Schizophrenia Podcast

Common and Commonly Unrecognized: Clinical High-risk Syndrome, Psychosis, and Schizophrenia

John M. Kane, MD; Scott W. Woods, MD


May 23, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

John M. Kane, MD: Hi. I'm Dr John Kane, professor of psychiatry at the Zucker School of Medicine in Hempstead, New York. Welcome to season two of Medscape's InDiscussion series on schizophrenia. Today we will discuss the clinical high-risk (CHR) syndrome, formerly referred to as the prodrome. First, let me introduce my guest, Dr Scott Woods. Dr Woods is professor of psychiatry at the Yale School of Medicine and director of Yale's Prime PRIME Clinic for CHR. Welcome to InDiscussion. Scott, can you tell the listeners what we mean by CHR syndrome?

Scott W. Woods, MD: Thank you, John. The CHR syndrome affects young people, typically 15-25 years of age, although there are some outliers at either end of that range who also are affected. These patients begin to develop symptoms that are like schizophrenia but milder. These symptoms sometimes progress and get worse to the point where they, perhaps 1 or 2 years later, are severe enough to meet criteria for schizophrenia. CHR is the prodrome for schizophrenia but identified ahead of time as opposed to in retrospect.

Kane: How often does that happen that the patient does go on to actually develop psychosis?

Woods: It varies depending upon how long we wait and how ill the patient is when you meet them, but it's about 25% of the time. One hypothesis is that some kind of resilience factors come into play. Patients may begin to develop what appears to be a psychosis-like syndrome, but they go into a spontaneous remission or stabilize with low level subsyndromal-type symptoms.

Kane: What brings these people to the attention of mental health professionals?

Woods: They have positive symptoms that we call attenuated positive symptoms because they are milder than the positive symptoms of schizophrenia. These symptoms themselves are often quite distressing and can lead to impairment in their social, work, or school functioning. Many of the patients also have other symptoms that are common in almost every psychiatric condition, such as anxiety and depression, and report that those symptoms are very distressing and what leads them to come to treatment.

Kane: What percent of the general population suffers from CHR syndrome?

Woods: For the general population of youth, meaning in this 15- to 25-year age range, it's a little under 2% of people at any one time are suffering from CHR syndrome. That makes this a relatively uncommon condition. To continue with your previous question, many people come to treatment encouraged by parents because a lot of these people are young and still living at home with their parents. The reason that the parents think the person needs treatment is because of a decline in school performance. The parent often doesn't even know about the attenuated positive symptoms that we use to diagnose the syndrome.

Kane: Are many of these young people initially reluctant to seek help?

Woods: They can be a little reluctant. As we know, psychosis is stigmatized in our society. Sometimes they have felt this stigma. If they mentioned to one of their friends that they were hearing a little sound that other people couldn't hear — not a full hallucination but something less structured — they may get a somewhat stigmatizing response from that friend, and they may decide not to mention it to other people again. This is one of the challenges in diagnosing CHR syndrome, even though it is relatively common.

Kane: If you were to look at the youth who actually are presenting to a general mental health service, what percentage of them would be suffering from CHR?

Woods: That's a great question, John. For most practitioners, this is the group of most interest to them — the kind of person who would be coming to see them. In that population, I think the percentage of patients suffering from CHR syndrome is astonishingly high. There have been a dozen or so studies that give structured interviews for diagnosing the CHR syndrome for psychosis to everyone who comes for the first time to a youth general mental health clinic. The proportion of patients suffering from CHR syndrome is almost 20% of people presenting for the first time to a youth or young adult mental health clinic. Most of the time, this is not recognized by the general provider, and it would not have been recognized if they hadn't been doing this study in the clinical population. It is possible for a general practitioner to have a high index of suspicion for young people, because this is a common illness among young people, and incorporate a couple very easy-to-remember probes into a review of systems that they would ordinarily do in a first psychiatric interview. Probably the best question for a clinician to ask is, "Has anything odd or unusual been going on?" A person who has the CHR for psychosis will often say, "Well, what do you mean by 'odd' or 'unusual'?" The clinician would respond, "Anything odd or unusual." The patient would tell the clinician that, yes, they have been wondering whether someone might be trying to influence their mind. That's just one example. This is a question that you can obviously follow up on in your psychiatric interview. A person who doesn't have CHR may still answer yes. We want a question that patients are going to say yes to. Then, the patient explains that what's odd and unusual is that they lost their car keys twice in 1 day — something relatively common, and they were just distracted

Kane: You've emphasized that this syndrome is common and potentially goes unrecognized. When it is unrecognized, how are these young people diagnosed? What are they considered to have?

Woods: Probably because of the stigma, when the person with CHR syndrome for psychosis comes to a general mental health provider, they focus on the more socially acceptable symptoms that they have — symptoms of depression or other symptoms of anxiety.

Kane: Does that lead to mistreatment? Do some of these young people end up getting antidepressants or anti-anxiety agents when in fact they are CHR?

Woods: I wouldn't necessarily say mistreatment. Unfortunately, we're still in the phase of working to develop highly specific treatments for this condition. If the patient does have depression and meets criteria for major depression comorbidly, there's nothing wrong with giving them an antidepressant as indicated, and they benefit from them. In this situation, the practitioner should prescribe.

Kane: Is there any risk that an antidepressant might actually precipitate psychosis?

Woods: There are, of course, clinical cases like that of people presenting to the hospital with psychosis relatively shortly after starting on an antidepressant. Those cases may reflect what's called the clinician's illusion. I'm sure you're very familiar with that, Dr Kane, because of the fact that you're working in a hospital, you see only people who are hospitalized. You don't know about the large number of cases for whom an antidepressant is given, and it doesn't cause psychosis and does benefit the person. There really isn't any evidence that antidepressant use in this population provokes psychosis. The evidence is neutral on that.

Kane: Scott is one of the leading researchers in the world on this topic. When thinking about some of the research that you and your colleagues have done, are there predictors of CHR syndrome? If you look at a population of CHR individuals, are there things that stand out as risk factors for the development of psychosis?

Woods: Absolutely. It's been demonstrated empirically over and over again: The more severe the attenuated positive symptoms, the more similar they are to schizophrenia, and the more likely the person is to develop psychosis. If they are getting worse as opposed to staying the same over time, their trajectory is another key predictor for these attenuated positive symptoms. In the clinical realm, a drop in functioning is a strong predictor of CHR. Those are the two strongest predictors. Severity of attenuated positive symptoms and a drop in functioning. Interestingly, the evidence is mixed about how distressing the symptoms are. The more distressing they are, obviously, the more the person needs help and deserves help. But it doesn't necessarily mean the more likely they are to progress to schizophrenia. Other things that you might think of, like the severity of their anxiety and depression, are actually completely unrelated in the empirical literature to whether they develop psychosis. It's really the attenuated positive symptoms that are the most important.

Kane: How about cognitive dysfunction? Is that common in these young people? Does that play any role in predicting outcome?

Woods: It does. Cognitive dysfunction is in the next tier of predictors — not as strong as attenuated positive symptoms or loss of functioning. On average, when CHR syndrome patients present, they have a mild cognitive deficit on average about a half of a standard deviation. The patients who have more cognitive impairment are more likely to develop schizophrenia.

Kane: I know that MRI is not necessarily available to everyone, but is there evidence utilizing neuroimaging to identify risk factors?

Woods: There is. There have been quite a few studies of this, and the most recent one conducted MRIs every 2 months for an 8-month period, so five MRIs. Over that time, a trajectory of decreasing thickness of the frontal cortex in the brain was predictive of later development of psychosis. Actually, that change could be detected in the group in as little as 2-3 months. By themselves, serial MRIs are probably not ready yet to be an individual screening tool. But taken together with other evidence, like change of positive symptoms, functioning, and cognition, we expect to be able to develop and improve upon an algorithm that we've developed for calculating an individual risk for each person. We expect the inclusion of the MRI into that algorithm, which hasn't been done yet but is an active area of research. We expect that that will improve the individual prediction.

Kane: So right now, if somebody presents to a clinic and they receive a diagnosis of CHR, what is the recommended treatment?

Woods: Like almost every illness, stress makes the CHR syndrome for psychosis worse. Some of that stress comes from not having a diagnosed condition. Very often, a careful and open discussion with the patient, or someone who is seeking a diagnosis, will be quite helpful for them. Often, they've gone to multiple doctors, and no one can tell them what seems to be wrong, what might happen in the future, or what to do about what they're experiencing. Having a frank discussion about that all by itself can not only be very reassuring for the patient but also be beneficial for them. Supportive-type treatments with an aim of stress management and psychoeducation about the illness are definitely helpful, as are pharmacologic treatment of any comorbid conditions that they may experience. That's pretty much the state of what we can do now. We, of course, would like to do very much better over the coming years. It's an extremely active area of research to develop a safe and specific medication treatment for this condition.

Kane: At present, antipsychotic drugs are not necessarily recommended. Are there some patients who may benefit from them?

Woods: Yes, both of those things are true. In general, 80% of patients will not need antipsychotic medication. There's a fairly high spontaneous remission rate anyway, even without treatment. With stress reduction, psychoeducation, and treatment of comorbid conditions, many more of these patients go into remission. There is a small number who are rapidly progressing despite these conservative efforts and/or in whom the symptoms are dangerous because they may be associated with suicidal ideation, for example. In those cases, antipsychotic medication certainly is indicated. There is not as much research evidence as we would like, but the research evidence shows that it definitely improves the patients attenuated positive symptoms. There is at least one good published placebo-controlled study, and it showed a very strong trend toward preventing future psychosis.

Kane: As you said earlier, there are new specific treatments that are under development. Hopefully, they may improve our ability to treat these individuals.

Woods: Yes, the US National Institute of Mental Health has developed a very high-profile program. They recruited pharmaceutical industry partners and other public and private partners from the US Food and Drug Administration (FDA) and private foundations to essentially make a Manhattan Project to develop a new treatment that would be able to prevent psychosis.

Kane: Very exciting. The audience should be aware that you're one of the leaders of that effort. Thanks so much, Scott. We've talked to Scott about the CHR syndrome for psychosis. I think there are three things to emphasize from his remarks. First, it's both a current syndrome and the indicator of risk for future psychosis. Second, it's common and commonly unrecognized. Last, CHR also shares biological abnormalities with schizophrenia and is a very important emerging focus of treatment. I want to thank the audience for tuning in. If you haven't done so already, please take a moment to download the Medscape app to listen and subscribe to this podcast series on schizophrenia. This is Dr John Kane for InDiscussion.

Listen to additional seasons of this podcast.



Schizophrenia and Clinical High Risk

PRIME Psychosis Prodrome Research Clinic

Conversion to Psychosis in Adolescents and Adults: Similar Proportions, Different Predictors

Clinical Validity of DSM-5 Attenuated Psychosis Syndrome: Advances in Diagnosis, Prognosis, and Treatment

Prevalence of Individuals at Clinical High-risk of Psychosis in the General Population and Clinical Samples: Systematic Review and Meta-analysis

Stability of Mental Disorder Prevalence Estimates Among School-aged Children and Adolescents: Findings From the Community-based Project to Learn About Youth-mental Health (PLAY-MH) and Replication-PLAY-MH (Re-PLAY-MH), 2014-2017

The Clinician's Illusion

What Causes the Onset of Psychosis in Individuals at Clinical High Risk? A Meta-analysis of Risk and Protective Factors

Association of Neurocognition With Transition to Psychosis: Baseline Functioning in the Second Phase of the North American Prodrome Longitudinal Study

Accelerated Cortical Thinning Precedes and Predicts Conversion to Psychosis: The NAPLS3 Longitudinal Study of Youth at Clinical High-risk

Treatment Outcomes for Young People at Clinical High Risk for Psychosis: Data From a Specialized Clinic

Real-world Effectiveness of Antipsychotic Treatment in Psychosis Prevention in a 3-year Cohort of 517 Individuals at Clinical High Risk From the SHARP (ShangHai at Risk for Psychosis)

The PRIME North America Randomized Double-blind Clinical Trial of Olanzapine Versus Placebo in Patients at Risk of Being Prodromally Symptomatic for Psychosis: I. Study Rationale and Design

Accelerating Medicines Partnership® Program - Schizophrenia (AMP® SCZ)

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.