Does biology read the DSM?

This was the provocative title of a symposium that took place during this year’s SIRS conference in Florence. New studies investigating whether the mechanisms underlying schizophrenia are specific solely to it or are also present in other psychotic illnesses were presented. And - spoiler alert - the overall consensus from genetic, imaging and clinical approaches is ‘No’!

Genes and genomics

Genetic data supporting this opinion came from Michael Owen, Cardiff, UK. He explained that psychiatric disorders have a complex, polygenic genetic architecture. Genome–wide association studies (GWAS) have been used in the systematic search for common alleles in mental illness. These show that considerable genetic risk is conferred by hundreds of variants with different small risk elements that likely exert differential effects over the course of the disease. Some variants do, however, confer relatively high risk of schizophrenia and, while these variants are rare, they do exhibit high penetrance.

Genetic risk is conferred by hundreds of variants with different small risk elements that likely exert differential effects over the course of the disease

Genes operate across current diagnostic categories

Dr Owen then showed that there is considerable pleiotropy with overlap in genetic risk between disorders as they are currently defined. Furthermore, genes operate across current diagnostic categories. Considering the conditions of intellectual disability, autism, ADHD, schizophrenia and bipolar disorder, there is increasing evidence not only for familial overlap but also overlap in clinical similarities e.g., impaired cognition, social cognition, developmental delay, neurological signs and motor abnormalities, and intrauterine and perinatal risk factors. Furthermore, there is significant comorbidity displayed in each condition which is often overlooked or deprioritized in diagnostic clinical practice.

He suggests that schizophrenia is one of a range of possible outcomes resulting from disrupted brain development caused by genetic and/or environmental factors. For example, with a decreasing number of copy number variants (portions of the genome that are repeated), there is a risk continuum than ranges from intellectual disability to autism to schizophrenia to bipolar disorder. 

Schizophrenia is one of a range of possible outcomes resulting from disrupted brain development caused by genetic and/or environmental factors

A meta-analysis of rare coding variants in whole-exome sequences supports this finding. In those individuals with schizophrenia, those patients co-presenting with schizophrenia and intellectual disability genetic defects have a higher burden of risk genes associated with neurodevelopment disorders than those patients without intellectual disability.

Genetic findings, thus, support the notion of a neurodevelopmental continuum and gradient of neurodevelopmental severity which may lead not only to schizophrenia but to other mental health problems.

Imaging studies

Neuroimaging studies also support there being common, dopaminergic alterations leading to psychosis across disorders. Oliver Howes, London, UK, presented data showing striatal dopamine synthesis capacity increases only in patients with schizophrenia or bipolar disorder who exhibit psychosis; striatal dopamine levels in those patients with subclinical symptoms showed no elevation. 

Striatal dopamine synthesis capacity increases in psychosis

However, he asked, is all presynaptic dopamine synthesis linked to all types of psychosis?  Differences in dopamine synthesis are seen in patients with schizophrenia who respond to dopaminergic agonists (and exhibit hyperdopaminergic responses) compared to those that are treatment resistant (and exhibit normodopaminergic responses).  This appears to be the case even from a first psychotic episode and suggests the disorder exists in at least two different forms and is, therefore exhibiting heterogeneity.

Brain heterogeneity – yes and no

Is there heterogeneity in other brain alterations in schizophrenia, Dr Howes asked. A meta- analysis of brain structural findings from 108 studies would suggest that there is but other data may suggest otherwise.

Using fMRI data, the relative variability of regional brain volumetric measurements in patients was compared with control groups using two statistical assessments borrowed from ecology (a field used to dealing with variability in systems): the variability ratio (VR) and coefficient of variation ratio (CVR). While increased heterogeneity was seen in temporal and subcortical regions, there was no alteration in the caudate. Intriguingly, increased homogeneity was noted in the anterior cingulate cortex suggesting this as a core region affected in schizophrenia.

Increased homogeneity in the anterior cingulate cortex suggests this as a core region affected by the disorder

How does this relate to dopamine function in schizophrenia? There appears to be an inverse relationship between striatal dopamine levels and anterior cingulate glutamate levels in patients exhibiting psychosis, suggesting both brain areas are closely involved in the pathology of psychosis.

B-SNIP clinical approach

B-SNIP wants to develop classifications of these conditions based on biological measurements

The symptoms used by clinicians when diagnosing psychotic and mood disorders (such as schizophrenia and bipolar disorder) overlap - a lot, Brett Clementz, Georgia, USA explained. The Bipolar–Schizophrenia Network on Intermediate Phenotypes (B-SNIP) wants to develop classifications of these conditions based on biological measurements, which may prove effective at identifying causes and treatments.

Professor Clementz demonstrated how it is possible, using EEG and cognitive data collected from patients with schizophrenia, schizoaffective disorder and bipolar disorder with psychosis, to pool and rearrange the elements of psychosis to create three different biotypes. That these biotypes were biologically distinct rather than a statistical anomaly was evidenced using the intrinsic brain activity data normally discarded from EEG paired stimuli task assessments. 

Biology does not read DSM guidelines 

Using DSM criteria for diagnosis of these patients, however, produced a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis) rather than distinct biological entities suggesting that, indeed, biology does not read DSM guidelines.

 

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