Deborah Brauser

May 15, 2014

NEW YORK ― Warfarin has been linked to a decrease in and even long-term remission of psychotic symptoms in patients with schizophrenia, preliminary research suggests.

A study examining adults at an anticoagulation clinic for deep venous thrombosis (DVT) showed that 5 patients who also had schizophrenia and who received long-term treatment with warfarin for recurrent DVT achieved full psychosis remission. In addition, these patients remained free of any psychotropic medication for 2 to 11 years.

The investigators note that the underlying mechanism could be tissue-plasminogen activator (tPA), a protein that not only promotes the dissolution of blood clots but also plays a role in neurogenesis after severe stress.

"Our findings suggest that normalization of [tPA] function may induce long-term remission of psychotic symptoms," they write.

However, lead author Silvia Hoirisch-Clapauch, MD, a hematologist specializing in vascular medicine at the Federal University of Rio de Janeiro in Brazil, told Medscape Medical News that she is not (yet) suggesting that psychiatrists should start prescribing warfarin for these patients.

"What we found seems to make sense, but we need other scientists to help us to search for markers in a population with schizophrenia that is medication naive," said Dr. Hoirisch-Clapauch. She added that larger studies, including randomized controlled trials, are also needed to clarify exactly how and if anticoagulation should be used in the treatment of psychosis.

The findings were presented here at the American Psychiatric Association's (APA's) 2014 Annual Meeting.

More Than a Coincidence

Warfarin, an anticoagulant medication, is commonly used to treat DVT and other clotting disorders.

Dr. Silvia Hoirisch-Clapauch

Dr. Hoirisch-Clapauch reported that her university's anticoagulation clinic takes care of patients with repeated episodes of DVT, including approximately 350 who are on long-term warfarin therapy.

While providing care for these patients, she noticed that the 5 who also had schizophrenia and schizoaffective disorders achieved psychiatric remission and became "psychotropic free."

"Finding this with 1 patient was strange, 2 was a coincidence, but with all 5 patients, I had to look for an explanation of what happened," said Dr. Hoirisch-Clapauch, adding that she wanted to work specifically with Antonio E. Nardi, MD, PhD, from the Institute of Psychiatry at the Federal University of Rio de Janeiro.

The researchers note that patients with schizophrenia commonly have a reduction of hippocampal volume, which is often explained as being caused by a trigger (such as use of illicit drugs or a previous traumatic event) and/or a predisposing condition that impairs neuronal plasticity.

In November 2012, they searched PubMed for data on a protein or proteins that could participate in both "the anticoagulation-fibrinolytic mechanism and in hippocampal neurogenesis or neuronal plasticity."

"The search pointed to a single candidate: tPA," they write. Warfarin inhibits activation of thrombin-activatable fibrinolysis inhibitor. And that process in turn increases tPA levels.

Low tPA Activity

All 5 of the patients with schizophrenia "had 2 or more conditions characterized by low tPA activity, including prothrombin G20210A, fasting hyperinsulinemia, hyperhomocysteinemia, or antiphospholipid antibodies in medium or high titers."

The researchers add that deficient dopamine transmission at D1 receptors in the brain's prefrontal cortex and "impaired cleavage of pro brain-derived neurotrophic factor" are among biochemical abnormalities that can be related to impaired tPA activity in patients with schizophrenia.

Other tPA-related abnormalities include reduced Akt phosphorylation, problems with N-methyl-D-aspartate receptor-mediated signaling, and deficient activation of reelin.

Overall, "plasminogen activator mediates hippocampal neurogenesis," write the investigators.

They add that none of the 5 patients with schizophrenia showed any ischemic brain injury on neuroimaging tests.

"At the very beginning, I thought maybe these patients had had a stroke, but they did not," said Dr. Hoirisch-Clapauch. Instead, she said that the research points to tPA activity.

"We knew we had found the joker that performs a role as a clot buster and in neurochemistry. And we were able to insert our joker in all these chemical reactions that occur during the pathogenesis of schizophrenia," she said.

"What we found with our 5 patients wasn't an accident. It was serendipity."

Inflammation and Psychiatric Illness

"One of the things that you're seeing in the literature more and more often is the role of the inflammatory system in psychiatric illness, particularly in people who have difficulty responding to the usual sorts of treatment," Jeffrey Clothier, MD, professor of psychiatry at the University of Arkansas in Little Rock, told Medscape Medical News.

Dr. Jeffrey Clothier

"This study presented some interesting pathways where some of that could be mediated for long-term effects. And it suggests that perhaps some of the things we do for patients we need to start rethinking, such as long-term antipsychotic use for those who don't really need antipsychotics," said Dr. Clothier, who was not involved with this research.

He noted that although the study only looked at 5 patients, it was interesting that all 5 entered psychosis remission.

"I think this brings back the whole question, how do we approach patients? Do we approach them at a diagnostic level, or should we be approaching them with more of a mind towards the RDoC, Research Domain Criteria?" he asked.

"And does this study give us a little bit of insight, even though it was a small number examined, into some novel pathways that need to be investigated in subgroups of patients we haven't really been thinking about?"

Dr. Clothier agreed that there are no clinical implications based on these early findings.

However, he said it is good information to keep in mind, especially because it could represent future possibilities.

"I just watched presentations on neuroimaging of schizophrenia [at the APA meeting] and how there's a loss of volume and loss of neuropil in some of these patients. And it makes you wonder: exactly what is the mechanism for this? Is it a loss or reduction of tPA activity?" he asked.

"It'll be interesting to see what happens with this."

The study authors and Dr. Clothier report no relevant financial relationships.

American Psychiatric Association's 2014 Annual Meeting. Abstract NR3-14. Poster presented May 4, 2014.

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