John J. Miller, MD: Dr Carney, this is a big question. What would you say are some of the risk factors that can influence the course of schizophrenia? And just to raise a few: the benefits of early intervention; the unfortunate effects of substance use disorders; medication nonadherence as Carlos [Larrauri, APRN] brought up, which can be caused for many reasons; and psychosocial stressors.

Caroline P. Carney, MD, MSc, FAPA, FAPM, CPHQ: If we start with the risk profile, what are those risk factors? One can often bucket those into genetic risk factors, external risk factors, maternal health risk factors, comorbid medical factors, and others that contribute [such as] infection or inflammatory disease. We know that the genetic risk factors are well described in schizophrenia, both in [findings from] individual studies and in [findings from] identical twin studies that show that genetic risk factors are key. Epigenetics plays a role in that as well with an individual who has a genetic predisposition to a condition, but something in the environment either triggers or doesn’t trigger…the risk for that disease to develop. We talked earlier about factors [such as] racial and ethnic issues related to immigration, living in adversity, living in lower socioeconomic status, and poverty. Having poor access to food, exercise, and so on. All those [factors] that lead to increasing life stressors also act as triggers to this. Infections have been well described in terms of what happens in an individual having been exposed to toxoplasmosis, influenza, and other [conditions] during the prenatal phase. And during birth and development, early birth, low-weight birth, ICU [intensive care unit] stays, those sorts of things have been described in [findings from] epidemiologic studies to be contributors. So there’s a lot to think about in terms of what those risk factors are for development. For someone who is developing schizophrenia, missing the prodromal phase where there is an ability to interact with that individual early and engage in symptom control and the kind of cognitive remediation or the cognitive strengths that we need to work on, developing psychoeducation at that point, those interventions that could happen early on are missed if we missed the prodromal phase. The early treatment of psychosis programs that we’ve described earlier are essential in determining long-term outcomes for the condition and another way that we can determine how we deal with some of those risk factors, how we can mediate some of those risk factors in that early phase to lead to a better outcome. Medication adherence is a multifactorial issue. Going back to social determinants, it may be something that individuals can’t afford. They may not know how to navigate the complex insurance world to get medications in hand or be able to have transportation to go to the pharmacy to pick them up. Or [they may] not have a consistent mailing address for medications to be delivered. In large data sets that I study across the country, we often, on a cross-sectional view, see 50% of individuals with schizophrenia on no form of treatment at any time. With a long look at that and following over time, the rates of hospitalization, emergency department use, and so on are much higher in that group. So again, [it’s] a modifiable risk factor that’s very predictive of what an outcome could look like for that individual. I think you may have said one other.

John J. Miller, MD: Substance use disorders.

Caroline P. Carney, MD, MSc, FAPA, FAPM, CPHQ: Absolutely. Substance use disorders contribute in a variety of ways. They can complicate the diagnosis from the beginning. I referred earlier to many clinicians having a simple cross-sectional view of an individual when they appear in a crisis setting, in an emergency department setting. They may or may not be on substances at that time. When they are, many substances can lead to the appearance of psychosis. So in individuals who are using substances, it’s often challenging to tease out what’s the schizophrenia, what are the core symptoms of the condition, vs what is related to the substance or are symptoms just being fueled? Or is that individual using substances to try to mediate the symptoms they may be having? So it’s very challenging to do that on a cross-sectional basis. When we look in the long term, substance use tends to lead to more cognitive decline, more social disruption for individuals, [and] and a lower ability to stay in employment or to stay in social settings. Complicated by the schizophrenia, it’s the perfect storm for an individual to have a poor outcome. It is something that can be addressed and should be addressed in the right kind of evidence-based programs.

John J. Miller, MD: And just to pull in your comment about the prodrome and how challenging that is, an issue that I hear wherever I go and get a lot of questions about is…the role of THC [tetrahydrocannabinol] in terms of increasing the risk of psychosis. And we know that the brain is neuroplastic and goes through prunings in early adolescents and [individuals in their] early 20s. We know that neurodevelopmentally there are always things going on. And there is strong literature that demonstrates that for heavy cannabis users. I should say heavy THC users, because cannabis is a complex array of different molecules. But for heavy THC users, there is up to a 500% increase in having their first psychotic episode or at least bringing that on earlier than it would’ve otherwise. The THC can also increase the time to relapse, and that’s difficult to [manage]. It’s one of those things where because it’s being legalized in so many states, a lot of people view it as a benign or safe drug. And I always rebut with, “Well, alcohol’s legal.”

Caroline P. Carney, MD, MSc, FAPA, FAPM, CPHQ: I am right there with you. And it’s a perfect example of looking at epigenetics as well. Do we know whether the THC in and of itself is the risk factor? Or is it triggering?

John J. Miller, MD: Amplifying an underlying predisposition.

Caroline P. Carney, MD, MSc, FAPA, FAPM, CPHQ: That’s exactly right. But I am with you in fearing what we’re going to see in the future with the legalization of THC because of the ease of access.

Transcript edited for clarity.