Before I get into this, I should frame my participation in this discussion by explaining my controversial belief that bipolar and schizophrenia are not different diseases. I believe that they are two faces to the same genetically-caused illness. I think that there are clusters of symptoms whereby the people typically labelled with having schizophrenia may appear to have a different presentation than people typically labelled with having bipolar. I do not deny that there may be some biological difference between the two presentations of symptoms, but I believe these differences are few enough as to consider bipolar and schizophrenia to be two subtypes of the same disease.
A primary driver of my belief is the growing evidence that bipolar and schizophrenia probably share common causes. This is born out with both genetic and neurological evidence. I will briefly describe the type of evidence along with providing references to the literature.
The evidence says that bipolar and schizophrenia have associations with some of the same regions of the genome. What does it mean for a disease to be correlated with a region of the genome? This means there is a statistical correlation between the presence/absence of the disease(s) and the nucleotides at a polymorphic position in the genome. Typically researchers are testing Single Nucleotide Polymorphisms (SNPs), but some studies have examined Copy Number Variations (CNVs). One can think of the association between a SNP and the disease as trying to place the disease in the genome at some position that explains the inheritance of the disease.
[Lichtenstein et al., The Lancet, 2009] This study looked at approximately 75,000 individuals with either schizophrenia or bipolar. They examined relative risk, that is the risk of disease for a relative of a diseased person as compared with the risk for a relative of a diseased person. They showed that relatives of people with bipolar had elevated risk of schizophrenia and vice verse. They measured heritability of schizophrenia as 64% and of bipolar as 59%. Heritability is the percentage of the disease variance that is accounted for by genetic factors. (It does not mean that the child of a schizophrenic has that percentage as risk of getting the disease.) The authors concluded that:
Similar to molecular genetic studies, we showed evidence that schizophrenia and bipolar disorder partly share a common genetic cause. These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities.[The International Schizophrenia Consortium, Nature, 2009] This study did a genome-wide association study (GWAS) of roughly 3,000 individuals with schizophrenia. They demonstrated the contribution of thousands of SNPs to the risk of schizophrenia. And, they showed that many of those SNPs also appeared in a GWAS study of bipolar.
[Cross-Disorder Group of the Psychiatric Genomics Consortium, The Lancet, 2013] This study is actually of five psychiatric disorders: autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. They found four SNPs that were significantly associated with all these diseases. They also separated the people with the disease into two categories child and adult onset of disease, which further refined the SNPs that they found. The authors say
Doubt remains about the boundaries between the syndromes and the degree to which they signify entirely distinct entities disorders that have overlapping foundations or different variants of one underlying disease.
The pathogenic mechanisms of psychiatric disorders are largely unknown, so diagnostic boundaries are difficult to define. Genetic risk factors are important in the causation of all major psychiatric disorders and genetic strategies are widely used to asses potential overlaps.
These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.
On the neurology front, brain imaging provides evidence both of the similarities and differences between schizophrenia and bipolar. Generally speaking, brain imaging can involve functional magnetic resonance imaging (fMRI) which images the blood flow in the brain and voxel-based morphometry studies which examine the gray matter.
[Ongur et al., Psychiatry Research: Neuroimaging, 2010] In this study the researchers selected 17 patients with bipolar and 14 patients with schizophrenia and did fMRI scans. They used independent component analysis to analyze the data and identify synchronous activity patterns. The data suggest abnormal functional organizations of the brain in both disorders when compared with controls. The people with schizophrenia have abnormalities in the frontopolar cortex/basal ganglia while the people with bipolar showed abnormalities in the parietal cortex. It is not clear how the abnormalities are related to the symptoms of the disorders. Indeed it is possible that eye movement during the fMRI explains some of the differences in the scans of bipolar and schizophrenic people. This paper leads us to think that there may be a reliable way to differentially diagnose bipolar and schizophrenia, however the sample sizes are small and eye movement may have confounded the results.
[Ellison-Wright et al., Schizophrenia Research, 2010] This paper did a meta-analysis of around 2000 patents with schizophrenia and around 350 patients with bipolar. The goal was to find whether there was similar brain imaging for the people with bipolar and people with schizophrenia. This was done in light of the genetic studies suggesting a common cause for bipolar and schizophrenia. The studies looked at gray matter using voxel-based morphometry studies. They found that the areas of gray matter reduction in bipolar overlapped the gray matter reductions found in schizophrenia with the exception of a region of anterior cingulate where the gray matter reduction was only found in bipolar. They also found that gray matter reductions in schizophrenia were more extensive.
[Chai et al. Neuropsychopharmacology, 2011] This paper looked at 14 patients with bipolar and 16 patients with schizophrenia. They remark that "a significant body of genetic, imaging, and neurophysiology research has established that schizophrenia and bipolar share substantial overlap in clinical features, as well as in contributing genetic factors." Their goal was to find if there are common neural substrates for bipolar and schizophrenia. This work also used fMRIs and independent component analysis (similar to the Ongur paper). To paraphrase the authors, they found that there is a decoupling of the dorsal lateral prefontal cortex from the medial prefrontal cortex in both bipolar and schizophrenia, and that this decoupling is consistent with the impaired executive functioning seen in these disorders. In addition to this commonality between bipolar and schizophrenia, they found a distinguishing feature. The authors say:
Functional connectivity between [medial prefrontal cortex] and insula/[ventral lateral prefrontal cortex] distinguished bipolar disorder from schizophrenia, and may reflect differences in the affective disturbances typical of each illness.
Due to the weight of genetic and neurological evidence that is establishing commonalities between bipolar and schizophrenia, it is reasonable to hypothesize that they share common causes. In light of this it might be better to revise the diagnostic categories so that bipolar, schizoaffective, and schizophrenia are subtypes under the same disorder. As The Lancet, 2013 paper suggests, we may also need to significantly revise our categorizations of other diseases, as well. We may be better able to diagnose and treat these diseases if we classify them according to common causes.
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