Kristin Cadenhead, MD.
Professor of psychiatry. Director, Cognitive Assessment and Risk Evaluation (CARE) Early Psychosis Treatment and Research Program, University of California, San Diego.
Dr. Cadenhead has no financial relationships with companies related to this material.
CCPR: How often does psychosis co-occur with autism?
Dr. Cadenhead: It’s more often than the 1% in the general population. A 2022 meta-analysis looked at 53 studies on children and teens and found the co-occurrence of psychosis in autism was about 9% and, separately, bipolar disorder (BD) was 7.5% (Varcin KJ et al, Neurosci Biobehav Rev 2022;134:104543). With BD you can also get psychotic symptoms. Interestingly, in this meta-analysis, autistic males were more likely to develop schizophrenia, and autistic females were more likely to be diagnosed with BD. Adults with autism with normal IQs have lower rates than those with low IQs. In one systematic review of psychosis patients, only seven studies met inclusion criteria, and the range was huge, with 9%–61% of psychotic patients showing autistic traits (Kincaid DL et al, Psychiatry Res 2017;250:99–105). More large-scale studies would be helpful to better understand the rate of co-occurrence.
CCPR: How severe are psychotic symptoms in autistic vs non-autistic kids?
Dr. Cadenhead: One study found the severity of psychotic symptoms was about equal in people with schizophrenia spectrum and patients who are autistic and have psychotic symptoms (Sunwoo M et al, Schizophr Res 2020;216:310–315).
CCPR: Are there shared risk factors for psychosis and autism?
Dr. Cadenhead: Yes, including obstetrical complications and urbanicity. Being a first-generation immigrant, the child of an immigrant, or in a minority within an immigrant population can put people at risk for both (Morinaga M et al, Eur J Public Health 2021;31(2):304–312; Brandt L et al, JAMA Psychiatry 2019;76(11):1133–1140). While I haven’t seen puberty as a risk factor for psychosis in autism in the literature, I have seen autistic teens who misinterpret the intent of others, thinking the other person likes them when they don’t. It can look like an erotomanic delusion, possibly driven by hormonal changes.
CCPR: Are autistic kids who use cannabis more prone to psychosis?
Dr. Cadenhead: Yes. Autism increases their vulnerability to psychosis caused by cannabis, but it may also reduce substance use behavior in some individuals (Bortoletto R and Colizzi M, Healthcare (Basel) 2022;10(8):1553). One study in the Varcin meta-analysis showed co-occurring psychosis and autism predicted less substance use and higher employment than neurotypical kids (Varcin et al, 2022).
CCPR: Symptoms like unusual affect, social isolation, misperceiving social interactions, and even suspicious thinking happen in both autism and psychosis. Are there specific questions that we can ask to sort out whether a patient has autism, psychosis, or both?
Dr. Cadenhead: I get a careful developmental history to look for psychotic symptoms in earlier childhood. I look for changes in behavior compared to baseline symptoms. They may have always had idiosyncratic interests or trouble reading other people. But when it changes into something that is not characteristic of that individual, like a belief that the government is monitoring them, that may be a psychotic symptom.
CCPR: Are there tests or other tools to differentiate psychotic symptoms from autistic ones?
Dr. Cadenhead: There’s no specific test. Neurocognitive tests can look at theory of mind and the ability to interpret the intent of others. People with schizophrenia have intact theory of mind and can read social cues prior to the onset of their illness. With autism, those difficulties would have been there from early on. Genetic tests are nonspecific; for example, schizophrenia and autism are both associated with 22q deletion syndrome (a multiorgan genetic condition also known as DiGeorge or velocardiofacial syndrome).
CCPR: Is there a general timing to the onset of psychotic symptoms for schizophrenia, BD, and schizoaffective disorder in autism that can help us to sort out the nature of the psychotic symptoms?
Dr. Cadenhead: In my clinical experience, the age of onset of psychotic disorders in autism is in line with what you see in non-autistic cases. Affective disorders can occur at younger ages than schizophrenia. It is rare for schizophrenia to begin before age 15, so if I see psychosis in a young adolescent, I am highly suspicious that it is an affective psychosis. There are also other clues: Sometimes young patients become psychotic after an antidepressant is initiated. This suggests that they have a predisposition to BD or schizoaffective disorder rather than schizophrenia.
CCPR: Does prodromal schizophrenia look like autism?
Dr. Cadenhead: It can look like autism and can last from a few weeks to a few years, with symptoms including neuromotor deficits and learning disabilities. Since it’s a retrospective diagnosis, you can’t say it’s prodromal until the patient becomes psychotic. To identify individuals at clinical high risk (CHR) for psychosis, we look for subsyndromal positive symptoms like perceptual changes where they think they hear things or see things, but they still have insight and realize “I know this sounds weird, but I think I hear a voice talking to me.” They have some insight and haven’t lost touch with reality. Same thing with delusions. They may be a bit paranoid, but if you push them, they’re able to say “Yeah, I realize I’m just insecure sometimes and self-conscious, so I think people are talking about me.” Negative symptoms like social isolation can also be present in CHR youth.
CCPR: Are there other risk factors that can predict which prodromal kids will become psychotic?
Dr. Cadenhead: We can predict about 25% who will become psychotic using clinical criteria alone. We developed a “psychosis risk calculator” that incorporates other variables, such as neurocognition, that can predict with greater certainty who will become psychotic. Use of the calculator requires the results of the Structured Interview for Prodromal Syndromes (SIPS), neurocognitive tests, and other specialized functional assessment scales (Cannon TD et al, Am J Psychiatry 2016;73(10):980–988).
CCPR: Is there an advantage to looking for a diagnosis other than psychosis to explain the symptoms?
Dr. Cadenhead: Yes, you may find other conditions that are more responsive to treatment. Many non-autistic kids have ADHD, anxiety, or depression, which are important to treat and might be present before somebody notices new odd thinking. With young autistic people, I look for bipolarity if psychotic symptoms are emerging because there may be a better prognosis for affective psychoses. Those tend to be episodic and don’t persist the way schizophreniform psychoses do.
CCPR: How do you talk with families about psychosis and autism?
Dr. Cadenhead: I talk to them about the psychotic symptoms, and we collaborate with clinicians with expertise in autism. These are complicated cases. But when the voices calm down and stop interfering, many patients care about relationships, independence, work, or school. A lot of young adults are annoyed about living with their parents. It’s about setting goals. I’ll ask “What kind of functionality do you want to get to? What steps do you need to take to get there?”
CCPR: Are there specific cultural impacts that might make it harder to clarify psychosis vs autism in certain populations?
Dr. Cadenhead: It varies by family and culture. Some children, depending on access to health care, are not diagnosed early with neurodevelopmental disorders. Certain communities avoid mental health care because of stigma. Some families have high expectations of kids and have trouble accepting their mental health issues. Some families don’t tell me that their child is autistic. This history is important in making a diagnosis of a psychotic spectrum disorder vs autism.
CCPR: How does treatment differ in the use of antipsychotics with kids who have a single diagnosis of autism vs psychosis?
Dr. Cadenhead: One study found that people with co-occurring autism may not be as responsive to antipsychotics (Downs JM et al, J Clin Psychiatry 2017;78(9):e1233–e1241). Autistic kids have increased stress related to sensory, motor, and communication challenges. They may have more psychotic symptoms related to stress, so reducing stress with individual therapy or helping them to reinterpret things through social skills training could relieve these symptoms. I also look for bipolarity or severe depression with psychotic features that might respond to mood stabilizers without an antipsychotic. But if it’s a persistent and fixed delusional belief or hallucinations, then you’ll likely need antipsychotics.
CCPR: What antipsychotic medications do you start with?
Dr. Cadenhead: I start with a second-generation antipsychotic that’s more weight-neutral (eg, lurasidone or aripiprazole) or has a long-acting depot form (risperidone, paliperidone, or aripiprazole). If the first antipsychotic doesn’t work, I switch to one that has different pharmacologic properties because some are dopamine D2 receptor-focused and some target multiple receptors like serotonin. Side effect profiles also help. For example, olanzapine can help sleep disturbances. Not all insurance plans approve newer antipsychotics, so I start with psychotropics that are typically covered.
CCPR: What can you say about the risk of seizures in autistic kids taking antipsychotics?
Dr. Cadenhead: I have not seen many autistic people with seizures, although I know this occurs. I saw one patient who had a lesion in his brain causing seizures. The neurology service put him on lamotrigine, and I continued him on antipsychotics but took him off bupropion because it can lower the seizure threshold. Work with a neurologist if the patient also has a seizure disorder.
CCPR: What do you do if people aren’t responding to antipsychotics? Do you use pharmacogenetic testing?
Dr. Cadenhead: Check blood levels and consider long-acting injectable antipsychotics to improve compliance. We move to clozapine early if somebody fails at least two atypical antipsychotics. If there are illicit drugs involved, that might explain why they haven’t responded. Pharmacogenetic tests don’t tell you about efficacy of an antipsychotic for a particular person, more about how they metabolize the drug, and that doesn’t necessarily correlate with clinical response, but there are rare ultra-fast metabolizers.
CCPR: If you think there is bipolarity, what mood stabilizers do you use?
Dr. Cadenhead: I favor lithium because it has both antimanic and antidepressant qualities. Some people use lamotrigine, but there is not much evidence for its use in mania. Lamotrigine is typically used more in BD II where depression is prominent. You can also use atypical antipsychotics like lurasidone or aripiprazole for mood instability. For a depressive component, I pick agents approved for bipolar depression (aripiprazole, quetiapine, lurasidone).
CCPR: How difficult might it be to treat schizoaffective disorder with autism?
Dr. Cadenhead: The treatment of schizoaffective disorder is similar to treatment of affective disorders and schizophrenia. In my experience, I use the same pharmacologic strategies as I do in non-autistic kids, but I often find a therapist experienced with social skills training, family therapy, and other therapies that are more specific for autism.
CCPR: What about the use of stimulants when we are concerned about psychosis?
Dr. Cadenhead: I’m cautious with stimulants in anybody who’s been psychotic. Clinicians who often treat BD may feel comfortable with patients on mood stabilizers using stimulants without inducing a psychotic episode. I would proceed with caution and treat the BD first before even considering targeting ADHD.
CCPR: Do you use alternative or complementary approaches?
Dr. Cadenhead: Some people hope to avoid medications or use unstudied herbal treatments. We recommend evidence-based psychotherapies like cognitive behavioral therapy for psychosis and social skills training. We are interested in omega-3, cannabidiol (CBD), anti-inflammatory interventions related to diet, and mindfulness meditation, but we need more studies. We have ongoing clinical trials with CBD, anti-inflammatory diet, and family-focused therapy.
CCPR: What are your thoughts about prognosis for these patients?
Dr. Cadenhead: Co-occurring autism and psychosis are more difficult to treat, and the patients I see tend to need more resources. I think there’s more negative stigma with purely psychotic patients because people worry that they’re dangerous. Autistic patients with psychosis may be less frightening, and that might explain why they may find jobs more easily, even though they too are underemployed.
CCPR: Thank you for your time, Dr. Cadenhead.
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