Interaction of Proline and COMT Genotype Influences Negative Symptoms in Schizophrenia & Bipolar Disorder

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The authors explored whether valproate (VPA) treatment effects vary by catechol-O-methyltransferase (COMT) genotype.
The authors explored whether valproate (VPA) treatment effects vary by catechol-O-methyltransferase (COMT) genotype.

Research by scientists at Columbia University Medical Center and New York University School of Medicine indicates that the negative symptoms of schizophrenia and bipolar disorder, as well as treatment efficacy, may be differentially influenced by the relationship between patients' COMT genotype and proline levels.

The positive symptoms of schizophrenia, such as delusions and hallucinations, are most responsive to medication, whereas the negative symptoms–including flat affect and avolition–often do not respond to treatment. “Indeed, negative symptoms are among the most persistent and debilitating in schizophrenia, and contribute significantly to the huge personal and economic costs of severe psychiatric illness,” wrote the authors of the study published in Translational Psychiatry.

Proline is a non-essential amino acid that is a precursor to glutamate, and may play a role as a neuromodulator. Peripheral hyperprolinemia indicates elevated proline levels in the CNS, and has been linked with schizophrenia and other psychiatric disorders. Studies using the hyperprolinemic Prodh-null model have shown the direct effects of hyperprolinemia on neurotransmission. The Prodh-null mice who had elevated peripheral and CNS proline demonstrated “altered glutamate and dopamine signaling, including an enhancement of glutamatergic synaptic transmission, prefrontal dopamine transmission, and functional hyperdopaminergic responses,” the authors of the current study reported.

The proline dehydrogenase gene (PRODH) encodes the enzyme proline oxidase (POX), which initiates proline catabolism. The gene has been implicated in schizophrenia and its endophenotypes, and it maps to chromosome 22q11.2, a region associated with the highest non-twin genetic risk of schizophrenia. The catechol-O-methyltransferase gene (COMT) also maps to 22q11.2, and some evidence shows that hyperprolinemia and COMT may interact to modify neurotransmission and behavior in Prodh-null mice.

The authors of the present research investigated whether an interaction between COMT and proline levels would influence symptom domains in 95 adult patients with schizophrenia. Specifically, theytested for effect modification between the Val158Met COMT genotype and fasting peripheral proline on both positive and negative symptoms of schizophrenia,” they explained. Additionally, they examined the effect of a proline-COMT link on negative symptoms in 43 patients with bipolar disorder. Finally, because valproate (VPA) increases proline levels and is a commonly used treatment for schizophrenia and bipolar disorder, the authors explored whether VPA treatment effects would vary by COMT genotype.

The results show a significant interaction between fasting proline levels and COMT on negative symptoms in schizophrenia (P<0.0001). Patients with the COMT Val/Val genotype and high proline had lower scores on the Scale for the Assessment of Negative Symptoms (SANS), whereas patients with a Met allele and high proline had higher SANS scores. “Speculatively, proline elevation may increase prefrontal dopamine signaling, through interference with glutamatergic pathways, reducing vulnerability to a prefrontal hypodopaminergic state in Val/Val patients,” the authors noted.

A significant interaction between proline and COMT was also associated with negative-symptom change in patients with bipolar disorder (P=0.007). In addition, negative symptoms were lower in Val/Val patients with schizophrenia who were treated with VPA, compared with Met allele patients treated with VPA, likely because of the drug's proline-increasing effect. “Our data have implications for treatment decisions, because proline-modulating medications, such as VPA which is commonly used to treat schizophrenia patients, may have beneficial, and conversely detrimental effects on negative symptoms, based upon the individual patient's Val158Met genotype,” the authors noted.


Clelland CL, Drouet V, Rilett KC, et al. Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder. Transl Psychiatry. 2016; 6(9):e891.

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