 Schizophrenia is typically more than 1 illness. It is a constellation of signs and symptoms that come together to allow us to form a diagnosis. There are multiple groups of symptoms. First of all, the positive symptoms. Positive symptoms are sensory experiences in the absence of external stimuli.

Patients hear voices telling them to run over here or do this or do that. People may see things that others don’t see. I’ve had individuals who have said that they felt as if people were punching them and they could actually feel it on their body. Hallucinations are 1 of the important symptoms. There are delusions, which are false beliefs in the absence of external evidence. People may believe that they’re being followed or that they are in the CIA [Central Intelligence Agency].

Those kinds of delusions can be annoying for family members. Family members will often argue with people. Nobody is following you or trying to hurt you, which isn’t very helpful. So the positive symptoms include unorganized speech and behavior. People will not be able to get their ideas across. Their sentences and word structure might be confused and made up, and you’re not really able to follow what they’re saying. And then, their behavior may be unorganized.

They may engage in unusual rituals. They may be afraid to shower because if they go in the shower, they don’t know who will be there to get them when they get out, and they won’t be able to run away because they won’t have clothes on. There are positive symptoms that are dramatic with schizophrenia, and they will need an ER [emergency department] visit or to be admitted to the hospital. There are also negative symptoms. Negative symptoms are abnormal because they’re things that are absent that people should have. They’re either absent or diminished. People should have motivation, goals, and physical emotion on their face when they talk, social relationships, and physical activity. They might not shower as much. Negative symptoms are experienced when family members will encourage someone to please go out with them, and they won’t go.

They don’t have friends, and they spend a lot of time idle. They might wake at 2 PM, smoke a cigarette, have something to eat, and smoke another. If this behavior consists, life becomes so negative and can be very difficult to treat. We don’t have good treatments for them at this point.

Schizophrenia is characterized by cognitive impairments. This is true for multiple domains. The ability to pay attention that requires effort is impaired. If you tried to explain to someone how to take their medicine, it’s very difficult for them to understand. You have to be succinct.

If you tried to give them important information and there are a lot of distractions, they’re not going to be able to pay attention and understand information they need.

Memory is also impaired—memory for faces and for verbal information. It’s difficult to learn new skills without help. Lastly, executive functions are impaired. This is our ability to plan and carry out goal-directed activity. Understanding an idea and be able to know what comes first and what comes second. This is impaired in many individuals with schizophrenia.

Their judgment might be impaired. They have difficulty because of these cognitive impairments in functioning. They also have difficulty with what we call social cognition. Social cognition is our ability to make good guesses about what other people are thinking, what their intentions are, what they want from me.

People with schizophrenia can’t follow conversations and understand what’s expected. This causes a lot of difficulty in social relationships. All the cognitive impairments cause severe role functioning in many people with schizophrenia. Only 20% of individuals with schizophrenia have jobs in the competitive marketplace. Many people have low education, lower than you would expect by their socioeconomic status. The disability associated with schizophrenia is attributable to cognitive impairments.

There are multiple risk factors that are associated with schizophrenia. When a mother is pregnant during influenza outbreak, when there are birth complications of any kind, there is a higher risk to someone to have the child develop schizophrenia. There’s a genetic reason: schizophrenia tends to run in families. You inherit vulnerability, and those vulnerabilities become a problem when you’re exposed to a certain amount or kind of stress that you have difficulty coping with.

Vulnerability will come out in symptoms of psychosis. There is some evidence that individuals who use certain drugs when they’re in their developmental years, and they’re 13, 14, 15 and they’re using marijuana and psychedelic drugs that they’re more likely to convert to psychosis later than people who don’t use those drugs. It’s difficult to tell. It doesn’t happen to everyone, but it can be 1 of the risk factors. Stress, poverty, abuse, any kind of long-term stress can be a risk factor for people if it interacts with that genetic vulnerability.

Overview of Schizophrenia

 The differential diagnosis for schizophrenia is a challenge because there are many medical illnesses that can [resemble] psychosis. Many people are abusing substances that can produce psychotic reactions. The differential diagnosis is difficult at times, but the DSM [

Diagnostic and Statistical Manual of Mental Disorders

] criteria that we use are reliable and valid.

For uncomplicated cases, it is not that difficult for a psychiatrist to make a diagnosis of schizophrenia. It’s important to have a longitudinal perspective to understand the course of the person’s signs and symptoms, to make sure that it wasn’t just a transient episode of hallucinations or unusual thoughts but that it has been persistent and has affected the person’s functioning. Then we can be confident that we are dealing with schizophrenia. I recommend we maintain a longitudinal perspective and that we’re constantly reevaluating the diagnosis to make sure it’s right.

My preference would be that a specialist makes the initial diagnosis of schizophrenia and implements treatment. Subsequently, it could be taken over by a family physician or a general practitioner, but they are not necessarily trained to make a diagnosis. It’s a challenge to elicit the psychotic signs and symptoms and understand their course and their impact. I know there are some situations where a psychiatrist might not be available to provide that initial evaluation, but when a person with that specialty is available, it’s preferable that they at least make the diagnosis, start the treatment, and then provide recommendations to the general practitioner or family physician.

There are many unmet needs and challenges when we treat patients with schizophrenia. It’s an illness that can affect judgment and insight, and sometimes people do not understand the fact that they are ill. They don’t accept treatment. That can be a real challenge, and families often struggle with that. We also have effective treatments, so the medicines that we call antipsychotic medicines can be highly efficacious in alleviating the acute signs and symptoms of schizophrenia and also in reducing the risk of relapse, but they don’t have as much of an impact on the negative symptoms and the cognitive dysfunction that patients with schizophrenia can experience. Those symptoms can contribute to the functional disability that patients struggle with. An important unmet need is to develop better treatments for those domains: cognition and negative symptoms.

In addition, we do have some patients who don’t respond adequately in terms of the positive symptoms. A proportion of people are what we call treatment resistant even from the very outset of the illness, and we need better treatments to offer those patients.

Challenges for the Treatment of Schizophrenia

 Relapse can be diagnosed in a number of ways. It’s important to catch it early and determine early signs of relapse. Sometimes people will define 

 as, they went back to the hospital. Or their psychotic symptoms became significantly worse. If people’s voices become louder, more distracting and frequent, they have more difficulty ignoring them and start to act on their delusions. There are signs that definitely suggest that people are in the midst of a relapse. But again, you want to catch that early. You want to know if people aren’t sleeping. You want to know if people are undergoing extra psychosocial stressors in their lives, if something negative is happening in their lives. And if they’re under a lot of stress, you want to know about that because you could prevent it with psychosocial support so it doesn’t go all the way to a relapse.

It’s important to discuss relapse with patients and family members when they’re able to be with you because everybody needs to know what to look for. Typically, I talk to people, especially recent onset cases. People don’t understand the illness. They’ve been given an antipsychotic medication, and everything got better quickly. They’re clear of their psychosis, and they want to forget that that ever happened to them, that it’s never going to happen again.

They don’t want to hear about it. It’s important for them to know what to look for. To prevent relapse, they’re going to need to stay on medication for an extended period of time. They really don’t like to hear that, so it’s important to have a good relationship and talk about shared decision-making.

They need to be prepared in case this is 1 of those times where this is going to be a recurring illness. The key to this illness is to stop relapses. We need them to recognize when they feel uncomfortable and they start to think that people at work are talking about them. At those first signs, we need to talk about that, and we need to do something that will help, whether it’s medication related or working in a cognitive behavioral treatment to get them to look at those thoughts and see what’s real and what’s not.

Where is there evidence? Where is there not evidence so that they can prevent themselves from going back to the hospital or the ER [emergency department]? [We need to catch] signs early and not have those experiences that cause them to lose their job or drop out of school.

 There certainly is a concern. There are many reasons why we want to prevent relapse. There are many psychosocial and vocational reasons and health economic reasons, but there is also a concern that relapse may contribute to changes in brain morphology.  We know that for patients with schizophrenia, when they’re followed longitudinally, we do see changes in structural MRI [magnetic resonance imaging] with progressive brain-tissue loss after the onset of the illness. The feeling is that recurrent relapses can play a role in that. It may not be the only role, or the only factor contributing to that, but the concern is that it is 1 factor. It underscores the importance of trying to reduce the risk of relapse.

 Relapses are a problematic life event, and on many different levels, for people with schizophrenia. A relapse means that patients are taken out of their usual environments, they are insecure about reality and whether they can trust people, and often relapse leads to disruption of interpersonal relationships, sometimes problems with the law, but also hospitalizations. Hospitalizations can be quite traumatic for patients, particularly when they’re admitted against their will and where initially, some treatments are also given against their will.

Quality of life has to do with being able to do things you want to do and being able to enjoy yourself. When you’re having recurrence of psychosis, when you’re in a treatment setting that is very restrictive, surely quality of life suffers. But quality of life is determined by not only psychosocial context, being able to do something meaningful with your life, and adequate self-care but also how you feel about yourself. And a relapse can highly undermine self-worth and lead to self-stigma and also be the beginning of a downward spiral of chronicity and hopelessness in patients who start seeing themselves as being chronically ill and being basically victims of the illness.

In this context, multiple relapses erode both the psychosocial fabric and any economic opportunities that patients have. We know that the recovery in people with schizophrenia is still far too little achieved. Only 13.5% of people with schizophrenia in 1 big meta-analysis were shown to achieve recovery, which means adequate self-care and psychosocial context but also doing something meaningful, including education or work, even work that is voluntary.

The problem with relapses is that people are taken out of their work or educational environments. That with each relapse, a subgroup of patients becomes treatment refractory. One in 6 to 1 in 7 patients will not respond as well anymore, will not be able to return to a meaningful psychosocial and economic situation, and also their contact with the educational and vocational system is disrupted. Finally, relapses can also reduce the gray matter in the brain, thereby making less brain available the cognitive and psychosocial and vocational rehabilitation.

Schizophrenia: Relapse Prevention and Adverse Effects

 Adherence to medication is important for a number of reasons. First of all, if the doctor doesn’t know what you’re taking and you’re not doing well, they’re going to give you more. They’re going to increase your dose, they’ll add something new, or they’ll switch medication. If they don’t know what you’re taking; it’s a problem for you and for them. The other reason that you want to be adherent is because you want to prevent relapse. Taking your medication regularly is the most important thing you can do to prevent the recurrence of symptoms. It forms the basis of your recovery. If you have to keep going back to the hospital because you’re not taking your medicine, there are a lot of consequences. You may have to quit a job or drop out of school. And you can’t receive any traction in your recovery. Medication forms the basis so you can work on the things you want to work on in your recovery. It’s important to take your medication. With somebody who has recent onset of psychosis, I will often say there is going to be a time when you’re going to think about going off this medicine. Or they’ll bring it up first. How long do I have to take this? And I’ll tell them it’s important to stay on, and these are the reasons. But if you’re going to go off, you need to tell your mom and your dad and your dog and your friends. Do you want to go all the way back to the hospital? Or do you want to go all the way back to where you’re running in the street because you’re afraid? Or do you want to catch this early and then at the first sign of hearing a voice or feeling that other people might be out to get you, you want to go back on? And if you let it go all the way to be very ill and having a relapse, what hospital do you want to go to? How do you want your parents to deal with it? Do you want them to call the police? What should they do? Let’s plan it out, just in case. And that’s the approach I take.

The psychiatrist will come to me and they’ll say, “You have to make this person take their medicine.” Unfortunately, it’s ultimately their choice. I’ve always had an open dialogue with people I work with, and I find that after a couple of weeks, most of them will go back on. But we increase our appointments. We make sure that we’re monitoring things. But first of all, I tell them it’s not the best idea.

 Monitoring adherence is very difficult. Clinically, what you do is obviously a simple question. Usually, clinicians ask, have you taken your medication? Obviously, this question prompts a yes in over 90% of cases, because patients don’t want to contradict you. Even if you rely on this very unreliable self-report, start asking how many medications, how many doses have you not taken since I’ve last seen you. That signals to the patient you’re aware that this can happen. You don’t feel like the patient is attacking you or not doing what you want them to do. It is more like nonadherence is part of the human condition. That’s what I would tell patients, that I would rather know about it and then discuss with the patients what to do about it than not know about it.

How do you supplement this self-report? Well, you ask informants. In patients who have very doubtful adherence, you might ask them to actually check on the patient, to check that the family members or caregivers hand out the medication. But that can lead to a lot of dispute, where patients feel infantilized and not able to do what they would do was an adult.

Another way to measure adherence is to ask the pharmacy whether the patient has at least picked up the medication. In large pharmacy record studies, you would do a medication-possession ratio, where you need at least 80% of the doses to be picked up. But when patients pick up the medication, this does not assure they have taken them.

For antipsychotic blood levels, therapeutic drug monitoring is another way of monitoring adherence. But that is complex and tells you only whether something is in the blood or not. If it’s zero, you know there is full nonadherence. But if there is some blood level, you don’t know. Is the patient taking every other dose? Had they stopped for 3 weeks and now they’re taking it just for another couple of days? Or they’re just taking it because they know there is a blood draw coming. We need better measures of adherence.

There is an ingestible medication event marker, where a biodegradable chip is inserted in the aripiprazole pill and then a signal is emitted from the gastric content when the patient swallows it, to be emitted to a sensor worn on a patch. This is another way of potentially measuring adherence.

The only 100% measure of adherence is prescribing a long-acting injectable. You will know the month, the week, the day, the hour when a patient becomes nonadherent. And you can do something about it. There is also a window of opportunity to get back to the patient while there are sufficient blood levels in the system.

 We know that the medication the person has been prescribed can also influence adherence and nonadherence. When we were using first-generation antipsychotics, we did see a fairly high incidence of neurological adverse effects. A drug-induced 

 , dystonia, akathisia, and so forth. With the second-generation drugs, we’ve seen a significant reduction in the risk of those adverse effects. It’s not completely gone, but there’s a significant reduction even with tardive-dyskinesia, which is a more long-term adverse effect. Our analyses of the existing data suggest that the risk of developing tardive-dyskinesia with the second generation or atypical antipsychotics is about one-fifth of what it had been with the first-generation or typical antipsychotic drug. That’s a significant improvement, and those reductions in adverse effects can also play a role in facilitating adherence because patients will stop taking their medication if they’re experiencing adverse effects. Some of the newer medicines are associated with metabolic adverse effects, weight gain, changes in lipid metabolism, and so forth. We have to be mindful of that.

Most medicines are going to have some adverse effects, we need to have a good understanding of how those adverse effects are affecting the patient we’re treating and how that might influence their willingness to actually take the medicine on a long-term basis.

Schizophrenia: Treatment Adherence

: Psychosocial treatments for schizophrenia are important. There are a number of treatments we use all the time for schizophrenia. The first one we developed at San Antonio [at the University of Texas Health Science Center] called cognitive adaptation training. This helps bypass the cognitive impairments that are often present in schizophrenia. We go into the home, and we help people set up their medication, and reminders to take their medication, like a voice alarm that says, “I want to take my medication because I want to get a girlfriend, or I want to apply for jobs.”

When they're recovering, we tie their goals to taking medication. We set up reminders, signs, and checklists for many activities. When they're taking showers, dressing better, and becoming more social they will receive a better reaction from others. Then they start to have a secondary gain. This intervention is important. Another one is cognitive behavioral therapy [CBT] for psychosis.

We work with people to look at the evidence. What is the evidence that when people cough or sniffle that they're having some kind of communication that only they understand? What are all the reasons that people might cough, sneeze, or sniffle? They can respond that maybe they smoke cigarettes, or they have allergies. And suddenly, there are more reasons. They're broadening their frame of reference, and it's not just a secret communication that people are having. Cognitive behavior therapy can be effective, and you can do behavioral experiments where you go to the community with someone who's afraid to take the bus because people are going to hurt them on the bus. When they ride the bus they look down, and they don't see anybody because they're afraid. You would then encourage them to look up and look around. Some people on the bus are scary. But there are many people on the bus who are smiling, or children playing their video games, who have no clue that you're even there. Maybe those people don't want to kill you. Now, only half the people on the bus want to kill you. This helps to chip away at delusional thoughts. Also, CBT is good for helping people to deal with persistent hallucinations. They use techniques to help cope with hallucinations, either by distracting themselves or by focusing on the hallucinations to control them. Can I make them louder or softer? Whatever works to help them gain a sense of mastery.

I would never recommend psychosocial treatment in the absence of pharmacotherapy for psychosis. The medication forms the foundation for recovery, and you need to have that in place so that people are stable enough to build on that. It's difficult to do cognitive behavioral therapy for psychosis with someone who is so psychotic that you can't even get them to calm down and focus. It's very important to have the medication on board to give people space and room to be able to think about things in a different way.

Psychosocial Treatments for the Management of Schizophrenia

: We have a broad range of oral medications. There are many that have been approved by the Food and Drug Administration. They differ largely in their adverse effect profile. They’re similar in terms of efficacy with the exception of clozapine, which is approved by the FDA for the treatment of treatment-resistant schizophrenia and patients with suicidality. The other nonclozapine drugs are similar in efficacy. We would make some distinctions based on adverse effects and the individual patient, what adverse effects are they vulnerable to and are most concerned about?

There are many challenges in using oral medicines. The most significant is the fact that patients have a difficult time taking oral medicine on a long-term basis. That’s true in any chronic illness, not just schizophrenia, whether we’re talking about diabetes, hypertension, epilepsy, or asthma. Everyone has trouble taking medicine on a regular basis, and when we use oral medicine, we’re not sure whether our patient is taking them. I’m a believer in the use of long-acting formulations because we can feel more comfortable in the knowledge that the patient is getting the medicine. 

With oral medicines, we don’t know. The way we try to find out is by asking the patient if he or she is taking the medicine, and they’re not always in a position to report accurately. I know when I’ve been taking medicine, there are times when I’m not sure whether I took it that morning or not. I forget, so imagine someone who is struggling with an illness like schizophrenia, it becomes more of a challenge. 

One of the biggest challenges with oral medicine is that we don’t know exactly how adherent the patient is, and that leads to confusion to determine is the medicine working or not? Is the patient having any [adverse] effects or not? That can happen if someone stops taking their medicine for a few days and then decides to go back on it again, suddenly they have an [adverse] effect they didn’t have before and it can get confusing. Those are some of the challenges with oral medication.

: Dose adjustments and frequency of oral medications have a relationship to adherence. We know the more complex a treatment is, the more doses per day are needed, the more complex it is for the patients to follow, who often have cognitive problems, who may be ambivalent about taking the medication, and may not have a caregiver with them when they need to take the medication. The less medication that needs to be taken, and the less often, the better. Long-acting injectable formulations reduce the ingestion of medication from 3 times, 2 times, or once daily to once every 2, 4, 6, 8, or even every 12 weeks.

The simplicity of long-acting injectable medication treatments reduces the time that patients can be ambivalent, or reject or forget, so the adherence is higher with long-acting injectables than with oral medications. Patients have to only consider whether they want or don't want to take the medication every 2, 4, 6, 8, or 12 weeks. Since nonadherence is immediately visible to both the patient's prescriber, but also to family members, if they can be reached, patients can be brought back before relapse occurs, and adherence is more likely assured, even in patients who are trying to stop the medication.

Use of Oral Therapy for the Management of Schizophrenia

: The 2004 guidelines that the APA [American Psychological Association] published for the treatment of schizophrenia underemphasizes the potential value of long-acting injectable formulations. They indicate they are  reserved for patients who demonstrated nonadherence by relapsing multiple times. That is a conservative approach. Once someone has already experienced relapses due to nonadherences, we’ve lost the battle. We want to prevent every relapse we can because the relapses can be so devastating. I’m not saying we can prevent 100% of relapses.

When someone is receiving a long-acting injectable formulation, there still is risk of relapse or breakthrough, but we can reduce the risk enormously. We should be less conservative in the use of long-acting formulations because there is no reason not to use them. There are no disadvantages in terms of [adverse] effects, so we should be asking ourselves why not use them? I’m hoping that the new APA guidelines, which have not been finalized yet, will have a more proactive approach to the use of long-acting formulations.

We’ve provided feedback to the APA regarding this issue. I hope they’re going to respond to some of the suggestions that we’ve made, but I have not seen a final draft.

: The National Council for Behavioral Health [NCBH] has developed guidelines for long-acting injection, which I support. I have been a big fan of long-acting injection since I used to do NIH [National Institutes of Health] trials. We would go to people’s houses and they had no idea how they were supposed to take their medication. I’ve been a proponent for long-acting injection. The council's guidelines suggest that you need to use long-acting injection earlier and more often, and long-acting injection can make sure that the medicine is getting into the person. It can ensure that they're able to have stable medication so that they can work on their recovery. The council guidelines suggest using it with recent onset, first episode patients. They suggest using it with anybody who prefers a long-acting [medication], anybody who has trouble taking medication daily, which is a lot more people than I think many providers recognize. Providers have a hard time recognizing who's adherent and who's not adherent. I recommend the guidelines of the National Council for Behavioral Health. I’d ask my patients, “Do you want a pill? Do you want an injection? These are the pros and cons,” and they could make a good choice about it.

Guidelines for the Treatment of Schizophrenia

: Long-acting injectable [LAI] medications, antipsychotics, have multiple advantages. Multiple studies and meta-analyses have shown that compared to oral medications, there is less chance of relapse with long-acting injectables, less risk of hospitalization. Patients have lower symptom levels. There is less exposure to medication because there's less peak-trough variation in terms of the exposure, which can also potentially reduce some [adverse] effects. Because there are fewer relapses, there is less secondary treatment resistance that can ensue. And mortality rates are lower. That's quite a package of advantages. If you told anybody, “Do you want treatment A or B, and B has all of these advantages,” everybody would say, “I want B.” But then the question is, “How is it given? Write the prescription for me.” “It’s not a prescription of an oral medication, it is an injectable.” “I don't want that.” “Well, let's discuss what the advantages are.”

When initiating a long-acting injectable, most of us want to know, at least for a period of time, that the oral formulation of that medication is both tolerated and efficacious. When we put together an expert panel, it was not clear among the experts and clinicians how long this initial period should last. Should it last just 1 or 2 weeks, when most of the initial adverse effects occur? Should it last 3 or 4 weeks, when you might be seeing more of a response? Or is the 2 week timeframe, when you see some response, sufficient?

Whatever the decision of the clinician is, knowing the patient, the acuity, or also the time that one has available to stabilize patients orally, it is important to move over from the oral formulation to an LAI. It’s easy when you come from the same drug that you’re testing out to the LAI, because there are dose levels that you can adjust. Some medications require booster injections. For example, paliperidone has a day 1, day 8, and then 1 month later the injection. Olanzapine pamoate has shorter injection intervals of 2 weekly or higher doses initially. Those do not require oral cotreatment.

Similarly, aripiprazole lauroxil has come out with a smaller dispersion formulation where you give 2 injections on day 1 and 1 oral dose of 30 mg, and thereby also obviating the need for oral cotreatment. Currently, risperdal consta, which is given every 2 weeks, requires for the first 3 weeks oral cotreatment with risperidone. And aripiprazole maintena requires 2 weeks of oral cotreatment. This could be a gap time where you're not sure whether the patient is taking it while the blood level is still rising. It’s important to make sure that family members can supervise the patient during that period, or that patients are in a setting where it's assured that they take the medication.

Some medications can also be switched from another oral medication directly to the LAI formulation. This is when you have knowledge that the medication was tolerated orally in the past and could have led to improvement. It’s important to know the differences of the pharmacology. If you come from a very tight D2-binding agent, be it haloperidol or fluphenazine, the first-generation LAIs or oral treatments, or you come from risperidone to a partial agonist, or you come from very sedating anticholinergic agents from olanzapine, clotiapine, or chloropromazine, then to an LAI, you would want to overlap in both these scenarios when the other drug is not so tight binding, or a partial agonist, when the new LAI is with a medication that is not as sedating or anticholinergic. You don’t want to abruptly stop the initial medication. That could lead to potential rebound phenomenon when you stop it too abruptly. An overlap and a slow taper of the initial medication can be helpful.

Switching From Oral Therapy to Long-Acting Injectables

: I take a different approach than asking what factors I consider in choosing a patient for LAIs [long-acting injectables]. I recommend everyone use an LAI. What are the contra-indications? It’s a treatment that’s appropriate for everybody. The first decision that the clinical team has to make is if medication is indicated. Are we confident in the diagnosis? How do we ensure that the patient is going to benefit from the medicine? We should be using a long-acting formulation whenever we can so we are confident the patient will benefit. Sometimes people are confused that it means I’m forcing the patient to take medicine, or I’m taking away the patient’s autonomy. Those arguments don’t make sense because we’re trying to help the patient achieve more autonomy by getting control over his or her illness. We’re not trying to control the patient; we’re trying to control the illness. I’d ask, why not use a long-acting formulation?

If a patient has a contraindication to the drug that I’m using then, yes, that might be an obstacle. There are some people who are frightened by injections. They’re in the minority. In my experience, people who are frightened by an injection after they’ve tried it once they say, “Oh that wasn’t so bad.” My strategy is to get the patient to try it once or twice to see how they feel. There aren’t any strong contraindications for the use of a long-acting formulation. Patients should be receiving it early in the course of the illness. Someone who has just been admitted for their first episode should receive a long-acting formulation when they leave the hospital even if they’ve only had 1 episode. As long as we’ve made a decision that medicine is indicated, then why not give it in a way that the patient is most likely to benefit? It’s ironic because there are many areas in medicine where they don’t have long-acting injectable formulations, and I know many of the clinicians treating patients wish they had long-acting formulations. Many of the patients wish they had long-acting formulations. We’re fortunate we do have them; we should take advantage of them.

We’ve been successful. A lot of it has to do with how you communicate this to the patient, and unfortunately a lot of clinicians are not great at communicating the potential benefits. They may be resistant themselves to the idea or uncomfortable. I’ve heard clinicians say, “I’m afraid I’m going to interfere with the therapeutic alliance if I suggest to my patient that he take a long-acting injection because I’m saying, I don’t trust him to take his medicine.” I don’t think that this interferes with the therapeutic alliance; LAIs can enhance it if we can spend more time talking about the patient’s problems rather than discussing their medicine. When someone is on oral medicine, you end up spending part of each session asking if they missed any of the medicine. That can be avoided if someone is taking a long-acting formulation.

: I talk to people about LAIs the first time they come to me. If they're in a recent episode, or if they’ve been seen in the community for many years, I find that there are people who aren't aware that LAIs are a choice. And why shouldn't they have that choice? I bring them up in the context of recovery roles. Instead of saying I have this injection, which is never going to work, I say, “It doesn't seem like you're doing as well as you'd like to be doing. You want to take better care of your animals? I have a medicine that might help with that. Are you interested in hearing more?” And they always say yes. I let them know, “You only have to take this medicine every month, or every 2 or 3 months. Are you interested in hearing more?” Now they're really interested in hearing more. And then I say, “You would come into the clinic and we would give you an injection.” Some people will say, “No, I don't like shots.” I don't like shots either. I don't know a lot of people who like shots. The issue is the amount of time it takes to get any injection, like a flu shot, the pain compared to the protection that lasts a very long time. The same with schizophrenia.

Consider the pain of a relapse. How much trouble is that going to cause? You have to weigh the pros and cons before you say no. I point out that studies show that on a scale of 0 to 100, the pain of an injection is below 10. “Do you think you could handle that?” Usually, they can. “Maybe you want to give it a try for a few months. Try it for 6 months. See what you think and we can talk about it again.” If they say no, I don't stop there. I bring it up again because I think it's a valuable tool to set the framework for somebody's recovery. If you tie any medication to what the person wants, it's easier for them to be accepting. I haven’t found difficulty trying to get people to accept long-acting injection.

I follow the protocol guidelines that are presented by the APA [American Psychological Association[ or other organizations for initiating long-acting injectables. I find there are some prescribers who use a lot of long-acting [medications] and some who use little. We've done a lot to try to get our prescribers in our organization to use long-acting injections. In the clinics I'm affiliated with, we use a checklist to identify people who aren't doing well. Maybe they've been in the [emergency department], a hospital, or they don't have good control of their symptoms. Or they tell you, “I missed a few doses here and there.” Chances are, they missed more than they remember. Have you tried multiple antipsychotics with them? Are they on more than 1 at once? Any of those things are red flags. It's a simple checklist with 5 questions.

If you answered yes to any of them, offer a long-acting injection. This reminds them of LAI and to make the patient an offer. We found using a checklist does improve or increase the use of long-acting injection. We also have used a patient facing video. It’s a video about decision-making. What's your role in shared decision-making as a patient? You need to tell the doctor certain things. You need to ask questions. And you need to make a choice. How do you make a choice between tablets and long-acting injection? The video discusses the pros and cons. When we show that video, many of the individuals will go in to their provider and ask about using long-acting medication. “Is this a good idea for me? Let's talk about it.” And they start the conversation. If you hit it at both of those angles, you're more likely to be able to increase long-acting injection use.

Initiating LAI Therapy for the Treatment of Schizophrenia

: Risperidone can be given as Risperdal Consta, which is micropsheres. This is given every 2 weeks as an injection. When initiating, since it takes a longer period until Risperdal Consta reaches therapeutic blood levels, there is a 3-week period where oral risperidone needs to be given. The safety and efficacy of Risperdal Consta is similar to that of risperidone oral. The efficacy has been demonstrated, leading to FDA approval.

Aripiprazole is delivered in 2 different forms. There is [Abilify] Maintena, which has a once-monthly injection. You start at 400 mg in all patients. And only in those patients who have tolerability issues, studies show it's less than 10%, you might be able to go down to 300 mg once monthly. Like with Risperdal Consta, there is a lag time until therapeutic levels are achieved. Here a 2-week time frame with oral aripiprazole between 10 and 20 mg is required.

There is also aripiprazole lauroxil, which comes in different dosages. Depending on the dose, it can be given once every 4, 6, or 8 weeks. If it's 6 or 8 weeks, the overall dose that is achieved in the blood is closer to 10 or 15 mg, maybe 20 mg, whereas if you have monthly injections, you can go up to an equivalent of 30 mg.

With the usual injection of aripiprazole lauroxil, there is a 3-week period that is required when oral aripiprazole is coadministered until the lauroxil formulation reaches its therapeutic blood levels. With the new formulation, the lauroxil reaches blood levels that are therapeutic within 2 or 3 days. There is only 1 dose of 30 mg oral aripiprazole required, and no further oral coadministration is needed.

: In the case of paliperidone, we have 2 different injection intervals, there is the once monthly and every 3 months. You start on the once monthly, and then once someone has demonstrated their response and stability on that after a few months, then you can switch to the every 3 month injection. It varies from patient to patient, but people taking an injection once every 3 months is a tremendous advantage. It eliminates a lot of burden if I can say to my patient and his or her family, “You only have to come and have an injection 4 times a year,” that’s a very low burden. What confuses people at times is they think that’s going to determine the frequency with which the patient is seen by a mental health professional. These are 2 different issues. When you receive your injection is 1 issue, and how often you see your therapist, group therapist, or your rehabilitation counselor, that’s a different question. They don’t have to be linked.

Having less frequent injections can be very helpful for people. You don’t have to remember to take pills every day and you know that you’re covered. The families are in favor of this because they don’t have to worry. If you have had a family member who has had a psychotic relapse, and you’ve had to call the police to take that person to a hospital potentially against their will, that’s a really traumatic experience for everyone, for the patient and the family. When that person improves and leaves the hospital, it’s understandable for that family to be very concerned about whether that person is taking his or her medicine. That can lead to family conflict, and if someone is receiving a long-acting formulation, then that’s not a necessary conversation. I think the families feel relieved when someone is receiving their medicine via that route.

There have been a number of studies. The one referred to demonstrated that in patients who had only been ill for 5 years, the long-acting injectable formulation of paliperidone was associated with a significant reduction in negative outcomes. There are several studies that have been done in first-episode and early phase patients that show that the use of long-acting formulations can be very powerful in reducing the risk of relapse and hospitalization, even in someone who has only had 1 hospitalization for schizophrenia.

It’s important to recognize that we can have an impact on the early course of illness, and reducing the risk of relapse at that point is particularly critical. If you think about a young person who has had 1 psychotic episode but is now feeling much better and going back to school or back to work, if that person has another psychotic episode and has to be hospitalized again, that can lead to tremendous disruption in their trajectory in trying to get back to a relatively normal life. At an early age, even 1 or 2 relapses can lead to a erosion of life opportunities, and we want to avoid that particularly in the early stages of the illness. That’s when we have a chance to facilitate recovery, so we want to work hard to avoid any possible relapse if we can.

Management of Schizophrenia and Available LAIs

: There are many advantages of long-acting injectables [LAIs] over oral treatments. These advantages in meta-analyses and in database studies are the greatest the more generalized and clinically relevant the samples are. Why are long-acting injectables not prescribed more? When you ask clinicians, “How many patients who see your colleagues do you think will be nonadherent over the next year or so,” they say between 50% and 70%. That is the number that we see in the studies. But still, in the United States, only 10% to 15% of patients get long-acting injectables.

Why is that? There is a disconnect when we see that long-acting injectables reduce the risk of relapse, the risk of hospitalization, and even prolong life. And not just to reduce the suicide-related mortality, but there is a lower risk of mortality that's associated with cardiovascular illness because patients are not as sick, they see their doctors for secondary prevention, they have a healthy lifestyle. Why are clinicians and patients not jumping on this? When you ask clinicians, they say, “My patients are adherent, why would I need to use it?” Their colleagues' patients are not, but our own patients are. We’ve seen in multiple surveys that [clinicians] overestimate adherence in their own patients.

Clinicians often say, “I would like to, but 80% of my patients say no, I don't want an injection.” When studies are done, it seems that 80% of patients have not even been offered an LAI. How can they reject it? It's a complex web. Yes, there are patients who say, “I don't want a needle; I'm needle-phobic, or I don't like the pain.” But if clinicians believe this is one of the best treatments we have and sell it to the patient, do motivational interviewing, share decision-making, and make sure that patients understand, if you want to achieve your goals, then clinicians need to listen to the patient's goals. “If you don't believe me, then maybe talk to Peter, who also didn't want that in the beginning, but now he's a peer counselor because he's doing so well on this treatment.”

There are multiple reasons why clinicians can't or do not want to offer LAIs. One big one in clinical care is time, because patients are seen very quickly. Writing a prescription is very fast. Having to explain why an injection and what's different, what's the advantage, and how is it done, that takes time. Psychoeducation is not a 1-shot deal. You can start it, talk to family members, and then revisit it later down the road.

Clinicians are sometimes afraid that they might undermine the therapeutic alliance. Patients might be adherent now, which is fine. Why would I then say, “You need an LAI, as if it's punitive, or you are lying to me. You're not taking the medication.” I would rather describe that as I take medications, and I don't always take them myself. It’s part of the human condition. “Don't you want to have a safety belt against this illness in order to achieve your goals?”

I think clinicians need to appreciate the data and that patients who are on LAIs like them. Data suggest that clinicians and nurses overestimate the issues that patients might have with LAIs. When you ask patients who are currently on oral treatment, they see fewer problems than clinicians. When you ask patients who have actually tried it, they have even fewer problems.

We did a study, the PRELAPSE study. It was a cluster randomized study to see if an LAI paradigm in first-episode and early phase patients beat in other clinics the oral paradigm. We trained treatment teams, everyone—doctors, nurses, psychologists, and caseworkers. And then we did role-play with them, frequently asked questions, gave them the data, but also the competence and the proficiency, and had the team aligned: “This is the best treatment we have.” It was astounding that in those patients, first-episode and early phase patients within the first 5 years who reached the sites and were offered, “We want you to be part of a study;” cluster randomization means the site is randomized so the patient doesn't have to decide between treatment A and B. They just agree, “Can I be assessed as part of the study?”

We told them, as part of the study, you will be offered an LAI at one point and 14.4% said, “Leave me alone. I don't want to be convinced because there is a needle involved.” We couldn't talk to them any further to convince them over time. But a lot of the people who said, “OK, let's see how it goes,” 91% received at least 1 injection within 3 months. 

those who didn’t receive an LAI, which leaves you with 76%. Three out of 4 patients with early phase schizophrenia within the first 5 years and first episode can be given, and accept and will try, will trust a team, and will try an LAI. That was an eye-opener and a lesson. We need to lower our own objections to the LAI treatment and not say that it's always the patients who have this objection.

Overcoming Barriers With LAIs in Schizophrenia Management

: When providers aren't cognizant of relapse very early in the treatment of schizophrenia, it's a problem. People should always understand that this doesn't have to be a chronic relapsing condition. People are having 8 or 9 relapses on average within 5 years. That's unacceptable. In any other field of medicine, we would not be complacent and accept that. We need to be aware of relapse from the beginning and work very hard to prevent it. It isn't good for your brain to have a psychotic relapse. It isn't good for your role functioning to have a psychotic relapse. We need to do everything possible to prevent it, and consistent medication can prevent that. If someone misses oral doses of medication and stops taking them and doesn't come to see you for a month, they're already likely to be in the midst of a relapse. You can prevent that from happening if you know they didn't show up for their shot today. Let's do some outreach. Go find them. Let's go talk to them. You can stop that inconsistent use of medication much earlier because you know when it starts.

It’s important to do what you can to prevent relapses. An LAI [long-acting injectable] is one of the most important tools we have as providers. LAIs keep people on consistent medication so that they can stay stable.

: Patients and families should be aware that this is an option, but I would suggest that it should be presented as not just an option, but it should be presented as a recommendation. If we say to somebody, “This is the way we treat your illness. This makes the most sense to treat your illness.” It’s similar if you go to a cancer hospital, the likelihood is that they will offer you a protocol and they’ll say, “This is the way we treat your type of cancer.” Most people will respond to that by saying, “OK, I appreciate this recommendation.”

We need to take a similar approach when we treat schizophrenia and say, “This is the way we recommend that your illness be treated.” In my opinion, a long-acting formulation should be part of that, and it changes the nature of the dialogue. It creates a routine, and it gets back to the conversation that if the medication is indicated, and if we want the person to be on that medicine for a relatively long period, a year, 2 years, then we should be thinking about how can we ensure that the person gets the benefit of the medicine.

There are a number of studies that show in first-episode patients, after they leave the hospital, they stop taking their medicine. More than half of them have stopped taking their medicine within a few months. But if someone is on a long-acting formulation we have a better chance of keeping them on their medicine, or at least we’ll know when they stop it. Another problem with the oral medicine is we don’t know what’s going on because it’s very hard to tell. With long-acting formulations, if someone misses their injection, you know it and you can do something about it. You can call the family, do a home visit, do whatever you think is necessary, so that alone is an important advantage.

The advice I give physicians is to think very hard of the advantages of long-acting formulations and try to overcome some of the biases that we occasionally hear. A physician might say, “I’m pretty sure that my patient is adherent, so I don’t need to think about a long-acting formulation.” You don’t really know for sure, and if your patient is adherent this week, that doesn’t mean they’re going to be adherent next month or 2 months later. We’re going to have much less anxiety about the treatment if we know it’s going to be delivered through long-acting formulations.

Also, some clinicians think they’re going to interfere with a therapeutic alliance if they offer or they suggest a long-acting medicine. That somehow that’s insulting or it’s punitive. We’re not punishing the patient; we’re just offering them what we think is the best treatment. We have to destigmatize nonadherence. If someone has trouble taking their medicine on a regular basis, that doesn’t mean they’re a bad patient or a bad person, it just means they’re a human being. We all have trouble taking medicine on a regular basis. The question is what can we do about that? Let’s recognize the fact that nonadherence is human nature. It’s very common, so what can we do to ensure that someone gets the benefit of the medicine?

We’re fortunate that we have some options. We have different medicines that are available in a long-acting formulation. The advice I would give to clinicians is to think about what we’re trying to do here. We’re trying to prevent relapse, we’re trying to help people recover, and we’re trying to ensure that they get the benefit of the medicine that we’ve prescribed. We have to do that in a very proactive way.

Early Initiation of LAIs in Treating Schizophrenia

: The North Carolina Psychiatric Association recently put out guidelines about what to do about LAIs [long-acting injectables] and COVID-19 [coronavirus disease 2019]. I've had this question from many of our providers, “Should I just switch everybody to oral so they don't have to come in?” Switching people to orals is not going to keep them from having contact with health care providers. In fact, doing that is likely to increase their risk because they're not used to taking oral medications. They don't have a habit of taking their medications. They may not be used to taking oral medications. It puts them at risk for hospitalization if you're suddenly going to take them off of an injectable medication. It's very important to be safe about how you do it. Make sure all the guidelines are followed and you have masks and all the things that you need to do this safely. But it’s very important for people to get their injections.

Then you know that for the next month or the next 2 months or the next 3 months that they're covered on their antipsychotic medication. It’s important because in COVID-19, people may not want to go to the pharmacy and pick it up. Mail delivery has been slow. They may not get their medicine in time if it's mail delivered, and then they have a gap and they're at risk for relapse. It’s important to consider the whole picture and not to jump to conclusions about we shouldn’t see people and put them on long-acting injection. You have to weigh the risks and benefits. The risks to me always seem greater if people with psychotic disorders like schizophrenia are not covered with medication.

: Long-acting injectable antipsychotics have various advantages. But another one is that there is less clinical contact needed, and you still can be certain that patients are covered, particularly in these very difficult times of COVID-19. In this pandemic and the interruption to access of care, we need video assessments, but also patients being quarantined and not being able to go to providers, pharmacies, or get their oral medication. Long-acting injectable treatments can be a very valuable tool to assure that more patients with schizophrenia get the medication that they need. Even if there is a gap, the gap is not 7 days after the oral treatment is gone, and the blood level is zero. It takes weeks for that patient to go back after the quarantine or after an interruption of care and get their injection without too many disruptions and with a low risk of relapse.

: The COVID-19 pandemic has underscored some issues. In my hospital and others in New York, we have been very concerned about people staying at home, so if you have been receiving a long-acting formulations, you don’t have to go to the pharmacy to get your prescription. You can come to the clinic infrequently, whether it’s once a month, or once every 2 months, or 3 months. That can enable you to be safer.

We’ve been recommending for our patients who are being discharged from the hospital now that clinicians consider using a long-acting medicine, so the patient doesn’t have to come back to the hospital right away, and we know that they’re getting their medicine. This is a time that makes everybody vulnerable to isolation, loneliness, to many issues, whether it’s unemployment, family disruption, even loss and grief.

We’re much more comfortable if we know that someone is actually getting the benefit of the medicine. This has underscored the potential value of long-acting formulations. I know some people may say, “Yes, but doesn’t it mean that someone has to go to a clinic and get an injection?” Yes, that’s true, but that can be done relatively infrequently. As I said, once a month or every 2 or 3 months, that can make it easier. We’ve kept our injection clinic open in the midst of the pandemic. Everyone is taking precautions, but we think it’s worked out quite well.

Early Initiation With LAIs to Optimally Manage Schizophrenia

EP 1: Overview of Schizophrenia

EP 2: Challenges for the Treatment of Schizophrenia

EP 3: Schizophrenia: Relapse Prevention and Adverse Effects

EP 4: Schizophrenia: Treatment Adherence

EP 5: Psychosocial Treatments for the Management of Schizophrenia

EP 6: Use of Oral Therapy for the Management of Schizophrenia

EP 7: Guidelines for the Treatment of Schizophrenia

EP 8: Switching From Oral Therapy to Long-Acting Injectables

EP 9: Initiating LAI Therapy for the Treatment of Schizophrenia

EP 10: Management of Schizophrenia and Available LAIs

EP 11: Overcoming Barriers With LAIs in Schizophrenia Management

EP 12: Early Initiation of LAIs in Treating Schizophrenia

EP 13: Recommendations for Using LAIs During COVID-19