# A Novel Personalized Approach Towards Treating Negative Symptoms and Reducing Alcohol Abuse in patients with Comorbid AUD and Schizophrenia.

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $201,085

## Abstract

Comorbidity of Alcohol Use Disorder (AUD) with schizophrenia (SZ) is highly prevalent at over 33% of SZ
patients. Comorbidity is associated with particularly unfavorable outcomes including increased mortality risk
and treatment non-adherence. Of particular relevance, some SZ patients have reported a decrease in negative
symptoms following alcohol ingestion. This is important because the negative symptoms of SZ (loss of
motivation, flattening of emotional responses, decreased speech and activity, and social withdrawal), are
disabling and persistent, and significantly contribute to the immense personal and economic costs of SZ. No
medications are FDA-approved for treatment of negative symptoms in SZ.
Proline is a precursor of the neurotransmitter glutamate and may function as a CNS neuromodulator. Elevated
proline stimulates dopamine (DA) signaling in murine models. The Catechol-O-methyltransferase (COMT)
enzyme catalyzes deactivation of neurotransmitters including DA. In our recent, replicated study we found that
fasting plasma proline levels (which reflect CNS levels) and the COMT Val158Met functional polymorphism (a
well characterized marker of DA metabolism due to the encoded high or low activity enzyme) significantly
interact, predicting negative symptom outcomes in patients with severe psychiatric illness. Specifically, in
Val/Val high enzyme activity patients, high proline is protective with low negative symptom severity or a greater
negative symptom reduction over time. Conversely, COMT Met carriers (low activity) demonstrated the
opposite: Significantly more negative symptoms or less symptom improvement as proline increased.
Alcohol ingestion upregulates circulating proline in those with a current or past AUD, and thus we hypothesized
that comorbid patients self-medicate with alcohol to relieve their negative symptoms; predicting more frequent
comorbid AUD in Val/Val SZ patients. In a preliminary study we indeed found a strong trend for a higher
proportion of AUD in Val/Val’s, as compared to Met carriers for whom alcohol-induced proline elevation would
be detrimental (p=0.065 two-tailed). Taken together, our findings are important because there are medications
that up-regulate proline levels, such as valproate (VPA), prescribed to ~35% of SZ inpatients. We propose that
personalized VPA treatment in comorbid AUD and SZ Val/Val patients, may relieve negative symptoms and
assist in maintaining abstinence due to this relief. As a necessary prerequisite to an RCT of VPA, the work
described under this exploratory R21 study should allow us to move towards such a personalized treatment
approach: Specific Aim 1: We will confirm our preliminary study, powered to show association of COMT with
AUD in SZ; Specific Aim 2: In a naturalistic, longitudinal setting we will test the innovative hypothesis that
COMT Val/Val SZ patients with co-morbid AUD, have greater negative symptom improvement if they are
treated with VPA (because of significant proline ele...

## Key facts

- **NIH application ID:** 10018457
- **Project number:** 5R21AA027392-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** CATHERINE L CLELLAND
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $201,085
- **Award type:** 5
- **Project period:** 2019-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018457

## Citation

> US National Institutes of Health, RePORTER application 10018457, A Novel Personalized Approach Towards Treating Negative Symptoms and Reducing Alcohol Abuse in patients with Comorbid AUD and Schizophrenia. (5R21AA027392-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10018457. Licensed CC0.

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