Researchers have discovered a gene that is likely to play a role in the risk of psychosis in bipolar disorders.
The condition involves recurrent episodes of mania and depression, interspersed with “euthymic” periods with no depressive or manic symptoms. Manic episodes sometimes trigger psychotic symptoms such as hallucinations and delusions that are similar to acute psychosis in schizophrenia.
This and other similarities may indicate a partially shared basis or pathophysiology for these disorders. Furthermore, a range of overlapping “susceptibility” genes for both schizophrenia and bipolar disorder have been identified in large genetic studies.
Previous research has shown that a chemical called kynurenic acid (KYNA) is present at higher levels in the cerebrospinal fluid and the prefrontal cortex of people with bipolar disorder with psychosis and people with schizophrenia. Now, a team from the Karolinska Institute in Sweden has confirmed this finding and looked at the reason for the phenomenon.
“KYNA affects several signalling pathways important to brain function,” said researcher Professor Martin Schalling, M.D., Ph.D. It is normally produced during inflammation caused by exposure to stress or infection, for example, which themselves have been linked to psychotic episodes.
Researching the Link
Levels of an enzyme called KMO, which is involved in producing KYNA, were seen to be significantly reduced in the brains of 36 patients with schizophrenia and 19 patients with bipolar disorder plus psychosis compared to bipolar patients without psychosis and healthy people.
Further gene analysis was carried out on 493 patients with schizophrenia or bipolar disease and 1,044 comparable healthy people. Among the bipolar participants, psychotic episodes were almost twice as likely if the patient had a particular gene variant called KMO Arg452.
Tests on samples from a separate group of 55 patients showed that the KMO Arg452 variant was linked to both increased levels of KYNA in the cerebrospinal fluid, and to levels of KMO in the brain’s hippocampus.
Full results are published in the journal Molecular Psychiatry.
The authors write, “Genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.”
They hope the work will contribute to our understanding of the link between inflammation and psychosis. “Psychosis related to bipolar disease has a very high degree of heredity, up to 80 percent, but we don’t know which genes and which mechanisms are involved,” said Schalling,
The study gives “a new explanation that can be linked to signal systems activated by inflammation,” he said. “This has consequences for diagnostics, and paves the way for new therapies, since there is a large arsenal of already approved drugs that modulate inflammation.”
Other teams of researchers have also focused on levels of KYNA in patients with bipolar disorder. Dr. Conny Nordin of Linkoping University, Sweden, and her team saw that KYNA levels are increased in the brain of male bipolar disorder patients in the in-between euthymic state. They also found that KYNA levels rose with age in these patients, but not in men without bipolar disorder.
This team also believes that KYNA represents a shared feature of bipolar disorder and schizophrenia. They point out that KYNA is closely linked to dopamine activity in the midbrain, “indicating a potential role of this compound in dopamine-related diseases.”
“The functional significance of the observed elevation in brain KYNA levels (about 50 percent) is unclear,” they write. But experiments in rats suggest that the same rate of increase is “associated with a marked activation of the firing of midbrain dopamine neurons.” So this rise in brain KYNA in bipolar disorder “likely influences glutamatergic, cholinergic, and dopaminergic neurotransmission in these patients.”
These dysfunctions are known to progress with the course and severity of the disease, the team adds, because numerous studies have shown “an intimate relation between cognitive function and glutamatergic and cholinergic neurotransmission.”
When rats have drug-induced rises in KYNA, they show symptoms also seen in patients with bipolar disorder during both acute psychotic mania and euthymia, as well as in patients with schizophrenia. In addition, it impairs contextual learning and working memory in rats.
“Taken together, these findings suggest that KYNA might causally contribute to the development of the decline in cognitive function during the progression of bipolar disorder,” the team concluded.
Lavebratt, C., Olsson, S., Backlund, L., Frisen, L., Sellgren, C., Priebe, L., … Schalling, M. The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and KMO expression. Molecular Psychiatry, 5 March 2013 doi:10.1038/mp.2013.11
Olsson, S. K., Samuelsson, M., … and Landen, M. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. Journal of Psychiatry and Neuroscience, May 2010 doi: 10.1503/jpn.090180