return to a normal life, and that the medication side effects have really interfered with her daily routines. The guidance counselor relates to you that he has seen the patient get somewhat more easily agitated and that she seemed preoccupied. At this point, what treatment options would you consider and discuss with the patient?

EPISODE 3: TOM

[00:00:06] Dr. Christoph Correll Our third and final patient case is Tom, a 21-year-old Asian male who has moved back in with his parents and has been living with them for the past three months. He had his first psychotic episode in college at the end of an intense one month exam period. He felt stressed, did not sleep enough, and use some marijuana to relax in between his study "sprints." Tom started hearing commenting and derogatory voices and became highly paranoid about his roommate, who he believed was tampering with his brain when he was asleep. He was also convinced his roommate was plotting together with several other peers to have him fail the exam. Tom was hospitalized after he attacked his roommate. He stabilized over three and a half weeks on oral aripiprazole, which he tolerates reasonably well, except for sleeping one to two hours more than usual and having gained two kilograms of weight. The weight gain stabilized, partially due to regular exercising. 

Tom wants to go back to college and is very concerned that a new relapse could interrupt his academic progress even more. He will also be returning into a dorm living arrangement and is ashamed of his past behavior and mental illness.

EPISODE 4: SELECTING A TREATMENT PATH: WHAT DO THE DATA SAY?

[00:00:05] Dr. Christoph Correll In a survey of 206 schizophrenia patients with more than three months of long-acting injectable antipsychotic treatment experience, 67 percent of such patients said they felt better than they had been feeling before when they were taking oral medication. And as many as 70 percent of patients reported that regular contact with a doctor or nurse who administered that injection made them feel better supported in their illness. Moreover, 88 percent of patients in the survey reported never having missed an injection without prior discussing this with their clinician.

[00:00:44] Dr. Christoph Correll Long-acting injectable antipsychotics, or LAIs, have other advantages over oral antipsychotics. In addition to markedly reducing or at least visualizing non-adherence, LAIs provide a stable blood level of medication, which avoids first-pass hepatic metabolism. LAIs also eliminate the risk of accidental or intentional overdose. Moreover, the risk of relapse and hospitalization is reduced and LAIs have been associated in several studies, including national databases, even with reduced mortality more than oral antipsychotics. Furthermore, because LAIs require regular contact with the clinical team, progress can be more closely monitored to identify early warning signs of relapse. In addition, since LAIs eliminate the possibility of covert non-adherence, treatment sessions can be used to discuss other aspects of care and a patient's life, and when relapse occurs, clinicians can focus on psychosocial issues, substance abuse, or other causal factors. 

[00:01:58] Dr. Christoph Correll Non-adherence to oral antipsychotic medication is one of the most common as well as preventable causes of a schizophrenia relapse. Research has shown that about 61 percent of patients with schizophrenia are at least partially non-adherent to oral antipsychotic treatment. In fact, early-phase and first-episode patients with schizophrenia who have the most to gain and the most to lose may be at particular high risk for non-adherence and related relapse. In a nationwide Finnish database study of 2,588 patients with a first hospitalization for schizophrenia, as few as 46 percent continued their initial antipsychotic treatment for 30 days or longer. 

[00:02:50] Dr. Christoph Correll Importantly, non-adherence is closely related to relapse risk. A naturalistic study that followed 876 patients with schizophrenia for one year after hospital discharge found that the relapse rate among adherent patients was only 21 percent, compared to 55 percent in non-adherent patients. One-in-five to one-in-two patients. In a survey of perceptions about medication use, patients with schizophrenia were less likely to agree that the good things about medication outweighed the bad, 61 percent of patients, than were psychiatrists, where 81 percent, or family members, 80 percent, said that the good outweighed the bad. However, patients who have tried LAIs often have a favorable perception of them, as do families and caregivers. Among those individuals currently receiving an LAI antipsychotic, as many as 73 percent reported a positive perception of LAI use, indicating again were more afraid of something we don't know about than learning about the benefits of something that we have experience. 

[00:04:08] Dr. Christoph Correll LAIs have been shown in multiple studies to be beneficial during first episode schizophrenia. Evidence suggests that although efficacy differences may not exist among oral non-clozapine and second-generation antipsychotic agents to a relevant degree, the injectable formulations have clear benefits over their oral counterparts. A recent study found that LAI treatment lengthened time to first hospitalization in patients with early-phase schizophrenia, and that many patients would try it when the treatment team was adequately trained to offer long-acting treatments. Additionally, in a real world, comparative nationwide database effectiveness study that included almost 30,000 patients, long-acting treatments and clozapine were the most effective treatments for preventing schizophrenia relapse. Re-hospitalization rates among patients receiving LAIs were 20 to 30 percent lower than for patients receiving equivalent oral formulations. 

[00:05:18] Dr. Christoph Correll Based on these accumulating data, the Florida 2019-2020 Psychotherapeutic Medication Guidelines for Adults with Schizophrenia recommend as a Level A strategy either continuation of an oral antipsychotic or even a pre-emptive or proactive switch from the oral to a long-acting injectable antipsychotic in first-episode patients with schizophrenia who are currently benefiting from and are currently adherent to an oral antipsychotic that works for them and that they tolerate well. 

 

EPISODE 5: SWITCHING FROM AN ORAL TO A LONG-ACTING INJECTABLE / STARTING AN LAI

[00:00:05] Dr. Christoph Correll Long-acting injectable antipsychotics, or LAIs, have the potential to reduce non-adherence, relapse, re-hospitalization, and even mortality, even among patients with first-episode schizophrenia and with comorbid substance use disorder, which are often hard to treat. Long-acting formulations can be a very powerful strategy in helping ensure that patients get the benefit of the medication they have been prescribed as the use of LAIs is more easily monitored than oral medications due to the nature of their administration to patients. Second-generation antipsychotic medications have been available as long-acting treatments since 2003. Several clinically proven LAI schizophrenia treatments are currently available, including paliperidone, aripiprazole, olanzapine and risperidone, and others are emerging. First-generation of antipsychotic LAI preparations, such as haloperidol decanoate and fluphenazine decanoate, have recently been compared with the second-generation LAI agents, and both formulations demonstrated comparable efficacy in preventing relapse. However, adverse effects and patient acceptability differ at times substantially, between first and second-generation oral antipsychotics, as well as long-acting injectables. 

[00:01:43] Dr. Christoph Correll LAIs differ regarding their initiation strategy, use of loading doses, or need for time-limited oral co-treatment, duration, and flexibility of injection intervals, in addition to the differences of the antipsychotic that the LAI formulation is based on. Patients should be offered the option of LAI antipsychotic treatment and should understand the logistics and the potential benefits of that kind of regime, as well as the potential side effects. To optimize outcomes, clinicians should employ shared decision making with patients that also involves motivational interviewing so that they understand that the treatment selection is there to help them reach their goals. Patients want to be involved in clinical decision making, but often feel uninvolved in the choice of their treatment. Those patients who have been allowed to take a more active role in the clinical decisions have clearly reported greater satisfaction with treatment, and relatedly, are more likely to accept the use of LAIs and be more adherent. 

[00:02:58] Dr. Christoph Correll Educating patients about the benefits of LAIs often results in greater acceptance. A 2013 study by Potkin and colleagues found that after clinicians address the issues causing patient resistance, more than half of the patients agreed to start an LAI treatment. Patients who started LAI treatment then reported perceiving more rapid symptom improvement and greater overall efficacy than they had experienced in the past with oral antipsychotics. Like their oral counterparts, LAIs vary considerably in the propensity to cause certain adverse effects that can interfere with patient acceptability and functioning, including sedation, weight gain, metabolic side effects, extrapyramidal symptoms and prolactin elevation, as well as related sexual side effects. And these differences can be used to guide the oral and then LAI selection that might be most appropriate to the given patient in front of us. 

[00:04:04] Dr. Christoph Correll Paliperidone palmitate is now available not only in a one-monthly and three-monthly, but also a six-monthly injection formulation, making it the first LAI antipsychotic agent to extend the dosing administration beyond the typical monthly or even two-monthly dosing interval. These longer duration formulations have demonstrated a low propensity for adverse events and a high rate of symptom remission, with reductions of positive and negative symptoms indicating meaningful functional remission. The reduced dosing frequency has a favorable impact on patient preference and diminishes the burdensome aspects of treatment, increasing patients' likelihood for treatment continuity, which is crucial. 

EPISODE 6: EXPECTED RESULTS

[00:00:05] Dr. Christoph Correll In general, long-acting injectable antipsychotics, or LAIs, are very well tolerated and efficacious. Relapse rates with LAIs have been shown to be significantly and clinically meaningfully lower than with oral treatment across actually all three available study designs, which includes randomized controlled trials, cohort studies where the clinician chooses either to use an oral or an LAI treatment, and especially in mirror image studies where the patient acts at their own control, which emulates clinical practice the most. We compare the time before we make a change to the time after we made the change, and in this case, the change is switching from an oral to an LAI medication. 

[00:00:55] Dr. Christoph Correll The superiority of LAIs across these three designs over oral antipsychotics is in large part due to the elimination of covert non-adherence and the reduction of non-adherence in general. LAI formulations of antipsychotic drugs offer additional advantages over oral medications. Evidence shows that LAIs are not only suited for situations of poor adherence, or when oral antipsychotics don't work and have failed, but also as an excellent option for first-choice treatment and long-term maintenance treatment. Database and randomized controlled studies favor the use of LAIs in early-phase schizophrenia patients, and time to first hospitalization is significantly delayed by treatments with LAIs. 

[00:01:47] Dr. Christoph Correll Maintenance therapy is pivotal in relapse prevention, and acute and long-term objectives must be linked early in the treatment of schizophrenia. In this context, the early use of LAIs is part of a preventive, as opposed to a reactive, approach as data indicate that relapses can seriously undermine the biological, psychological and social underpinnings of subsequent treatment success. 

EPISODE 7: STEPS TO TAKE IF BREAKTHROUGH PSYCHOSIS OCCURS OR RELAPSE CONTINUES

[00:00:06] Dr. Christoph Correll Relapses are serious events that alter disease trajectory and are most often related to non-adherence. However, symptomatic worsening can also occur during LAI treatment, also called breakthrough psychosis. Management options include ruling out or addressing medical illness or substance abuse or misuse as a contributing factor of breakthrough psychosis, addressing psychosocial stressors, optimizing nonpharmacologic treatments, treating medical and/or psychiatric comorbidities. We also need to ensure proper LAI administration technique and addressing missed LAI doses or a delay in the injection that is taking place, subsequently diluting the blood level. That can lead also to a lack of steady-state attainment, which results to then inappropriate low blood levels. Finally, we may have to add an oral medication to the LAI to check whether that is helping the patient so that at the next injection time point, we can then elevate the dose of the LAI. If we're already at the maximum dose, that could be the off-label practice of then shortening the injection interval to indirectly elevate the blood level, but again, after we have checked that the addition of oral medication of the same type as the LAI has improved efficacy and not reduced tolerability. 

[00:01:44] Dr. Christoph Correll If none of these strategies are successful, though, the patient might need to be switched to another antipsychotic, either an oral or ideally again in an LAI formulation, given the benefits of LAIs over oral treatments. Finally, inadequate treatment response to antipsychotics should be assessed clinically and ideally using a rating scale. This could include, for example, the one-item Clinical Global Impression Scale or CGI, or the more comprehensive but still short 6-item Positive and Negative Syndrome Scale, the PANSS-6, that both due to their brevity can be applied in clinical settings. If the clinical impression or either of these two rating scales reveals ongoing symptoms of moderate or greater severity, such as delusions, hallucinations, conceptual disorganization and/or disorganized behavior after at least six weeks of treatment with two different antipsychotics that are tolerated and given at a dose that is therapeutic, and if functional impairment of moderate or greater severity exists, then the patient can be considered antipsychotic treatment resistant. 

[00:03:04] Dr. Christoph Correll However, in order to rule out the so-called "pseudo-resistance," the TRRIP guideline group also recommended trying at least one LAI antipsychotic for three-to-four months to ensure continued presence of relevant psychosis, despite a short medication intake. Since a lot of the treatment resistant patients might be resistant because they are not taking adequate doses that they are prescribed. If treatment resistance is confirmed, guidelines recommend initiating low-dose clozapine treatment and titrating the dose upward while monitoring blood plasma levels until symptoms subside or improve sufficiently. If symptoms and functional impairment continue despite of adequate clozapine dosage, guidelines then recommend electroconvulsive or ECT therapy or augmentation of clozapine with another antipsychotic agent. 

PISODE 8: SUMMARY

[00:00:05] Dr. Christoph Correll Having reviewed the relative merits of long-acting and oral antipsychotics, let's check back in with our three cases. So let's think back about James, who had a mother who was very worried about another episode, who had been re-hospitalized, likely to not having taken the medication as prescribed, was beaten up by strangers because he was acting most likely strangely, and who may not be taking medication as he should. Plus, maybe weighed down by the interaction problems with the mother who belittles him by always checking on him. Would this patient not be able to benefit potentially from a long-acting treatment, taking away the conflict at home, assuring treatment, but also with his prolactin increase, having maybe less peak trough variation so that the prolactin levels will decrease, also. 

[00:01:01] Dr. Christoph Correll Let's now think about Joanna, what were her problems? She was on medication that gave her side effects, weight gain, metabolic abnormalities that are in the borderline range, but also feeling sedation and complaining that the side effects interfered with her daily routines. She is seriously questioning whether she should even take the medication, feeling fine. What we often see, then, is patients stop the medication and feel shortly better because the immediate effect of the medication is gone and they don't get a relapse right away. So they are lulled into the safe security that they can stop. Talking about a long-acting injectable can help the patient re-stabilize, who was just getting more easily agitated and preoccupied, who may run into trouble with other patients in the group home or even potentially lose the ability to live there or have to be re-hospitalized. So talking to her about the long-acting treatment option, finding a medication where she may not be as impaired by the side effects, and then linking the stability to the medication she's taking as a long-acting formulation, could help resettle the treatment plan into an area where she can remain stable and have an improvement in her functioning and quality of life. 

[00:02:26] Dr. Christoph Correll Now, let's think back about Tom. Tom is young, is 21 years old, he's in college, and he had this psychotic episode that really unhinged him. But he's back on track. He responded well, like many first-episode patients do. He's on a medication he can tolerate reasonably well, and he's really worried that he will have a relapse. What can assure being relapse free for the longest time? It is a long-acting treatment and is also a long-acting treatment where in a dorm environment, he will not be seen taking medications where the self-stigma and potential discrimination will not add to the stress that he wants to avoid to avoid further psychosis. Also, as we all know, in college environments, there is some marijuana or other drug taking, and in that environment, often the medication is not taken at the same time, bringing the risk for psychosis even higher. So here again, having the backbone and the seatbelt that we can give Tom to have a stability in the college environment, putting his mind to his studies rather than having to remember taking the medication would be a best start on the road to recovery and also success. 

 

About Christoph U. Correll, MD


Christoph U. Correll, MD
Professor of Psychiatry and Molecular Medicine
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Hempstead, NY

Christoph Correll is currently Professor of Psychiatry and Molecular Medicine at the Hofstra Northwell School of Medicine, New York, NY, USA and Medical Director of the Recognition and Prevention (RAP) programme at the Zucker Hillside Hospital, New York, USA. He is a board certified general psychiatrist and child and adolescent psychiatrist.

Professor Correll’s research and clinical work focuses on the identification, characterization and treatment of adults and youths with severe psychiatric disorders. His areas of expertise include the prodrome, first episode, multi-episode and refractory illness phase of severe psychotic and mood disorders, including schizophrenia, bipolar disorder, major depression, as well as aggressive spectrum disorders. He further focuses on the risk-benefit evaluation of psychotropic medications, including the extent and mechanisms of cardiometabolic and neuromotor adverse effects.

Professor Correll has authored or co-authored over 200 journal articles. He has served on several expert consensus panels on the use of antipsychotics across a range of psychiatric disorders, is a reviewer for over 70 peer-reviewed journals and an editorial board member of 11 scientific journals. He is the principal investigator or Steering Committee member of several large, federally funded grants and has received over two dozen national and international research awards and fellowships for his work.

Since 2014, the year of inception of this metric, he has been listed every year by Clarivate/Web of Science as one of the “most influential scientific minds” and “top 1% cited scientists in the area of psychiatry.”

SCHIZOPHRENIA RESOURCES

 

Schizophrenia Clinical Resource Center

Psychopharmacology Clinical Resource Center

The Use of Long-Acting Injectable Antipsychotics in Schizophrenia: Evaluating the Evidence (J Clin Psychiatry 2016)

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