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## Rethinking the Concept of Psychosis and the Link Between Autism and Schizophrenia

Bodil Aggernæs

Child and Adolescent Psychiatry, Region Zealand, Roskilde, Denmark

Corresponding author:

boag@regionsjaelland.dk

While  searching  for  a  connection  among  the  four articles  included  in the  present  issue  of  SJCAPPand  under  the  inspiration  of  both  Craddock  and Owen (1)  as  well  as  selected  previous  research  on psychosis-I found myself on a trail leading back to Kraepelin.

## Prior experiences and delusion content

The Italian pilot study by Catone and colleagues (2) in  this  issue  focuses  on  the  relationship  between stressful experiences and delusion content in adolescents  with  psychotic  disorders.  The  authors hypothesize that a biographic continuity or 'thematic link'  can  develop  between the  themes  of  previous life experiences and  the  content of a patient's delusions.  They  examine  the  relationship  between the prior experiences and delusions of a sample of 16 patients experiencing their first psychotic episodes. The  researchers expected to find a statistically significant association between past experiences and psychotic symptom content, and they did discover a significant association between humiliating experiences and persecutory delusions. The authors suggest that the thematic link concept may provide clinicians  with  a  greater  awareness  of  the  patient's thoughts  and  emotions  and  that  addressing  past experiences and linking them to emerging or consolidated  delusions  may  make  experiences  like bullying less frightening for the patient.

## How to make sense of delusions

Although bullying may sometimes lead to psychosis, it  more  than  likely  will  not.  What  triggers  the development of psychosis? How and why are past experiences  linked  to  psychosis  in  some  patients?

How do these experiences influence the content of a patient's delusions?

With regard to the psychopathology of delusions, the  authors  of  the  Italian  pilot  study  (2)  introduce Jaspers' notion  of 'understandability' (3).  They discuss the essential problem of whether it is possible to distinguish between primary or true delusions and secondary or delusion-like ideas (2). They ask whether the application of the term understandability should  be  related  to  the  patient's  psychological history or to his or her life history, and they suggest the thematic link for use as a new way of interpreting classical psychopathology. The patient's history may offer  a  historical  understanding  that  is  easier  to comprehend  as compared  with a psychological understanding in phenomenological terms.

In a recent article, Mishura and Fusar-Poli (4) also discussed Jaspers' notion of understandability. They related  his  phenomenological  approach  to  current neurobiological  research.  Those  authors  refer  to Kapur and colleagues' concept of 'aberrant salience' (5).  They  suggest  that  primary  delusions  develop during the prodromal state to provide an explanation of the experience of the aberrant salience of innocuous stimuli that results from abnormal dopamine firing in the striatum (4).

When considering the notion of understandability, in  addition  to  the  insight  given  by  the  patient's psychological  and  life  histories  and  the  possible experience of aberrant salience, does it make sense to include knowledge about how an experience at both the conscious and unconscious levels forms through neurocognitive processing? If so, it will be important to realize how delusion content may be affected by cognitive impairment during the cognitive process of integrating the previous and present conscious and unconscious experiences.

## The origin of delusions

The authors of the Italian pilot study (2) refer to two main hypotheses regarding the origin of delusions: the  basic  reasoning  hypothesis  and  the  anomalous experience  hypothesis.  Both  of  these  hypotheses were formulated by Maher in an article that focused on the relationship between delusions and hallucinations  (6).  The  basic  reasoning  hypothesis suggests that a basic defect exists in the reasoning of deluded  individuals.  According  to  Maher  (6),  this hypothesis  dates  back  to  Kraepelin  (1889).  The second hypothesis-the anomalous experience hypothesis-states that the delusion arises in response to an attempt to explain anomalous conscious experiences (6). In addition to these two hypotheses, the authors of the Italian study refer to a third transdiagnostic approach to delusions that was presented  by  Garety  and  Freeman  (2).  In  a  recent review of the empirical cognitive psychology literature  about  delusions,  Garety  and  Freeman  (7) updated the empirical evidence regarding the relevance of a cognitive model of positive psychotic symptoms that they had previously developed together  with  their  co-researchers  (8).  This  model highlights the contribution of psychological mechanisms that involve both emotional and cognitive  reasoning  processes  (8).  When  applying this  model  to  persecutory  delusions,  Freeman  and colleagues (9) suggested that explanations considered during the search for meaning may be influenced by specific  cognitive  biases  associated  with  psychosis, including theory of mind dysfunction as well as the jumping-to-conclusions  bias  and  the  attributional bias. At least three mediators may be involved in the choice of explanation: individual beliefs about mental illness, social factors, and little belief flexibility. The assumption that the emergence of symptoms depends on an interaction between vulnerability and stress underlies this model. However, as stated by the authors,  it  remains  to  be  determined  whether  the cognitive biases associated with persecutory delusions are state or trait variables, and it is also not yet understood how  psychotic processes,  nonpsychotic processes, and the environment affect each other.  To  predict  how  and  when  precipitants  in interaction with a given vulnerability lead to psychosis,  the  dynamics  of  these  interactions  will have to be included in the model.

## Subtyping  thought  disorders  as  a  means  of identifying subgroups

The  Danish  study  by  Bundgaard  Andersen  and colleagues (10) in this issue explores the contributions of the Thought Disorder Index of the Rorschach  Inkblot  Method  to  clinical  assessment, and it examines whether the Rorschach test is helpful for the assessment of early-onset schizophrenia as a result  of  its  ability  to  detect  thought  disorder.  In addition, the researchers examine whether the Thought Disorder Index is superior to the Comprehensive  System,  which  is  another  simpler index of the Rorschach test. Although a small sample size  limits  the  conclusions  that  can  be  drawn,  the authors report results that indicate that specific types of thought disorder may be specific to schizophrenia, and they state that the Thought Disorder Index may be  superior  to  the  Comprehensive  System.  The authors conclude that, if their findings are replicated in larger studies, there may be implications for other assessments and for the subtyping of schizophrenia. Such  findings  may  help  to  define  the  underlying mechanisms of the disorder itself.

However, questions may remain about whether the identified subtle differences in the types of thought disorder  are  of  any  specific  clinical  or  research relevance. This will be the case only insofar as these different  types  by  themselves  represent  relevant targets  for  treatment  or  research.  For  example,  do they  represent  specific  domains  of  symptoms  of relevance  for  the  identification  of  early  signs  of psychosis or for preventive interventions in  at-risk individuals? Do they reflect specific biomarkers that can be used in research efforts to identify subgroups?

## Exploring 'experienced reality'

Forty  years  ago,  while  analyzing  the  concepts  of disturbed  states  of  consciousness  and  psychosis, Aggernæs  (11)  suggested  future  clinical  research should  be  inspired  by  the  academic  psychological literature  addressing  concepts  related  to  defects  in integration or differentiation and lack of coherence. Since then autism research has benefited from this type of approach. An example of this is reflected by the  central  coherence  theory  suggested  by  Frith  in 1989 (12). Cognitive theories of autism have guided autism research (13). One of the three main cognitive theories of autism focuses on impairments related to integrative  processing  (e.g.  Frith  (12)),  another  on executive dysfunctions.

With inspiration from Piaget, Aggernæs and colleagues (14) developed a reliable clinical technique to investigate experienced reality and unreality qualities that are connected to everyday life experiences in psychotic and non-psychotic individuals.  In  contrast  with  projective  techniques like  the  Rorschach  test,  the  developed  instrument provided a direct evaluation of reality testing and a more  general evaluation than that obtained by methods  that  had  been  constructed  to  uncover hallucinations  and  delusions.  The  researchers  went on to explore experienced reality in a series of clinical studies, including studies of 3- to 6-year-old children, non-psychotic adults, and patients with schizophrenia (14-16). The researchers found marked differences in the reality testing of children, non-psychotic adults, and schizophrenic patients. By the age of 3 years, children have already experienced real  items  as  being  real  with  regard  to  the  reality qualities of behavioral relevance, publicness, objectivity,  and  existence  in  the  same  way  that  has been observed in non-psychotic adults. In addition, normal  3-year-old  children  showed  a  pronounced tendency to feel able to change the real world simply through  acts  of  thought (magical  thinking); this tendency was observed to have declined rapidly and nearly disappeared in 6-year-old children. The 3-yearold  children  showed  a  pronounced  tendency  to experience imaginary items as being like real items and to think that they were not able to change such items simply by wanting them to change. This rigidity of  thinking  seemed  to  reach  a  peak  in  5-year-old children  and  to  decline  thereafter;  it  was  a  rare finding in non-psychotic adults.

In  patients  with  schizophrenia,  Aggernæs  and colleagues (16) observed that patients with schizophrenia were more prone to experience nonexisting  items  as  being  real  than  to  experience existing items as being unreal. In other words, these patients  were  more  prone  to  a  rigidity  of  thinking than to magical thinking. In conclusion, the authors stated 'that 'the real world' continues nearly completely to be real for schizophrenic patients but that there is an important tendency to experience the imaginary, non-existing world as being real too' (16).

## The link between autism and schizophrenia

Is it possible that this rigidity of thinking may reflect the core of a link between autism and schizophrenia? Could this be what connects the two disorders at the phenomenological level? In patients with autism, this rigidity is observable at the clinical level as a concrete, inflexible, and at times even literal type of thinking that-regardless  of  the  patient's  cognitive  levelmay reflect difficulties with the handling of symbolic or abstract language concepts. Although it is sometimes directly observed in patients with schizophrenia,  the  rigidity  of  thought  identified  by Aggernæs and colleagues may be less apparent at the clinical level. However, from a neurocognitive perspective,  these  cognitive  impairments  may  be comparable in nature but less severe to those seen in patients  with  autism.  In  other  words,  cognitive impairments of the same type and origin may operate at different levels of cognitive complexity in patients with  autism  and  patients  with  schizophrenia.  This would  be  comparable  to  the  different  levels  of complexity  of  thought  and  reasoning  distinguished by Piaget and suggested by him to relate to several different cognitive stages of development (17). Torres and colleagues (18) referred to Piaget's theory of intelligence and the development of thought in a study  that  compared  a  group  of  schizophrenic patients with a group of healthy controls using the Longeot Logical Thought Evaluation Scale, which is a non-verbal psychometric instrument. Their results showed marked differences between the two groups, with the schizophrenic patients performing at lower cognitive levels as compared with the control group. These findings were consistent with those of Aggernæs and colleagues (16).

The suggested view of a link between autism and schizophrenia may be consistent with a model of the complex  relationship  between  biological  variation and some major forms of psychopathology that was recently proposed by Craddock and Owen (1). Those authors also  support  the need  to reconsider a relationship between psychotic disorders and other neuropsychiatric phenotypes  (e.g., autism).  They refer to evidence that shows that structural genomic variants are a common cause of genetic variation in humans  and  that such variants are present in neuropsychiatric phenotypes, including autism, intellectual disability, and schizophrenia.

## Beliefs and practices of treatment

It  has  long  been  recognized  that  cognitive  deficits may be involved in the development of psychosis and the  pathogenesis  of  schizophrenia  (19).  Even  so, treatment  seldom  directly  addresses  the  specific cognitive deficits involved and instead focuses on the level  of  psychosis,  with  the  aim  of  reducing  the abnormal experiences with the use of antipsychotic medical treatment. Alternatively, treatment may indirectly address cognitive impairments with the use of social support or psychotherapeutic strategies to help patients cope with their symptoms.

In  the  third  article  in  this  issue,  Haapasalo-Pesu and colleagues (20) demonstrate a several-fold increase  in  the  prescription  of  antipsychotics  for children and adolescents that occurred during the 10year  period  from  2000  to  2010,  according  to  their nationwide register study from Finland. The authors state that the prescription of antipsychotic medication to minors is common and that there is frequent off-label use of antipsychotics, despite accumulating  evidence  of  serious  side  effects.  The lack of scientific data supporting these prescriptions is a serious problem that is addressed by the authors.

The growth in the prescription of antipsychotics may reflect a strong belief in hypotheses that suggest that  mental  illnesses,  including  psychoses,  result from  the  dysfunction  of  certain  neurotransmitter systems.  However,  antipsychotic  medications  have been shown to be of only moderate effect for the treatment of schizophrenia. Unfortunately, as stated by Garety and Freeman (7), no major breakthrough took place for the treatment of schizophrenia from 2000  to  2010,  regardless  of  whether  medication, psychological therapies, or social interventions were considered.

## Developmental disorders in 'adult disguise'

Symptoms of schizophrenia may evolve via several different  pathways,  thereby  reflecting  the  fact  that brain events initiated at different levels are involved in the pathogenesis of the disease.

Increasing  evidence  suggests  that  informationprocessing deficits, neurocognitive impairments, and genes involved in schizophrenia may be of essentially the same nature as those observed in children with neurodevelopmental disorders. Therefore, it may be plausible to assume that differences in the severity of illness,  the  comorbidity  of  conditions,  age-related symptom expression, and a focus on psychosis may be  what  separate  childhood  neurodevelopmental disorders  from  schizophrenia  at  the  clinical  and phenomenological levels. If so, schizophrenia may in fact be childhood neurodevelopmental disorders in 'adult disguise.' This is consistent with the observed heterogeneous character of schizophrenia, the suggestion that the term may apply to several varied conditions (21-23), and the varied effects of antipsychotic medical treatment that  have  been observed in affected patients (24-25). Differences in the severity  and  type  of  information-processing deficits  and  neurocognitive  impairments,  together with the overall degree of neurobiological involvement,  may  contribute  to  the  polymorphous and heterogeneous character of schizophrenia. Consistent  with  this  hypothesis  is  that  fact  that increasing evidence suggests that schizophrenia shares  common  genes  with  autism  and  attentiondeficit/hyperactivity disorder (26-34). Furthermore, autism, attention-deficit/hyperactivity disorder, and schizophrenia may share neurocognitive impairments (35-43) and certain symptoms (44-46).

From a genetic perspective, many genes-and not always the same ones-may be involved, with each one contributing only small psychopathological effects (23). Recent results from genome-wide association studies support this hypothesis and show genetic  overlap  among  several  major  psychiatric disorders, including schizophrenia and autism spectrum disorders (30,33). Increasing evidence suggests  that  rare  genetic  variants  of  moderate  to large  effect  size  may  play  an  important  role  in  the development of neuropsychiatric disorders as demonstrated by several studies involving the genome-wide  analysis of copy number  variants (28,31,34).  These  results  show  an  overlap  in  copy number variant loci in patients with schizophrenia, attention-deficit/hyperactivity  disorder,  and  autism

(28,31,34).  The  gene  expression  may  depend  on complicated interactions between genetic and environmental factors; for example, it  is  likely that schizophrenia develops as a result of an interaction between genetic liability and the negative impact of environmental factors (47).

From  a  neurobiological  perspective,  deficits  in information processing make up a basic vulnerability that is present before the development of manifest disease (19). Consistent with the present hypothesis is  the  idea  that  information-processing  deficits  are not  specific  to  schizophrenia;  they  may  also  be present  with  other  neuropsychiatric  disorders  (4850). Several neurocognitive and psychophysiological measures are considered candidate endophenotypes in patients with schizophrenia (36-37,51).

The  significance  of  basic  cognitive  impairments (e.g.,  dysfunctions  of  executive  functions,  working memory,  or  perception)  may  depend  on  and  be related to the level of global intellectual functioning. This is consistent with evidence that indicates that a lower  premorbid  level  of  intelligence  may  increase vulnerability to schizophrenia (52). In addition, intelligence  may  genetically  overlap  with  known cognitive endophenotypes for schizophrenia (53).

Alcohol and drug abuse may further contribute to the  development  of  manifest  disease,  with  alcohol acting  via  a  genetic  pathway  at  the  neurobiological level and via the environment at the social level (54).

## Psychosis as a social signal

From a neurodevelopmental point of view, over the course  of  an  individual's  development,  cognitive challenges increase from childhood through adolescence  and  into  adulthood.  The  relationship between the development of the brain and resulting behavior is complex, with evidence suggesting that changes  in  the  structural  brain  mirror  functional changes that coincide with improvements in cognitive and behavioral skills (55). Although subcortical  structures  appear  similar  to  their  adult forms  at  birth,  the  cerebral  cortex  is  immature  in terms  of  connectivity  between  and  within  regions, and it continues to develop into adulthood. According to Parson and colleagues (55), the timing and  changes  of  connectivity  during  the  course  of development and their relationship to environmental factors (e.g., the important parent-child relationship) require much  further  exploration, including the obtaining of longitudinal structural information and more fine-grained temporal and spatial information about the functional neuroanatomy of infant brain activity.

As  suggested  by  Garety  and  Freeman  (7)  and Freeman  and  colleagues  (9),  stress,  anxiety,  and depression  may  worsen  already  present  cognitive impairments, thereby contributing to the appearance of  symptoms  and  increasing  the  risk  for  manifest disease. Stress may be triggered by major life events, trauma, or drug misuse.

With reference to the different cognitive stages of development  suggested  by  Piaget  (17),  it  may  be hypothesized that-across the course of development and with normal distribution at different levels of cognitive complexity-some individuals  may  reach  the  limits  of  their  cognitive abilities. In addition to stress that results from major life  events  and  trauma,  some  individuals  may  be predicted to experience more enduring stress merely as a result of events related to normal development. A cognitive challenge may arise for adolescents and young adults when they leave home and have to cope all by themselves in an increasingly complex reality. Until then, family and school may have compensated for minor impairments in cognitive function or social ability.  With  increasing  age,  social  expectations  are likely to increase; this time increases pressure on the executive functions involved in the tasks of planning and  flexible  adjustment  according  to  context  in addition  to  the  need  to  be  able  to  handle  abstract thoughts and to engage in hypothetical reasoning and metacognition.  Under  these  conditions,  stress  may develop  as  a  result  of  a  discrepancy  between  the cognitive  abilities  of  and  the  cognitive  challenges presented to vulnerable individuals.

Why do apparently normal and even very intelligent  people  develop  psychosis?  Why  do  they not  question  their  unrealistic  ideas?  Why  is  it  that people in the social environment-including health care  professionals-often  do  not  realize  until  full symptoms  appear  that  individuals  who  go  on  to develop schizophrenia are vulnerable and at risk?

As proposed by Kapur and colleagues (5), psychosis  may  be  a  dopamine-mediated  state  of 'aberrant salience' of stimuli and ideas. Antipsychotic medications may dampen the salience of these symptoms  via  the  modulation  of  the mesolimbic  dopamine  system.  The  experience  of aberrant  salience  that  results  from  an  increased dopaminergic  level  may  contribute  to  the  realistic quality  of  an  experience,  thereby  reinforcing  the sense of reality of the experience. This may contribute to a resistance to questioning the content of the experience. In this way, psychosis may act as a signal that is transmitted at the social level that makes the  rest  of  society  aware  of  processes  taking  place within an individual.

## Rethinking the concept of psychosis

Psychosis  may  develop  as  a  result  of  a  primary dysfunction in the dopaminergic system and related transmitter systems, with reactions to these dysfunctions molding the individual's experience (5). This  prevalent  hypothesis  is  consistent  with  the previously mentioned anomalous experience hypothesis  (6),  and  it  may  be  in  line  with  the suggestion by Mishura and Fusar-Poli of a relationship  between  the  experience  of  aberrant salience and primary delusions (4).

In addition to hypotheses suggesting that psychosis results from dysfunctions in neurotransmitter systems, is it possible for psychosis to consist of a purely natural phenomenon that involves sensing or understanding  the  salient  features  of  a  cognitive experience  that  may  reflect  a  distorted  picture  of reality? If this is the case, cognitive impairments with no measurable abnormal changes within the neurotransmitter systems may  be sufficient for psychosis  to  develop.  The  individual  may  not  be aware that his or her thinking deviates from normal. In contrast with-although inspired by-the hypothesis suggested by Kapur and colleagues (5) is the  idea  that  psychosis  may  consist  of  a  state  of 'normal salience' of aberrant experienced stimuli or ideas. The experience of normal salience may involve a transient elevation in the dopaminergic level within the normal range that may contribute to the realistic quality  of  the  experience  by  enhancing its salience. Because changes in the dopaminergic level may not necessarily be present for this kind of psychosis to develop,  antipsychotics  may  be  less  effective.  This last  definition of psychosis may be in line with the basic  reasoning hypothesis suggested by Maher (6) while referring to Kraepelin (1889). It may also be consistent  with  the  suggestion  that  the  rigidity  of thought observed in patients with schizophrenia may reflect the same cognitive impairments that are seen at  a  more  severe  level  in  patients  with  autism  and with the observation that patients are more prone to experiencing non-existing items as being real than to experiencing existing items as being unreal (16).

## ESSENCE and developmental history

Society may affect mental illness by defining mental disorders, including psychosis and schizophrenia, as diagnostic constructs or phenomena (i.e., as categorical or dimensional representations of psychopathology or gestalts) (1,22,56-59). It is likely that symptoms may develop in processes depending on  how  they  are  conceived  and  defined  and  that these processes may therefore themselves influence the course of illness.

A few years ago, Gillberg (57) introduced the term ESSENCE -Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations-to  cover  a  group  of  often-overlapping neurodevelopmental syndromes observed in preschool  children  and  to  point  out  the  risk  of overlooking  some  symptoms  while  focusing  on others. With  the introduction of the  acronym, Gillberg sought to acknowledge that these syndromes are to some extent arbitrary endpoints or cutoff  points  on  normal  distribution  curves,  with most syndromes comprising a mixture of symptom collections from different normal distribution curves. Rather than being discrete categorical disorders, these syndromes represent brain dysfunctions and neurodevelopmental problems. Children  who  present  with  ESSENCE  problems require assessment from a multifactorial and multidisciplinary point of view.

Instruments that can be used to collect developmental  history  information,  like  the  Motor  Skills History  Form  and  the  Developmental  and  Motor History Form offered by Reiersen, author of the final article  in  the  present  issue  (60),  may  be  useful  to enhance the level of developmental and psychiatric history  gathered  during  clinical  assessment.  The author is in line with Gillberg when she states that such tools may assist with decision making related to further  diagnostic  testing  in  addition  to  providing information that is relevant to treatment needs and patient prognosis. Although the collection of developmental  history  information  is  an  important part of the clinical assessment of neurodevelopmental  disorders  in  children,  it  may  not necessarily  be  part  of  the  clinical  evaluation  of  an adult  patient  with  schizophrenia.  The  traditions  of clinical assessment in the fields of child and adolescent psychiatry and adult psychiatry may differ, with a stronger emphasis being placed on developmental history assessment for pediatric patients.

## Future perspectives

The field of psychiatry appears to be at a crossroads. To secure the progress of psychiatric research and clinical  practice, there is a need to revise concepts, methods, and overall models and to integrate knowledge from different fields. A fruitful approach may  involve  focusing  research  on  the  interface between  normal  and  deviant  thinking  and  relating processes  at  the  genetic,  physiological,  cognitive, psychological,  and  social  levels.  As  suggested  by Craddock and Owen (1), models of mental illness will have  to  consider  both  normal  and  abnormal  brain function, and psychiatry research will have to integrate evidence from various levels (e.g., molecular biology, cognitive and affective neuroscience) to move toward a coherent understanding. Such a strategy could focus on what separates  normal  from  deviant  thought  processes and whether both can be present at the same time. Future research is encouraged to focus on the tasks of  identifying  when,  how,  and  why  thought  and perceptual processes deviate from typical development;  defining  normal  and  abnormal;  and suggesting  methods  to  identify  the  mechanisms behind  all  possible  levels  involved.  The  suggested neurodevelopmental  approach,  the  cognitive  link between  autism  and  schizophrenia,  and  the  added general concept of psychosis may serve as steps in this direction.

From  a  clinical  perspective,  the  application  of complex multilevel models in research may add to our knowledge of the multifaceted nature of mental illness.  It  may  also  encourage  clinicians  to  employ multiple strategies for the treatment of schizophrenia and related disorders and to differentiate treatment according to more specific knowledge of the different subtypes of disease and their etiologies.

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