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Treatment-Resistant Schizophrenia: From Diagnosis to Management CME / ABIM MOC / CE

www.medscape.org/spotlight/diagnose-treatment-resistant-schizophrenia

Treatment-Resistant Schizophrenia From Diagnosis to Management

CME / ABIM MOC / CE

Supported by an independent educational grant from Lundbeck, Inc.



Target AudienceThis activity is intended for psychiatrists, primary care physicians, pediatricians, and obstetrician/gynecologists.

Goal The goal of this activity is to educate members of the healthcare team about treatment-resistant schizophrenia (TRS), including diagnostic criteria and current and emerging treatment options, with a focus on how an interprofessional approach can help maximize patient outcomes.

Learning ObjectivesUpon completion of this activity, participants will:

• Have increased knowledge regarding the• Current and emerging treatment strategies for TRS

• Have greater competence related to• Diagnosis of TRS• Team-based roles in management of TRS

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Disclosures

Moderator

Oliver Freudenreich, MDErich Lindemann Mental Health CenterMassachusetts General HospitalBoston, Massachusetts

Disclosure: Oliver Freudenreich, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alkermes, Inc.; Janssen Pharmaceuticals; Neurocrine Biosciences, Inc.; Novartis Pharmaceuticals Corporation; Roche Served as a speaker or a member of a speakers bureau for: Neurocrine Biosciences, Inc. Received grants for clinical research from: Avanir Pharmaceuticals; Janssen Pharmaceuticals; Otsuka Pharmaceutical Co., Ltd.; Saladax Biomedical, Inc.

Panelists

Andrew J. Cutler, MDChief Medical OfficerMeridien ResearchBradenton, Florida

Disclosure: Andrew J. Cutler, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: ACADIA Pharmaceuticals Inc.; Alkermes, Inc.; Allergan, Inc.; Avanir Pharmaceuticals; Intra-Cellular Therapies; Lundbeck, Inc.; Neurocrine Biosciences, Inc.; Otsuka Pharmaceutical Co., Ltd.; Sunovion Pharmaceuticals Inc.; Takeda Pharmaceuticals North America, Inc.; Teva Pharmaceuticals USA Served as a speaker or a member of a speakers bureau for: ACADIA Pharmaceuticals Inc.; Alkermes, Inc.; Allergan, Inc.; Avanir Pharmaceuticals; Lundbeck, Inc.; Neurocrine Biosciences, Inc.; Otsuka Pharmaceutical Co., Ltd.; Sunovion Pharmaceuticals Inc.; Takeda Pharmaceuticals North America, Inc.; Teva Pharmaceuticals USA Received grants for clinical research from: ACADIA Pharmaceuticals Inc.; Alkermes, Inc.; Allergan, Inc.; Avanir Pharmaceuticals; Intra-Cellular Therapies; Lundbeck, Inc.; Neurocrine Biosciences, Inc.; Otsuka Pharmaceutical Co., Ltd.; Sunovion Pharmaceuticals Inc.; Takeda Pharmaceuticals North America, Inc.

Jonathan M. Meyer, MDClinical Professor of PsychiatryUniversity of California, San DiegoSan Diego, California

Disclosure: Jonathan M. Meyer, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: ACADIA Pharmaceuticals Inc.; Neurocrine Biosciences, Inc.; Teva Pharmaceuticals USA Served as a speaker or a member of a speakers bureau for: ACADIA Pharmaceuticals Inc.; Alkermes, Inc.; Allergan, Inc.; Neurocrine Biosciences, Inc.; Otsuka Pharmaceutical Co., Ltd.; Sunovion Pharmaceuticals Inc.; Teva Pharmaceuticals USA



Editors

Marcello Morgan, MD, MPH Scientific Director, Medscape, LLCDisclosure: Marcello Morgan, MD, MPH, has disclosed no relevant financial relationships.

Shira BermanScientific Director, Medscape, LLCDisclosure: Shira Berman has disclosed no relevant financial relationships.

CME Reviewer / Nurse Planner

Amy Bernard, MS, BSN, RN-BCLead Nurse Planner, Medscape, LLCDisclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Alkermes, Inc.; Harmony Biosciences, LLC; Jazz Pharmaceuticals, Inc.; Shire; Sunovion Pharmaceuticals Inc.; Supernus Pharmaceuticals, Inc. Owns stock, stock options, or bonds from: M-3 Information, LLC



Treatment-Resistant Schizophrenia: From Diagnosis to ManagementOliver Freudenreich, MD: Hello. I am Oliver Freudenreich from the Erich Lindemann Mental Health Center and Massachusetts General Hospital in Boston, Massachusetts. Welcome to this program titled, “Treatment-Resistant Schizophrenia: From Diagnosis to Management.”



PanelistsJoining me today are Andrew Cutler, who is Chief Medical Officer at Meridien Research in Bradenton, Florida, and Jonathan Meyer, who is Clinical Professor of Psychiatry at the University of California in San Diego. Welcome to both of you.

This program may include a discussion of off-label treatments and investigational agents not approved by the US Food and Drug Administration for use in the United States and data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal.



Schizophrenia[1-3]

Let me start with a few background points about our topic of treatment-resistant schizophrenia (TRS). Schizophrenia is a complex mental disorder, which typically has its onset in late adolescence or early adulthood. It affects a significant minority of people in the United States, about 1%, which translates to 3.5 million people. It impacts all aspects of a patient’s life. Particularly problematic, of course, is that disease onset is at a very early age, as opposed to other diseases such as Alzheimer disease, which strikes people at the end of very productive lives.

The overall estimated economic burden for this disease is $156 billion in direct and indirect costs. The indirect costs are driven by excess unemployment and caregiving costs. We will come back to this point, because I think it is an important one.



Treatment-Resistant Schizophrenia[4,5]

Despite intensive and ongoing research, clinical outcomes and treatment are often suboptimal. Approximately one-third of patients with schizophrenia are considered treatment resistant. In addition, more than 80% of patients considered treatment resistant are really treatment resistant with initial treatment effort -- they do not become resistant after years and years or decades of treatment.

This is a disease that strikes early and there are patients who might struggle from the get-go to find good treatments. That is what we want to discuss today.



Definition of TRS: TRRIP Working Group Consensus[6]

Jonathan, let us talk a little bit more about what TRS actually is. How do we define it? Can you tell me a little bit more?

Jonathan M. Meyer, MD: It is important to at least put some parameters on this -- and part of it is a nomenclature issue. The old terminology was ‘treatment-refractory schizophrenia.’ Recently, we have moved more toward ‘treatment resistance,’ with the idea that it is not a dire diagnosis. There may be options that we can look at for improving the quality of care for these patients.

There was a review paper that looked at this very recently with the idea of establishing criteria for both research and clinical purposes. We focus on positive symptom treatment resistance most of the time -- people who have inadequate reduction in positive symptoms with antipsychotic treatment. We do recognize that negative symptoms and cognitive deficits are often a big part of persistent illness and functional disability, but we are mostly focused these days on positive symptoms in people who have had an inadequate response to an adequate dose of an antipsychotic.

The paper defined this as 6 weeks of ≥600 mg/d of chlorpromazine equivalent. But you need to consider adherence as well. If the person does not take the drug, then how can they be treatment resistant?

Dr Freudenreich: It is interesting, isn’t it, that after years, decades of treatment, only now as a field have we established a consensus definition of this vexing issue.



Pathophysiology of TRS[7]

Andy, is there anything that we know about the pathophysiology of treatment resistance? Why are people resistant?

Andrew J. Cutler, MD: This is a very important question. It turns out that this is a heterogenous illness. We all know that clinically it can present with heterogenous symptom complexes, but also the pathophysiology is very heterogenous and there are likely many different forms of schizophrenia biologically.

Some patients may have a pathophysiology that is very responsive to D2 antagonism, for instance. This is how most of our current medications work, with some degree of D2 antagonism. However, there are probably other patients who may have predominant disturbances in receptors or parts of the dopamine system other than the D2-dominated part of the system.

There also may be serotonergic mechanisms. For instance, we know that if someone uses LSD, which is a 5-HT2A receptor agonist, you can have psychotic-like symptoms. We know that there may be glutamate systems involved as well. Ketamine, for instance, is a model for causing psychosis by overstimulating the glutamate system.

There may be a significant percentage of patients, as you said, perhaps as many as one-third, for whom our current manipulations or current treatments are not really addressing the particular pathophysiology that they predominantly have.

Dr Freudenreich: We might come back to this point when we talk about drug development at the end of our talk.



Economic Burden of TRS Healthcare Expenditures[8]

Let us bring it back to a practical level. What are the consequences of being treatment resistant?

Dr Cutler: There are significant consequences, as we know. The annual cost for patients with schizophrenia ranges from $15,500 to $22,300. These costs are actually 3 to 11-fold higher for patients with TRS.

Although these estimates vary greatly, TRS conservatively adds more than $34 billion in annual direct medical costs in the US. We are talking about something that not only affects patients and their ability to function and connect with life and their family members, but also affects society at large.



Clinical Burden of TRS[8,9]

Jonathan, what do you think are the consequences of this?

Dr Meyer: A big part of this is direct medical cost. Patients with TRS, not surprisingly, have more hospitalizations. They also have poorer quality of life, more impaired social functioning, and often a higher burden of negative symptoms as well.

Dr Freudenreich: It is a highly disabling disease -- a terrifying disease that comes at a high cost for patients and families.



Diagnosis of TRS: Clinical Considerations[4,6]

We talked a little bit about consensus criteria, but let’s speak practically about it. How do we actually diagnose TRS? Is a poor response to treatment always considered to be due to being treatment resistant or are there other considerations when you encounter this phenomenon?

Dr Cutler: It is critically important to do a thorough clinical evaluation and to try to get other pieces of data. Particularly, ideally, you want to review as much of the patient’s medical record so you can document that adequate trials of medications have been tried. We always talk about adequate dose and adequate duration, for instance. But we also want to see if there are any clues that this patient might be a fast or even an ultra-rapid metabolizer, in which case perhaps the dose was not optimized.

Always you want to consider issues of adherence. There are many factors that influence adherence. You want to make sure, again, that the duration of the treatment has been long enough and look for other things that could impact this, such as psychosocial issues, substance abuse issues, and things like this.

Of course, clearly, there are many different conditions that can cause psychosis. You want to make sure you have an accurate diagnosis of the syndrome of psychosis to make sure it is actually schizophrenia.



Diagnosis of TRS: Definitions of Adequate Treatment and Response[6]

Dr Freudenreich: Can I come back to the point of what actually is an adequate duration? How many weeks is that?

Dr Cutler: That is a terrific question. As we heard Jonathan mention earlier, some people say at least 6 weeks. Some people would say as long as 12 weeks might be adequate.

What we are learning is that earlier markers of response may be important. For instance, there are some data suggesting that if you do not see at least a 20% or 30% improvement within 2 weeks, as you had mentioned, sometimes people out of the gate initially are evincing treatment resistance. Maybe we do not want to wait too long. This is an illness that is probably inducing negative pathologic changes in the brain and may be to some degree neuropathic. I think that we really need to make sure patients have had an adequate treatment duration, but you do not necessarily want to sit and wait too long.

Dr Freudenreich: That is clinically quite an important point that you are making for people who are in inpatient units, too. Yes, you have to wait long enough, but not too long.

There are some people who are seemingly getting the right dose for the right duration and then they struggle. They do not get better. There are other reasons to keep in mind.

Dr Cutler: Dosing is part of it, but the other part is whether the patient actually takes the medication as well, and in some instances, whether they are an ultra-rapid metabolizer. The point is that simply because a patient looks treatment resistant does not actually mean they have had adequate antipsychotic exposure.



Therapeutic Drug Monitoring[10]

A number of studies looked at therapeutic antipsychotic levels in people deemed treatment resistant. In the largest case series, 35% of people who were deemed treatment resistant simply had inadequate drug exposure -- in some cases, non-therapeutic or zero plasma levels.

Dr Freudenreich: That is a huge number. A third of patients that you would mislabel as being treatment refractory.

Dr Cutler: Absolutely. Although therapeutic drug monitoring is not common for most antipsychotics -- although people often do it for clozapine -- there is clearly a role, particularly when patients are not responding and not showing evidence of adverse effects, meaning there is a doubt about whether they are actually taking the drug.

Dr Freudenreich: I think what you said about therapeutic drug monitoring being somewhat underutilized in our field, particularly in clozapine, is important. There seems to be this idea that there is no good relationship between dose, plasma levels, and response. I think that is wrong, particularly if we look at the extremes. We are mostly interested in those people who actually have zero.



Long-Acting Injectables[4,11]

Dr Cutler: Another modality that is quite underutilized is long-acting injectable (LAI) medication. Certainly, we are confident that the patient has gotten the medication and that it is bioavailable. Unfortunately, we know that in America, LAIs are only used in approximately 10% of patients with schizophrenia, whereas in many other countries, it is more common.

We have some information that suggests LAIs can improve upon our outcomes with orals, and even maybe maximize the potential of orals, particularly atypical antipsychotics. We know that the relapse risk, for instance, is 20% to 30% lower for LAIs compared to orals. We have real-time accurate information about adherence, as I mentioned. You know right away if the patient is becoming nonadherent, because they do not show up to the clinic for their injection appointment.

A reasonable strategy in first episode can be to offer an LAI. Really, it is important to offer all the treatment options, just as we would in any other field of medicine. One nice thing that I have had patients tell me is if you use LAIs, you do not have that daily battle of “did you take your medicine or not.” It becomes more of a smooth way to avoid family conflict.



Addressing Medication Adherence[12]

Dr Freudenreich: If we think about going back to an adequate trial, we already said 6 weeks, maybe a little bit longer. I think most people would say at least 2 antipsychotics, perhaps more. Should not an LAI be one of those? Would it not be a logical thing to propose to patients and their families?

Dr Meyer: It is certainly worth considering, particularly where there is documentation of poor adherence. At least 50% of schizophrenia patients take their medications less than 70% of the time. Once you can document that with a plasma level, then you have an option, for a lot of patients at least, to say you gave them adequate drug exposure. It was assured. Now if they are not responding, perhaps it is because of inherent biological factors of the illness.

Dr Cutler: This is an excellent point. It is not always complete nonadherence that can be a problem. Even partial adherence may also result in relapse.

Dr Freudenreich: Very true. I think they settled in the consensus criteria 80% [adherence rate] as a judgment, but you reach 80% pretty quickly. When you ask a patient, “In the last 7 days, how many doses did you miss?”, they’ll say, “Maybe 2.” It could mean maybe 3 and all of a sudden, you end up with partial adherence, which is very often completely unrecognized. The perniciousness is underappreciated.



Assessing Severity of Schizophrenia Symptoms[13]

I know this is always a big issue -- I want to bring in the issue of how to actually measure symptoms in psychiatry. Are there tools that you would propose to use without necessarily overburdening clinicians who are going to say it’s yet another form to fill out, yet another rating scale? Is there something simple perhaps?

Dr Meyer: The simplest scale, and one that I have endorsed, particularly in inpatient settings with more acute patients, is something we do every day, every time we see a patient -- the 1-item Clinical Global Improvement-Severity (CGI-S).

Dr Freudenreich: It sounds easy enough.

Dr Meyer: It is a 7-item Likert scale. Every time you see a patient, you say in your mind -- this person is moderately ill, this person is the most severely ill patient I have ever seen, or this person is not ill at all. We already do it. All you have to do is write it down.

Particularly in inpatient settings, it correlates very well with the gold-standard rating scales for schizophrenia, such as the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS). There is a way to capture disease severity, particularly since the Diagnostic and Statistical Manual of Psychiatric Diseases (DSM)-5 removed the Global Assessment of Function (GAF) score, which was a bit of our crutch for describing severity even though it was this unholy alliance of function and severity.

Dr Cutler: I think Jonathan is right. We would not treat hypertension without measuring blood pressure. We would not treat diabetes without measuring glucose. It is important to measure something.



Using Symptom Severity Scales in the Clinic[13]

We do clinical trials; I do a significant amount of clinical trials. I am certainly not advocating that people need to do the PANSS, which can be quite lengthy, but instead, as Jonathan said, something straightforward and simple like the CGI, which correlates with these more sophisticated scales. It is just a way of capturing what we already do clinically and then you have something documented.

Dr Freudenreich: It might just reinforce that clinicians actually pay attention -- “This patient is sicker than I realized” -- once they have to put down a number perhaps.



Team Approach to Managing SchizophreniaIt is a complex issue. A complex disease. Complicated patients. Complicated environments. We cannot do this by ourselves. We have 3 physicians sitting here. There has to be a team. Are there other members of a team, like nurses, social workers, or nurse practitioners who can help in this endeavor managing patients better?

Dr Cutler: Certainly, there are many other members, as we know. Treating schizophrenia really does need to be a comprehensive team of people. When we see the patient, very frequently, we are seeing them in a pretty short period of time. We get a little snapshot. Sometimes the patient puts on their best outfit or their best behavior when they come to see the doctor. We may not adequately experience and see the patient in all different environments and how they are really doing.

Other members of the treatment team play a critical role as far as assessing the overall clinical picture. They can bring to our attention things they have seen or heard from talking to other people that know the patient or see them. They can bring to us things the patient has said that the patient may not say to us directly. I think they can also play a very important role in managing safety and tolerability of our medications. They can also do adjunctive forms of treatment that we may not be able to do, such as therapies and various ways of quality of life and skills management.

Dr Freudenreich: I work a lot with nurse practitioners. We could not do it without them. They do all the legwork. All the ‘little’ things -- and they have to spend 2 or 3 hours of work to get somebody to have the blood work done or get somebody to a primary care doctor.

Dr Cutler: Also, psychoeducation is so important and critical. Helping to educate the patient. Some patients with schizophrenia are cognitively impaired and they may not pick up what we say right away. They may need to have things reinforced or explained.

Dr Freudenreich: It is incredibly important to recognize this is not a dyadic disease where it is you and your patient. It is really the patient, the whole team, and family around them.



Assessing the Patient With TRSIn the end, we have somebody with TRS. How should we manage them?

Dr Meyer: First you want to document that they actually are treatment resistant and not simply inadequately treated, whether it is due to underdosing, drug metabolism reasons, or nonadherence.

There are also other reasons that people are symptomatic. Ongoing substance use is a big problem. High-potency cannabinoids are out there. We know many people who, while they are using, will have difficulty responding adequately to treatments. We also know that additional stressors can play a big role in symptomatic relapse, such as people who are homeless, people who live in a stressful environment with their family where there is high emotional expressivity. All of these play a role before deciding that the solution to this problem is a pharmacologic one.

Dr Freudenreich: This also comes back to the interdisciplinary treatment team, the role for the treatment team to address some family strife, to address the psychosocial stressors like homelessness, something that we cannot do as physicians.



Clozapine in Patients With TRS[14]

We do need to talk about clozapine. It is a very critical part of managing this illness.

Dr Cutler: Clozapine is really the first medication that was demonstrated to be effective for patients with TRS. It is a very interesting model, because there was a mystery here of how clozapine works when it has very low affinity for the D2 receptor. Clozapine is a very interesting pharmacologic. It is really a multimodal agent with a lot of different receptor activities. A lot of people have tried to parse which of the receptor activities are the ones that may give this the unique efficacy. It is a medicine that is vastly underutilized and really should be considered perhaps earlier. Right now, I know many people use it fifth line. We really need to think about using it earlier for patients with refractoriness. It has also been shown to help with certain types of symptom complexes such as aggression or especially repetitive self-injury. It also has been shown to decrease suicidality better than another antipsychotic



Underuse of Clozapine in Patients With TRS[15,16]

Jonathan, why would we not prescribe clozapine? What do you think is going on here? What are the risks of not doing it?

Dr Meyer: There are a number of barriers. Sometimes the barriers are related to the patient -- they may have difficulty with the blood work, or they may have an unstable housing situation in which that type of follow-up is impractical.

Sometimes a lot of the resistance, though, comes from a provider who feels inadequately trained to provide clozapine. Hopefully, through educational efforts, this can change. At our state hospital, through numerous lectures about how to use clozapine and manage its adverse effects, we have more than doubled the use of clozapine.

To your point, the risks of not prescribing clozapine seem to be that the patients tend to get worse. There may be a window in which people may preferentially do a bit better when given a clozapine trial -- 2 or 2.5 years down the road, their response may not be quite as robust.

Dr Freudenreich: When I teach about this to the residents, I tell them there is psychosocial toxicity that comes from not being well. There is a high cost that you pay socially just from being out of commission, from dropping out of school, because you are psychotic. It is a really critical piece.



Maximizing Benefit From Clozapine[6,17]

Is clozapine monotherapy or are we combining things?

Dr Cutler: I would say the standard of care first -- it would be great if people would try monotherapy clozapine, and maximize using an adequate dose and duration of clozapine. Clozapine is one antipsychotic where therapeutic blood monitoring is relatively widely available and is the standard of care. That really is a nice feature as well.

Also, we talk about clozapine clinics. We do tend to have much more thorough monitoring of our patients on clozapine. Often, they will have a dedicated case manager who can assess compliance and adherence.

There is some evidence that perhaps adding another antipsychotic to clozapine for some patients could be beneficial. There is some evidence that electroconvulsive therapy (ECT) augmentation, which is also another underused modality, could be beneficial.

Dr Freudenreich: The most important thing might be to use a clozapine clinic as a model now to ensure metabolic monitoring before you get creative with advanced psychopharmacology. That, in the end, is unfortunately one of the reasons why our people die 20 years before their peers.

Dr Cutler: You see a lot of what I call creative psychopharmacology where people start making these combinations and cocktails of things that do not always have very much evidence that they are effective.

Dr Freudenreich: There is always hope -- a time where research thankfully is still happening, even though things have gotten more difficult in psychopharmacology research.



New Therapeutic Approaches in Development[18-22]

What do we know about drug development at this point specifically to target people with schizophrenia who are resistant to treatment?

Dr Meyer: Starting off, people look to clozapine as the model. As Andy said, what is special about clozapine? There are many theories. It is, as we say, a dirty drug with multiple receptor affinities, multiple mechanisms, which still are not clearly understood. If they were understood, we would have another drug like clozapine with its efficacy but without its baggage.

One hypothesis is related to some of the serotonergic properties. Certainly, this is an area which people have looked at based upon not only the evidence indirectly from clozapine, which has a moderate affinity for the serotonin-6 receptor, but also animal data as well.

Compounds are in development, which are exploiting serotonin-6 antagonism in addition to a D1 or D2 traditional antipsychotic model, with the idea that maybe this is a combination that might give us some unique properties in a way that we did not get from traditional D2 antagonists.

Dr Cutler: Jonathan is right. We are looking for a secret sauce or a special sauce of different receptor profiles in combinations. Sometimes the whole is greater than the sum of the parts. It is not just one receptor, if you will. As I said earlier, maybe it is not a D2 responding psychosis. Maybe it is a psychosis that needs more D1 manipulation or needs some of these other serotonin receptors involved. Let’s face it. There are probably other receptors and other neurotransmitters that we just do not know about as well that may be involved.



Dr Meyer: There is a compound, AF35700, that we are interested to see what will happen with. Some of these drugs do not always work, as we know, but this a company that has staked out the idea that maybe this is one of the special properties of clozapine. We are curious to see how this pans out.

Dr Freudenreich: Unfortunately, this drug, while it seems to be an antipsychotic that works, it is not better than olanzapine or risperidone for TRS. The holy grail of drug development remains to develop a drug that works in patients for whom we do not have good treatment at this moment in time.

Challenges of Drug Development in TRS: Disease Heterogeneity[23]

Dr Freudenreich: Why is it so hard to develop new drugs for a pretty heterogenous syndrome, but a syndrome that affects a lot of people?

Dr Meyer: There are the disease elements. For one thing, we have disease heterogeneity. We do not have good biomarkers for disease either. Schizophrenia is still a clinical diagnosis. Just recently in the American Journal of Psychiatry there is a paper published which looked at polygenic risk scores with the idea that people who have greater genetic burden of disease will be less likely to respond to antipsychotic therapy. This is great, but this is not still the way we diagnose. We do not have robust predictors of treatment response.

Dr Cutler: Part of the problem is that clinical trials that we use to base our determinations are averages over hundreds of patients. That does not always inform me about the N of 1 or the patient sitting across from my desk. They may do much better with one of these medicines than another. We really have a lot of work to do to get more of a personalized approach.

Dr Meyer: This is what we would want. It would be nice to define people perhaps a little more homogenously as treatment-resistant because even within that group, there probably are biologically different subgroups who, as Andy says, might preferentially respond to certain strategies. There are also the practical issues. Maybe you can speak to that a little bit better than I can.



Challenges of Drug Development in TRS: Trial DesignDr Cutler: I am a clinical trialist. I run clinical trials full-time. There are a number of issues that go into this. Essentially, what we are trying to do is separate a drug from placebo in a clinical trial using a rating scale. It is a bit of an artificial environment. There are a number of factors that can enhance placebo response. You may have a drug that works very well, but unfortunately, in the trial, the placebo also works very well. It is actually very hard to separate an effective drug from placebo.

We also have, as Jonathan said, a big problem with not having real targets or accurate biomarkers to predict a biologically homogenous population that really has a possibility of responding to this target.

Another problem is picking the right dose you are going to study -- sometimes it is a little bit of a shot in the dark. We make our dosing predictions based often on animal models and other kinds of pharmacokinetic studies. To be honest, sometimes frankly we get the dose wrong.

Again, we may also see a result in a clinical trial that has a relatively narrow group of people because you have to have inclusion/exclusion criteria. It may not be broadly representative of the whole population of patients, so the results of the study do not translate into the real world as well.

Dr Freudenreich: What I hear is that clinical trials methodology is one big factor some drugs might fail in development.

Then I have to say listening to you, in the end, it is hard to find the optimal treatment for a disease if you do not know the pathophysiology.

Dr Cutler: Many of our treatments have been discovered by serendipity. Jonathan?



Managing TRS in the Clinic Dr Meyer: Absolutely. We still muddle along with clinical criteria and to be honest, it is still a very practical way to approach this very difficult-to-treat population.

I think the only take-home message for a lot of people is that, more and more, we are starting to define TRS as someone who maybe has only failed 1 or 2 adequate drug trials and it is time to really look at them and say what is going on. If we have assured adherence, maybe you need to move to strategies like clozapine earlier in the course.



ConclusionsDr Freudenreich: On that note, we will conclude. We do have treatment, but we need to make sure that everybody gets the treatments that we do have and we need to sequence it well. We need to be thoughtful about each of those steps. Is somebody actually treatment resistant? Are there issues of adherence? Therapeutic drug monitoring comes in as well.

Once that is established, you are going to have a clear trial. Maybe LAI was part of that. Patients need clozapine not 5 years down the road, but maybe within 6 to 12 months of illness onset.

We are going to do this as a treatment team with other people -- primary care doctors, internists, nurses, and nurse practitioners who help us to bring the best treatment to the patient. I think if we just did that, our outcomes would be better.



Thank YouThank you, Andy and Jonathan, for participating in this activity with me today. It was a very lively discussion. Hopefully educational for people listening to us, watching us.

Thank you, the audience, for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation as well. Thank you.

This transcript has been edited for style and clarity.



Abbreviations

BPRS = Brief Psychiatric Rating Scale CGI-S = Clinical Global Improvement Severity DSM = Diagnostic and Statistical Manual of Psychiatric Diseases ECT = electroconvulsive therapy FGA = first-generation antipsychotic GAF = Global Assessment of Function GWAS = genome-wide association study LAI = long-acting injectable PANSS = Positive and Negative Syndrome Scale PRS = polygenic risk score REMS = risk evaluation and mitigation strategy SGA = second-generation antipsychotic TRRIP = Treatment Response and Resistance in Psychosis TRS = treatment-resistant schizophrenia

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