Neurodegenerative Nature of Schizophrenia Makes Case for LAIs

Jim Kling

August 27, 2021

Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Dr Henry Nasrallah

The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson's disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.

The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.

This pattern in schizophrenia makes it all the more important to ensure that patients stay on medication to prevent future episodes. "The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians," said Nasrallah in an interview.

That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.

Reconceptualizing the Illness

Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.

The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.

Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.

Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don't bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine2A antagonists, according to Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.

In the Q&A session after the presentation, Nasrallah was asked whether treatment should be kept up for the rest of the patient's life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.

"It's an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine," he said. "You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose."

Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. "I don't tell the patient, 'You're going to take this the rest of your life.' It depresses them. So I say, 'Let's keep this on board for a year, and I'll see you regularly, and I'll monitor you, and we'll see how it goes, and then we will make another decision at the end of the year.' "

During that year, Nasrallah educates the patient and develops a rapport. "I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: 'Yeah, I agree. Let's continue the good thing and let's not fix something that's not broken.' "

Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker's bureau for most of those companies, in addition to that of Noven.

This article originally appeared on, part of the Medscape Professional Network.


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