– As data mount confirming the neurodegenerative effects of psychotic episodes in schizophrenia, one expert urges psychiatrists to think of psychosis as a “brain attack” which, like heart attacks, must be prevented from recurring.

“Schizophrenia doesn’t have to be progressive neurodegenerative unless patients relapse again and again, but that happens all the time because we give our patients pills they don’t take as prescribed. There are many reasons for poor adherence,” Henry A. Nasrallah, MD, said at the meeting held by Global Academy for Medical Education.

Dr. Henry A. Nasrallah
Dr. Henry A. Nasrallah
The solution is for the field to update its treatment standards so that giving long-acting injectable atypical antipsychotics (LAIs) directly after the first episode of psychosis becomes standard treatment, according to Dr. Nasrallah.

In a presentation dedicated to the emerging science reshaping views on how schizophrenia occurs, how it can be prevented, and why it is a syndrome with genetic etiologies, Dr. Nasrallah emphasized that there now exist enough data to show that timely intervention with LAIs reliably prevent relapse in most patients, thereby averting progressive neurodegeneration and subsequent disability in people who develop schizophrenia.

“Researchers now stage schizophrenia. Just like cancer, the more advanced the stage, the worse the outcome,” said Dr. Nasrallah, the Sydney W. Souers Endowed Chair and professor of psychiatry and behavioral neuroscience at Saint Louis University, told his audience. “The additional damaging effects of the second episode is what leads to clinical deterioration and can start the process of treatment resistance. But if no psychotic episodes are allowed to recur after the first episode, many patients can return to their baseline functioning, such as school or work.”

The field still is clarifying the neurodevelopmental aspects of schizophrenia, including genetic and in utero adverse events that disrupt brain development, as well as the appropriate types and timing of intervention in the prodromal phase. However, Dr. Nasrallah explained, science already has demonstrated how the neurotoxic effects of psychosis in the brain of a person with schizophrenia lead to brain tissue degradation with every psychotic episode. The result is a progressive decline in social and vocational functioning.

Psychosis is associated with activation of microglia, which are monocytic cells that cross the blood-brain barrier during fetal life, settling in the brain and ultimately comprising 10%-15% of all brain cells. Once activated, they trigger an immune response, leading to neuroinflammation and oxidative stress (free radicals). However, Dr. Nasrallah said, rather than protect the brain, these processes destroy gray and white matter – particularly in the cortical region – degrading the brain and leaving it more compromised, especially if another episode of psychosis occurs.

Another factor in the vulnerability of the brain in schizophrenia is mitochondrial dysfunction. As mitochondria are the primary source of antioxidants – such as glutathione – the deficit in antioxidants increases oxidative stress, furthering the brain’s vulnerability to tissue loss.

Among other biological processes thought to be implicated in neurodegeneration with schizophrenia, Dr. Nasrallah said, are impairment of antiapoptotic signaling, glutamate excitotoxicity, hypercortisolemia, and gamma-aminobutyric acid hypofunction.

The overall effect of these neurotoxic blows is a brain that experiences white and gray matter pathologies, leading to impaired neuroplasticity with increasing levels of white matter disconnectivity, Dr. Nasrallah said.

He pointed out that studies have shown a loss of 1% of total brain volume and 3% of gray matter volume with the first psychotic episode. Cerebral ventricles expand by about 7%. “The different parts of the brain no longer communicate properly with each other across myelinated fibers, which is postulated as an explanation for cognitive impairment, thought disorder, negative symptoms, and lack of insight – all of which can contribute to nonadherence to treatment.”

Prompt treatment of the first episode of psychosis and starting the patient on an LAI can protect the brain from another destructive round of neuroinflammation and oxidative stress. He recommends that his patients take omega-3 fatty acids to expedite the anti-inflammatory response of the antipsychotic drug. First-generation antipsychotics are not neuroprotective, according to Dr. Nasrallah, whose own research shows that haloperidol is itself neurotoxic and kills neurons – although it is an efficacious antipsychotic.

Updated American Psychiatric Association practice guidelines for treating first-episode psychosis, published in 2010, do not recommend LAIs as a first-line treatment. Neither do the National Institute of Mental Health’s Schizophrenia Patient Outcomes Research Team treatment recommendations and summary statements, published in 2009. Similarly, neither document stresses atypicals over first-generation antipsychotics.

However, Dr. Nasrallah cited a randomized, controlled study from the University of California, Los Angeles, showing that in 86 patients with first-episode psychosis who were given the same antipsychotic in either oral or LAI form, at the end of 1-year follow-up, the researchers reported a 650% higher relapse rate in the oral group (33%), compared with the LAI group (5%) (JAMA Psychiatry. 2015 Aug;72[8]:822-9).

“I tell my residents to behave like cardiologists,” Dr. Nasrallah said. “When cardiologists have a patient who experienced the first heart attack, they make it an absolute goal never to let the patient have another myocardial infarction because the first one permanently killed part of the myocardium, and a second heart attack will either kill the person or make him need a heart transplant. They implement a multifaceted intervention to achieve that goal. We psychiatrists should regard [the first episode of psychosis] as a ‘brain attack,’ and we should never let patients have another one again. The best intervention we have for this is starting an atypical LAI in first-episode patients.”

Global Academy and this news organization are owned by the same company. Dr. Nasrallah has conducted Food and Drug Administration clinical trials with LAIs and has several industry ties, including with Alkermes, Janssen, and Otsuka.