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John M. Kane, MD: Hi. My name is John Kane. I'm a professor of psychiatry and molecular medicine at the Donald and Barbara Zucker School of Medicine in Hempstead, New York. Welcome to season two of Medscape's InDiscussion series on schizophrenia. Today we're going to discuss comorbidities — particularly, psychiatric comorbidities. First, let me introduce my guest, Dr Christoph Correll, who is a professor of psychiatry at the Donald and Barbara Zucker School of Medicine in New York. He is also a professor of psychiatry at the Charité University Hospital in Berlin, where he is also head of child and adolescent psychiatry. Thank you so much for joining us, Christoph.
Christoph U. Correll, MD: Thanks for having me.
Kane: We have a range of topics to discuss. When we consider comorbidities in schizophrenia, there are a number of different ones to consider. Which ones do you think are most important?
Correll: I think we all struggle with the heterogeneity of schizophrenia, the presentation, the course, and the treatment response, and some of it has to do with comorbidities. It's very important to have comorbidities in mind when evaluating patients, when having a treatment plan, and also when looking at what could facilitate or be in the way of a good outcome. The ones that come to mind are the morbidities that are quite common in the general population that also afflict people with schizophrenia — for example, anxiety disorders, social anxiety disorder, and panic disorder. Some of it might also have to do with the trait of being a little bit wary around people or having had bad experiences. That brings the next cluster of disorders — either acute stress or posttraumatic stress disorders — because people with schizophrenia may be in risky environments, singled out, become the target of attacks, or misinterpret cues and attack others, which can then lead to posttraumatic problems. And in this anxiety cluster in the DSM-5, it's repositioned, but obsessive-compulsive disorder (OCD) can be another disease group that is relevant. When evaluating patients who have not yet had their first episode or already had their first episode, it can sometimes be quite difficult to differentiate people with obsessive thinking and behaviors from people who think that somebody else is making them do something and wonder, "Are these my thoughts?" And then having the category of OCD with loss of insight in the DSM-5 makes the schizo-obsessive overlap quite difficult. In one situation, our most potent medication for psychosis can actually increase obsessive-compulsive symptoms, which is clozapine. Maybe we want to stop here and talk about that first cluster — anxiety disorders and OCD.
Kane: I think that's really important. Which one of these comorbidities do you think clinicians are most likely to miss when they first evaluate a patient?
Correll: I think some social anxiety disorder might be misinterpreted as negative symptoms. And if you address it either with therapy and/or with medication, people might be able to be more outgoing. OCD might be missed because of this closeness to a delusional type of thinking. Generalized anxiety disorder, on the other hand, might be missed when patients are seen as only "being paranoid." But there might be other anxieties that are also quite impairing.
Kane: The next question is the evolution of comorbidities because certainly in some patients with recent-onset schizophrenia, we see a pretty high risk of depression. Maybe it's demoralization or maybe it's overlapping with negative symptoms, but this can often be missed as well, don't you think?
Correll: Yes. That's the second cluster we should definitely talk about. Let's first put a couple of numbers on this. It seems that panic disorder occurs in about 15% of people with schizophrenia and in about 30% of people with posttraumatic stress disorder. A quarter might have OCD, but half have depressive disorders. And there are different types of depressive disorders that clinicians should bear in mind. The first is if the depressive disorder is due to an underlying medical condition. What about malnourishment, B12 problems, and lack of folate? What about thyroid disease or having hypothyroidism? What about having another chronic disorder because people might have more risk of tuberculosis or other problems related to infection because they are not always in safe environments? The second is if the depressive disorder is a side effect of a medication. What if we have something that really dampens the mood by having too many extra pyramidal side effects or interference with reward? So, postsynaptic D2 blockades might be problematic. Then there is the depression that might be secondary to the acute psychotic disorder because people get really depressed when they think the whole world is against them. And then there could be something you could call demoralization that is related to the so-called postpsychotic depression. That might sometimes be like a total exhaustion, but it might also be demoralization. The patient might say, "I've been in the hospital against my will, again. I didn't see it coming. Everybody tells me that I'm wrong. And I now see all of my options and opportunities go away. My brother, my cousin, and my sister all have a different life." So that's another possibility. People with postpsychotic depression are also more likely to have a relapse, there might be some type of mourning that they go through, or they experience a lot of stigma. So, we need to bear in mind that depression that arises in the first 5 years of the illness is a very strong marker of low quality of life, suicidality, and actually killing oneself. The highest risk of mortality due to suicide is in the initial phases of the illness where depression may be a response to the illness that has really altered someone's life. The overall mortality in schizophrenia, recently shown in a meta-analysis, is about two-and-a-half times higher than in the general population. But suicide is actually 10-fold higher. And then there is something that you mentioned, depression and anxiety that occur in the initial phases — the so-called clinical high risk for psychosis or the prodrome where there's something going on in the brain. There might also be a delusional atmosphere, a social withdrawal, a problem with hedonic drive and motivation that is on the way toward the schizophrenia and might actually be related to it. And then there's the true comorbidity. People have schizophrenia and boom, they also get depressed either with a trigger, such as losing someone, or without a trigger. So it's important to have these different facets of depression in your mind when evaluating a person and be open to this comorbidity instead of saying you see a person with schizophrenia and most likely negative symptoms. Negative symptoms and depression are hard to differentiate.
Kane: You make a very important point in there. There are different aspects to comorbidities. There are those that may increase the risk of developing a psychotic disorder. There are those that may occur concurrently and then those that may occur subsequently. There are those that may be influenced by the treatment we're providing. So it just underscores the fact that clinicians have to be aware of and alert to these possibilities no matter what stage of illness or treatment the patient is in.
Correll: Absolutely. And what you mentioned, this difficulty in differentiating primary and secondary negative symptoms and also primary and secondary cognitive symptoms, is difficult when depression might be in the mix. There's actually a very nice meta-analysis that compares the symptom domains in people with depression, people with major depressive disorder, and people with negative symptoms without comorbid depression. And you might be surprised — one way to differentiate between depression, major depressive disorder, and negative symptoms is to ask the patient if they are depressed. People who are depressed feel sad and have low moods, and people with negative symptoms generally don't. Also ask them if they are pessimistic. Ask if they have a pessimistic outlook and if they are suicidal. So the three signs that are semipathognomic for depression are low mood, pessimistic thought, and suicidality. On the other side, what's more pathognomic for depression would be affective blunting, alogia, and also active social withdrawal. Now, this is not as clear cut because people with melancholic depression might also not talk much, not have much expression, and actually avoid people because they don't want to be a burden because they feel exhausted. But underneath that is the wish that they would like to be with people but don't feel they are good enough and can't do it right now. However, people with negative symptoms often say they don't have friends, they don't have a job, and they don't have a life, but they really don't care. Here, hopefully new treatments, be it pharmacologic or even nonpharmacologic, can activate patients and help them see the reasons why they may want to be motivated, get in touch with life and with people, and also do something meaningful with their time.
Kane: You raise the issue of treatment and how we think about managing these comorbidities in patients with schizophrenia. Let's talk about that for a minute. Suppose you have someone who does appear to have depression. How would that affect your pharmacologic management of that patient?
Correll: Let's talk about broader management. First, we need to identify triggers. Is there anything that triggers the depression or maintains it that we can address? For example, are they ostracized or stigmatized in a certain environment? Or in a work or social situation where they're constantly not meeting the goals set for them or that they set for themselves? So, this is expectation management and also the setting. What about psychotherapy? Could they learn from other people in a skills training situation or group therapy, or would it be individual treatment? When that doesn't work, we need to understand if there are secondary depressive symptoms. Is there too much dopamine blockade? Are they very sedated during the day? When we reduce medications that are sedating, can we switch them? Do they have tardive dyskinesia that makes them really depressed because people stare at their face? Once we've addressed the issues, we can then discuss treatment of the depression itself. We fortunately now have antipsychotics, all of the most recently approved ones that are not just approved for the treatment of psychosis but also either monotherapy for bipolar depression or an augmentation for bipolar or unipolar depression. We could use those preferentially. If that doesn't work alone, we could potentially add an antidepressant into the mix of the antipsychotic.
Kane: Is there any fear that the use of antidepressants might exacerbate the psychosis? I know that was a concern at one point in time. What are your thoughts about that?
Correll: Yeah, that's interesting. I think that goes back to the 5-HT2A — the psychedelic receptor where we felt that blocking serotonin could actually help psychosis. That is the piece in clozapine that seemed different and made it atypical. That was dialed into the dopamine antagonism in the so-called atypical antipsychotics. But we now know that some of the serotonin blockade also helps depression. And we know that SSRIs (selective serotonin reuptake inhibitors) and SSNRIs (serotonin and norepinephrine reuptake inhibitors) are not like tricyclics that seem to sometimes unhinge psychosis. There are no good data to suggest that adding an antidepressant exacerbates psychosis. Maybe sometimes patients also had an underlying schizoaffective or bipolar tendency. And these antidepressants, particularly the tricyclics, were given and then exacerbated mania, which could then also present with psychotic symptoms.
Kane: I want to reemphasize the point that you made earlier — that we shouldn't immediately think of going to other medications. We should evaluate the potential causes and also try psychosocial interventions. One of the things that we saw in the RAISE study is that the patients getting the coordinated specialty care did better in terms of depressive symptoms, but yet they got fewer antidepressants, which suggests that the psychosocial treatments may have been playing a role there.
Correll: Absolutely. And they also received antipsychotics for longer periods of time. Most likely, their positive symptoms were also reduced, which then hopefully somewhat reduced their depression. Now, we talked about the reward system already in the context of depression, but the reward system seems to be somewhat down in people with schizophrenia, and that may make them more vulnerable to engage in another comorbidity, and that is substance use disorders. We said already that 50% of people with schizophrenia might be depressed at one point of their life, but it's the same number for people with schizophrenia with a substance use disorder. With smoking and schizophrenia, it's 80%. And when you look at casual use, including marijuana, it's likely between 60% and 75% of people with schizophrenia who might at one point in their life use it more regularly. Maybe you want to review what the discussion has been the around marijuana use and also making it more accessible for the risk of psychosis.
Kane: I think it's a very tricky issue, and there's certainly some concern that if the people who are vulnerable to psychosis are exposed to a lot of marijuana or cannabis, it may precipitate or facilitate the emergence of psychosis. But even that is debated. It's very hard to collect really good data on that subject. Once someone has a diagnosis of schizophrenia and they are on antipsychotic medication, it is a big clinical issue. It's interesting, I was talking to a clinician the other day who said that he believes that many clinicians lose their credibility with patients if they tell them they can never smoke marijuana again, and that it's absolutely forbidden. So what he tells his patients is that it's a judgment call. Ultimately, it's up to them, but they know what he thinks. He doesn't approach the patient with a very strict forbiddance because what he senses is that when many patients hear that, they basically say they don't want to see the doctor anymore. It's a tricky situation.
Correll: I think many people who work in the substance abuse arena have given up the strict aim of abstinence. It's reducing use and making it safer use. But going back to the risk of psychosis, there seem to be various variables at play at the same time. It has to do with the age when you start smoking. If it happens during adolescence when there is a lot of pruning in the brain going on, it may be problematic because THC (tetrahydrocannabinol) or the cannabinoid receptor agonist may interact with the formation and linking of the dopamine system. Also, when there are attenuated psychotic symptoms during childhood or when there is a family history, people seem to be at higher risk. So marijuana, per se, doesn't necessarily cause psychosis. It requires a stress diathesis combination. But what's interesting is when you look at people who have psychotic symptoms during substance use, the highest conversion to a chronic psychotic disorder actually happens with marijuana. A third of people using cannabis will have a chronic psychotic disorder. Look at methamphetamine and amphetamine — these are dopamine-related topics of substance abuse. About 20%-24% of people using these substances that have a chronic disorder. And when you look at downers, alcohol, or also opioids, it's only 10% that have chronic psychosis after having psychotic symptoms during use. So, it shows again that marijuana seems to have a very specific interaction with people who have a tendency to have psychosis. It might happen earlier, or it might actually be brought out by a trigger and stressor and wouldn't have happened otherwise. But we shouldn't forget that people have anxiety disorders, which we mentioned, and they sometimes self-medicate. They want to be more mellow and also maybe less anxious around people and use substances together so they have some social life. We need to explore this with patients. We can ask them the reason they use and determine if we can give them something else to make that reason happen. Now, when people have psychosis and use substances, there can be multiple bad effects — in addition to lots of physical problems that can ensue, there might also be more positive symptoms. There's a higher risk of relapse. There's a higher risk of nonadherence to medication because either we tell patients not to mix their drug with our drug, or they just want to not have the extra sedation or not feel the effect of the drug. There's a heightened risk for violence, suicide, and legal complaints and a greater propensity to antipsychotic-related side effects that might bring out tardive dyskinesia more. It might also cause more sedation and more weight gain. So we need to educate people about substance use. But as you say, we shouldn't bedevil it and instead see what role it plays in their life and how we can give them something else so they feel good about themselves.
Kane: Probably the reactions that patients have are very individual and idiosyncratic, so to speak. And at the same time, we have some data suggesting that adding cannabidiol to antipsychotic drugs might actually offer some benefit. So, it does paint a somewhat complicated picture.
Correll: Absolutely. We need to understand that more. The problem is that with the current tendency in cannabis production, the cannabidiol percentage has gone down so much, and THC, which is psychogenic, has gone up so much. And then there's also the synthetic cannabis that is being laced into this, which can make for a very, very strong mix that people don't even know how to handle. They want reward in their life, so how can we give something else as a reward?
Kane: The other scary thing is that when people buy these drugs on the street, they don't really know what they're getting. Some of them are laced with fentanyl. And in some ways, we could say it's good news that marijuana is legal in some states because at least people will know what they're getting. But it's obviously complicated. And then now we're dealing with this wave of interest in psychedelics. Some of our patients are also taking psychedelics. I don't think we believe that psychedelics cause psychosis, but it could be another example of something that could act as a trigger in a patient who is vulnerable. I know that everyone doing research with psychedelics is trying to be very careful about screening patients and providing the right kind of therapy as both an introduction and also management of the actual experience. So, we have to keep an eye on that, as well.
Correll: We really touched upon lots of very important comorbidities — anxiety disorders, mood disorders, and substance use disorders. In order to have a complete picture of the patient and help them as best as possible, we need to understand and manage both the underlying psychotic disorder and the psychiatric comorbidities.
Kane: Christoph, one of the challenges we see in many of our patients with schizophrenia is that they have a very high rate of smoking tobacco. Do you have thoughts about that for the clinicians listening?
Correll: It's amazing that about 80% of people with schizophrenia abuse nicotine. It seems to be something where the cholinergic system and the dopaminergic system that talk to each other are affected in people with schizophrenia. They're more prone to starting to smoke and continuing to smoke. With first-generation agents, we thought patients would smoke in order to counter some of the very distressing extrapyramidal side effects. But the smoking hasn't been going down now that we have agents that result in much fewer extrapyramidal side effects or tardive dyskinesia. I think it has something to do with the illness and again, with the reward system disruption that patients with schizophrenia experience. Helping them to not destroy their body and have much earlier cardiovascular illness, which we might want to talk about in a subsequent podcast, is important. Smoking cessation programs and nicotine patches or gums are things patients can do when they're in the inpatient unit. We shouldn't just equate and assume that schizophrenia means smoking and not even address it.
Kane: Today, we've talked with Dr Christoph Correll about comorbidities, and he's emphasized both the prevalence of a variety of comorbidities in patients with schizophrenia and the importance for us clinically to evaluate patients for the presence of these comorbidities, which may evolve at different points in the person's illness. We always have to be on the alert to identify comorbidities that might influence a patient's outcome and our decisions about treatment. We talked about the importance of psychosocial treatments, and the potential importance of psychopharmacologic treatments, and we do have a number of options. But I think the key ingredient is obviously awareness and detection. Thank you so much for your comments. I want to thank the audience for tuning in today. If you haven't done so already, take a moment to download the Medscape app to listen and subscribe to this podcast series on schizophrenia. Thank you again. This is Dr John Kane for InDiscussion.
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Cite this: Psychiatric Comorbidity in Schizophrenia: Assessing Patients and the Impact on Treatment Decisions and Outcomes - Medscape - Apr 19, 2023.