Autism spectrum disorder (ASD) and schizophrenia spectrum disorder (SSD) have been associated for decades. In 1911, Eugen Bleuler1 coined the term “autism” to describe detachment from reality and associated it with fundamental symptoms of schizophrenia.2,3 Although there is continued research into the causes of each of these conditions and how they affect the development of children, there is still difficulty in diagnosing psychotic episodes in these patients. This article reports a case of an 18-year-old man with a previous diagnosis of ASD and seizure disorder who presented to the hospital with increasing auditory and visual hallucinations along with paranoid delusions. The patient presented a unique constellation of symptoms that demonstrates the difficulty clinicians face in diagnosing them and furthers the discussion on the relationship between psychosis and ASD.
The patient was an 18-year-old man with a past medical history of ASD, attention-deficit/hyperactivity disorder (ADHD), and a seizure disorder. He presented to the emergency assessment unit accompanied by his mother due to a 2-week history of auditory and visual hallucinations. The hallucinations were persecutory and commanding in nature and caused him to be fearful for his mother's life. His mother stated that this behavior was a significant departure from his baseline. His mother reported that at baseline he usually slept little, was uncomfortable in social situations, was resistant to changes in schedules, developmentally could read and write, and was generally friendly toward others. Furthermore, although the patient was developmentally delayed, he was relatively high-functioning and was enrolled in a school-to-employment program to train for a job outside of the home. Due to these recent changes in his thought content and behavior, he was removed from the training program in which he was previously doing well. A dismissal for these reasons was of great concern to his mother.
Further concerns included a note typed on the patient's electronic tablet stating that the “demons” had told him to kill himself with poison. The hallucinations had been increasing in severity and frequency over a 2-week period, with the patient later claiming that these thoughts started bothering him up to 3 years ago, although this was difficult to assess as he was not a reliable historian. The patient reported no symptoms of mania or depression aside from difficulty staying asleep and some distractibility that had been present throughout his life. At the time of admission, the patient denied any suicidal or homicidal ideation. The review of systems was otherwise negative, and he had no physical complaints. The patient's laboratory evaluation was unremarkable, and a urine drug screen was negative for illicit substances.
The patient was deemed to not have medical decision-making capacity and was admitted on a 96-hour hold that eventually progressed to a 21-day hold. He was immediately started on 2 mg daily of oral aripiprazole and continued taking his home medications of methylphenidate for ADHD, lacosamide for seizures, lamotrigine for seizures, propranolol for tremors, and trazadone for insomnia.
The patient was born at 40 weeks of gestation to a primigravid 23-year-old woman. His mother reported no complications during pregnancy, and denied smoking, alcohol, or illicit drug use. His mother's medical history included anxiety, depression, and possible bipolar disorder. He had an uncomplicated birth but was diagnosed with pneumonia at age 2 days and was discharged from the hospital at age 5 days. He began to smile at age 1 to 2 months, rolled over at age 3 months, sat up at age 6 to 7 months, crawled at age 8 months, pulled up at age 9 months, and began walking at age 13 months. Shortly after, he was seen by neurology for enlarging head circumference and hypotonia. A diagnosis of Soto syndrome was a concern but never established. A magnetic resonance imaging scan of his brain showed possible delayed myelination but was otherwise normal. Physical, occupational, developmental, and speech therapy services were started shortly after the patient was age 1 year.
At age 3 years the patient was noted to have significant speech-language delays with echolalia as well as gross and fine motor delay. By report, he was not interacting well with peers his own age. He was observed by developmental pediatrics for these concerns. At age 5 years the patient had a partial complex seizure and was hospitalized with a confirmatory electroencephalogram (EEG). He was started on carbamazepine extended-release at discharge. A chromosome and Fragile X analysis were ordered and were negative. At age 6 years, the patient was diagnosed with ADHD. Upon entering school, he underwent extensive testing that revealed he was in the 2nd percentile in fine motor skills and had a decrease in gross motor skills that affected his participation in the educational environment based on the Peabody Developmental Motor Scale. The Wechsler Intelligence Scale for Children IV showed a full-scale IQ of 67. At age 6 to 7 years, he began to exhibit atypical behavior and rigidity with routine. For example, the patient's mother reported that he always had to be the third person in line at school and would become frustrated if this changed. He also began to exhibit aggressive behavior toward animals. He began to swing the family's ferret around on a leash by the neck. He also began to dunk the family's kittens in the toilet as well as hit their heads against the wall and laugh. After these events he was referred to a psychologist to discuss family concerns and was no longer seen in the development clinic after age 7 years. He continued to stay in communication with neurology for his seizure disorder, and he continued to have support through his school with an individual education plan and therapy services.
At age 15 years, the patient presented to a psychiatry clinic as a result of experiencing domestic abuse by his stepfather. According to the patient's mother, his stepfather did not allow him to eat at the dinner table and he was required to eat in his room. He was also required to urinate in a cup in his room and was only allowed to use the restroom to defecate. He was physically abused by his stepfather once, and he witnessed many episodes of abuse from his stepfather toward his mother. During the examination at this clinic visit, it was noted that he was appropriately dressed, had good hygiene, maintained eye contact, was friendly and cooperative, had normal speech, and his thought process was logical and goal-directed. He did not return for a follow-up appointment.
At the beginning of the patient's 21-day stay, neurology was consulted, a medical examination with an EEG and head computed tomography scan were found to be unremarkable, and B12 and folate levels were within normal limits, leaving a differential diagnosis to include psychiatric causes of the patient's new-onset psychosis. Early on in his stay, the patient was pleasant at the start of any conversation. He was often sitting by himself with his journal either writing or drawing. Journaling was not new to him as he liked reading “fan fiction” online about his favorite characters and also liked to write his own stories. During these early conversations, when asked about the visions and hallucinations, he reported that the characters he was seeing were like some of his favorite anime characters but “the evil versions.” These “premonitions,” as he called them, were previously in his dreams but recently started bothering him during the day. He was open about sharing that these premonitions were “listening to our conversation.” He insisted on showing what he had written in his journal about these premonitions and what they were telling him. A review of his journal showed lists of names of the characters that were talking to him and statements he had written to these voices such as, “I bind and cast you out.” His insight into these premonitions was intact and he repeatedly asked for help getting rid of them as he knew they were not supposed to be there. During these conversations he ruminated on specific topics such as the time and when he was going home.
Further into the patient's stay, he was still agreeable at the start of a conversation but there was increasing evidence of thought blocking. The patient would begin to stare when asked a question or simply ignore the interviewer altogether. Direct questions about the hallucinations or visions went unanswered at times, as did questions about sleeping and appetite. He still was pleasant and engaged with staff and peers on the unit at times, but his group participation was minimal, and he would frequently leave group sessions. The patient's positive attitude waxed and waned, as he sometimes reporting that he was not hearing or seeing anything and other times reported continued delusions and hallucinations, such as claiming there were ghosts in his room and that he needed an exorcism.
Toward the end of his 21-day stay the patient continued to give a complex picture of his delusions. He reported that the anime characters he saw “may be able to come to the physical world” and that one may have stolen his body and was controlling his mind. He stated that he went to another universe in a dream even though that seemed impossible for him to do in real life. He expressed multiple times that he was supposed to “save” certain characters. He reported a dream of a “Goddess” and stated he was in “phase trooper armor” almost as if he was to guard the Goddess. He reported that these characters were in his dreams and that he does not see them when awake, but also repeatedly asked the interviewer when the Goddess would return. The patient denied that these delusions were affecting his thoughts or behaviors and he was not concerned about any harm coming to his mother, which further complicated the discussion. Was he distorting reality from fantasy or were these active hallucinations?
The patient was started on 2 mg of aripiprazole upon admission, and during the hospitalization aripiprozole was increased to 20 mg daily with no relief of symptoms. It was decided to switch the patient to 3 mg daily of extended-release paliperidone, and the aripiprozole was tapered off. On the last day, the patient reported no auditory or visual hallucinations, denied suicidal ideation, and denied fears of his mother being harmed. He was cheerful and smiling in the week leading up to his discharge and had been smiling when talking about his delusions, which was a change from admission when he appeared fearful and was asking for help. Although there was discussion of some symptoms occurring as early as 3 years prior to his admission, due to the patient's history of autism and lack of clinical presentation during that time, along with the acute change from baseline, a tentative diagnosis of schizophreniform disorder was given. The patient was discharged as it was felt that although his condition may wax and wane, he appeared stable overall and posed no danger to himself or others at that time.
Although the diagnostic criteria of schizophrenia and ASD are seemingly distinct, there appears to be some relationship between these two disorders. Cochran et al.4 explained that there is a group of people with atypical neurodevelopment that increases their susceptibility to hallucinations, social deficits, and excessive interest in fantasy. They suggest that these people are at greater risk of developing psychiatric disorders in adolescence and young adulthood.4 Sahoo et al.5 furthers this discussion, stating that it can become difficult diagnosing someone with a prior diagnosis of ASD when they present with these psychotic symptoms.
According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition,6 the diagnostic criteria for schizophrenia include symptoms of delusions, hallucinations, disorganized speech and behavior, as well as negative symptoms. Along with these symptoms, there must be a significant decrease in baseline functioning and symptoms must be present for at least 6 months. In contrast, ASD has its own distinct criteria with deficits in social communication and social interaction across multiple contexts with restricted repetitive patterns of behavior causing a significant disturbance in functioning.6 Furthermore, epidemiologically, these two disorders seem distinct at first glance. The prevalence of ASD in the United States has been increasing in recent years, and it is now estimated that 1 in 38 boys and 1 in 151 girls have ASD.7 Further, ASD affects boys 3 to 4 times more than girls, and the age of onset is in the early developmental years.7 Meanwhile, the prevalence of schizophrenia spectrum disorders are close to 1.5 per 10,000 worldwide and most commonly have an onset in the late adolescent and young adult years.8 Furthermore, males are only slightly more affected than females, with a ratio of 1.4:1.9
When looking at these disorders from this viewpoint, it may be difficult to see a connection, yet Cochran et al.4 feel that the conversation can become complex when psychotic symptoms are reported and that it takes a careful history and time to sort out the details. For example, impairment in nonverbal communication in ASD can be viewed similarly to social withdrawal, abnormal preoccupation with stereotyped interests can be misinterpreted as delusions, and impairments in social communication can be attributed to negative symptoms of schizophrenia. Furthermore, there are many studies and case reports of presentations of autism in childhood with progression to a schizophrenic-type disorder. There is also controversy, with case reports arguing that patients exhibit these symptoms as manifestations of their autism. In a longitudinal study, Mouridsen et al.10 observed 89 patients with atypical autism and found that 68.5% had been in contact with psychiatric hospitals and 38.4% had been diagnosed with SSD. Additionally, a study by Hallerback et al.9 showed that of the 46 patients who were diagnosed with schizophrenia, about one-half showed symptoms of ASD. In contrast, Van Schalkwyk et al.11 report five cases of psychosis in which patients had a previous diagnosis of ASD. They pose that each individual case can be better understood as “part of their underlying ASD diagnosis.”11 Even with opposing theories, there seems to be some connection between these two disorders as the prevalence of schizophrenia in patients with autism seems to be above the international rate of 1% per 10,000.8
Although our diagnostic systems delineate these disorders, further study seems to show that these disorders are closer than we may appreciate. Genetic associations appear to link these two disorders, as both are highly heritable. Although almost one-third of patients with schizophrenia have a genetic contribution and 49% of patients with ASD have a genetic component, the genetic overlap between schizophrenia and ASD is small.12 With that in mind, recent data from genetic studies showed comorbidity with ASD and schizophrenia in the 22q11.2 deletion syndrome. In patients with this genetic syndrome, there were higher rates of ASD (20%–50%) and psychotic symptoms (26.7%).3 Although this specific connection needs to be investigated further, it gives credence to the idea of a genetic association.
Continued research seems to implicate even more overlap between the two disorders. A review by Meyer et al.13 discusses the idea that these disorders share common qualities at the behavioral, anatomic, cellular, and neurochemical level. They also suggest that schizophrenia and ASD share environmental risk factors such as prenatal exposure to infection and subsequent prenatal inflammation. One hypothesis poses that exposure to inflammatory mediators can alter brain development in the fetus and increase the risk of brain dysfunction later in life.13 A similar theory regarding these disorders is presented by Prata et al.12 They suggest inflammatory cytokines are players in aberrant neurodevelopment and contribute to vulnerability to conditions such as ASD and schizophrenia. Prata et al.12 highlight many of these possible biomarkers and found that a pattern of dysregulation of specific cytokines and micro-RNAs was seen with SSD and ASD. Although specific associations and functions require further exploration, there is ample evidence to suggest a connection between these biomarkers and these two disorders. For example, increased levels of interleukin-6 were seen in ASD, specifically in children with regressive autism. Interleukin-6 was also increased in schizophrenia, specifically correlating with negative symptoms. Prata et al.12 suggest that with the increasing study of noncoding RNA, information will be gleaned as to the association of inflammation and behavioral disorders and measurement of specific biomarkers. With further study, the use of these biomarkers may assist in the prognosis and treatment of these disorders and will shed light on the understanding that these disorders may be part of similar spectrums, with each person presenting at a specific locus on that spectrum based on their neurodevelopment, inflammatory cytokines, biomarkers, and genetic profile.
Although the patient was diagnosed with autism as a child, there were signs pointing to an underlying psychotic disorder as well. The patient had significant developmental delay and atypical neurodevelopment exhibited by his seizure disorder and intellectual disability. His family history is significant for mental illness. He exhibited aggressive behavior as a young child with cruelty to animals and saw a counselor for unspecified family concerns. As discussed previously, associations between brain development and inflammatory pathways suggest that he was at higher risk of developing a psychotic disorder. Furthermore, the patient experienced significant stress at age 15 years exhibited by his presentation to a psychiatrist's office after abuse from his stepfather leading to a social factor in his trajectory toward a diagnosis of psychosis. This is consistent with studies that have shown that childhood adversity, acute stress, and impaired stress tolerance are associated with prodromal symptoms and play a role in triggering psychosis.14
The patient in this case paints a unique picture of the relationship between autism and psychosis. It appears that his previous diagnosis of ASD placed him at an increased risk of experiencing a psychotic episode. As discussed, this case is difficult to parse out because his positive symptoms of hallucinations could be attributed to his overwhelming interest in fantasy or could be an early manifestation of schizophrenia. His negative symptoms of withdrawal and isolation could be part of his autism disorder, or they could represent the negative symptoms of schizophrenia. It is clear, though, that the patient had a decrease from baseline functioning and required stabilization through medical and therapeutic management.
At the time of this writing (more than 1 year from his initial admission to the hospital), the patient has been followed in clinic regularly. Just 8 months after his first admission, the patient was admitted to the hospital for 25 days for hallucinations telling him to shoot himself. Specifically, he was having hallucinations of a movie character entering into this dimension and telling him to kill himself. A note was written on his electronic tablet that was found by his mother and provided to physicians upon admission that conveyed his concerning thought process. At this admission, the patient was taking olanzapine, which was continued for a short time. During his hospital stay, it was thought that he was experiencing anxiety and depression so citalopram was started and titrated up to 40 mg daily. He continued to hallucinate during his hospital stay and it was decided to prescribe clozapine. An initial dose of 12.5 mg daily was started and titrated up to 150 mg daily while the olanzapine was discontinued. Additionally, he was started on lorazepam for catatonic features, which responded well to a dose of 1 mg four times per day. He was discharged with close follow-up for blood work and monitoring of his mental health. While being observed in clinic every 6 to 8 weeks, it was decided to increase the clozapine to his current dose of 225 mg daily. He continues to hallucinate and reference fictional characters demanding things from him, although they are not violent or harmful in nature. He currently attends a day program during the week as his mother did not want him left alone at home. They day program is going well and his mother reports improvement from his baseline.
The line between ASD and psychosis appears to be distinct on the surface, but further study suggests that these two disorders share a commonality and a vulnerability toward each other. Careful discussion, history taking, and long-term follow-up is warranted to elicit understanding into the perceptual experience of the patient. Genetics, birth and developmental history, behavioral observations, and response to treatment may help in diagnosing and treating a person with suspected psychotic episodes. Intricacies between SSD and ASD are difficult to discern but may have implications in the patient's overall prognosis. Furthermore, future discussion and study of patients with atypical autism and psychotic episodes may lead us to discovering molecular pathways underlying these symptoms. These discoveries could show great promise into preventing aberrancies at key intervals in development.
- Bleuler E. Dementia praecox oder gruppe der schizophrenien. In Aschaffenburg G (ed): Handbuch der Psychiatrie. Spezieller Teil 4. Abteilung 1. Hälfte. Leipzig/Wien, Austria: Deuticke, 1911:1–420.
- Hoff P. Eugen Bleuler's concept of schizophrenia and its relevance to present-day psychiatry. Neuropsychobiology. 2012;66:6–13. doi:10.1159/000337174 [CrossRef]22797272
- Raja M, Azzoni A. Autistic spectrum disorders and schizophrenia in the adult psychiatric setting: diagnosis and comorbidity. Psychiatr Danub.2010;22(4):514–521. PMID:21169891
- Cochran DM, Dvir Y, Frazier JA. “Autism-plus” spectrum disorders: intersection with psychosis and the schizophrenia spectrum. Child Adolesc Psychiatr Clin N Am. 2013;22(4):609–627. https://doi.org/10.1016/j.chc.2013.04.005 PMID: doi:10.1016/j.chc.2013.04.005 [CrossRef]24012076
- Sahoo S, Padhy SK, Singla N, Singh A. Psychosis in a child with atypical autism: a case report and a brief review of the association of psychosis and autism. Innov Clin Neurosci. 2018;15(3–4):33–36. PMID:29707425
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
- Augustyn M. Autism spectrum disorder: Terminology, epidemiology, and pathogenesis. Uptodate.com. https://www.uptodate.com/contents/autism-spectrum-disorder-terminology-epidemiology-and-pathogenesis?search=autism%20spectrum%20disorder&source=search_result&selectedTitle=4~146&usage_type=default&display_rank=4. Accessed October 3, 2019.
- Fischer B, Buchanan R. Schizophrenia in adults: epidemiology and pathogenesis. Uptodate.com. https://www.uptodate.com/contents/schizophrenia-in-adults-epidemiology-and-pathogenesis?search=schizophrenia&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3. Accessed October 3, 2019.
- Hallerback M, Lugnegård T, Gillberg C. Is autism spectrum disorder common in schizophrenia?Psychiatry Res. 2012;198(1):12–17. https://doi.org/10.1016/j.psychres.2012.01.016 PMID: doi:10.1016/j.psychres.2012.01.016 [CrossRef]
- Mouridsen SE, Rich B, Isager T. Psychiatric disorders in adults diagnosed as children with atypical autism. A case control study. J Neural Transm (Vienna). 2008;115(1):135–138. https://doi.org/10.1007/s00702-007-0798-1 PMID: doi:10.1007/s00702-007-0798-1 [CrossRef]
- Van Schalkwyk GI, Peluso F, Qayyum Z, McPartland JC, Volkmar FR. Varieties of misdiagnosis in ASD: an illustrative case series. J Autism Dev Disord. 2015;45(4):911–918. https://doi.org/10.1007/s10803-014-2239-y PMID: doi:10.1007/s10803-014-2239-y [CrossRef]
- Prata J, Santos SG, Almeida MI, Coelho R, Barbosa MA. Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations. J Neuroinflammation. 2017;14(1):179. https://doi.org/10.1186/s12974-017-0938-y PMID: doi:10.1186/s12974-017-0938-y [CrossRef]288702095584030
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