Schizophrenia Treatment Past and Future


By Marvin Ross

Those of us with lived family experience of schizophrenia are well aware of the complexity of the condition. Listening to the “woke folk” who posit causes of familial dysfunction, trauma, and/or social determinants as causes tend to infuriate us. What infuriates us further is their lack of understanding of the need for medication (imperfect as they may be) and their often very simplistic solutions. Those beliefs often tend to be on the same level as those who blamed the Buffalo Bills cardiac arrest as having resulted from covid vaccinations.

The true complexity of schizophrenia and the efforts to help ameliorate the symptoms was just outlined in an excellent article in Psychiatric Times by Dr. John J Miller. His essay called the RX Evolution: Pharmacological Paradigms for the Treatment of Schizophrenia reminds us that schizophrenia is not just the positive psychotic symptoms of delusions which are easier to control but the more debilitating, intractable negative and cognitive symptoms. These are the symptoms that previously resulted in lifelong institutionalization and led to the historical term of dementia praecox or early onset dementia for the disease.

Prior to the accidental discovery of chlorpromazine in the 1950’s, patients would be hospitalized for life or, in third world countries, locked in cages or chained to things. Chlorpromazine was a dirty molecule that acted on a wide range of dopamine receptors but quieted psychosis. Haldol and Prolixin which followed were cleaner but led to movement disorders and  hyperprolactinemia. These drugs helped with the positive symptoms but made the negative and cognitive symptoms worse.

Over enthusiasm about their efficacy coupled with a desire to save money led to the closing of psychiatric hospitals and the mass exodus of patients to the streets, shelters and jails of North American cities. The money saved was to be transferred from the institutions to community resources but never was.

Clozapine appeared next targeting two of the serotonin receptors rather than dopamine and proved to be very effective save for one serious side effect. In some patients (about 1%) it resulted in destroying the white blood cells. Today, it is mostly used for treatment resistant schizophrenia but with regular blood checks. In order to overcome the white blood cell problem but preserve the clozapine efficacy, scientists developed what Miller called the apines – olanzapine, quetiapine, and asenapine – and the odones – risperidone, ziprasidone, paliperidone, iloperidone, and lurasidone.

This class of drugs operated at the dopamine and serotonin receptors but still resulted in movement disorders but not as frequently. They also resulted in  weight gain, hyperglycemia or increased insulin levels, elevated lipids, sedation, and elevated prolactin.

In 2002, a third generation of anti-psychotics appeared which Miller calls the ABC class – aripiprazole (Abilify), brexpiprazole (Rexulti), and  cariprazine (Vraylar). It had been hoped that these agents would not produce movement disorders or the risk of tardive dyskinesia but that has not happened. The other drug newly approved in 2019 called  lumateperone (Caplyta) is in a class of its own. Miller says very little about its efficacy or side effects but it has “extremely potent 5HT2A antagonism and modest D2 antagonism, serotonin reuptake inhibition, and D1 receptor modulation.”

He sums up all these treatments with:

Despite an impressive and heroic progression of research into the pathophysiology of schizophrenia, development of novel agents, and improvements in developing and delivering an accompanying essential array of biopsychosocial treatments and supports, the lifetime prognosis for many individuals with schizophrenia remains poor. Epidemiological data indicate that an individual with schizophrenia will die on average 20 years earlier than age-matched healthy individuals. Looking at the 1 dimension in which pharmacotherapy has had the greatest treatment results, psychotic symptoms, a staggering one-third of individuals with schizophrenia remain psychotic despite aggressive treatment. Another third continue with intermittent relapses of positive symptoms combined with progressive negative symptoms and cognitive decline. Currently there are no FDA-approved treatments to treat the negative and cognitive symptoms, which ultimately cause the greatest lifetime functional impairment.

Despite these modest gains, scientists continue to explore other viable treatments that do not rely on dopamine. These avenues involve serotonin activity, Muscarinic Cholinergic Agonism and Trace Amine–Associated Receptor 1. Scientific progress is slow and science has been at this since the early 1950s with the discovery of chlorpromazine. I doubt most of us will see real progress in our lifetimes as nothing is more complex than the brain. Miller points out that “Significant progress has been made in the understanding of the interplay of numerous risk factors through wide-ranging research, from genetics and epigenetics to developmental and environmental factors, neuroimaging, and more”.

He concludes with  “as is the case with many chronic disorders such as cardiovascular disease and diabetes, we remain challenged to improve our treatments and outcomes. Treating all 3 domains of schizophrenia—positive, negative, and cognitive symptoms—continues to be a high priority and significant unmet need.”

Neuroscientists world-wide have been working on this complex puzzle for years and continue to do so. Why do those “woke folks” think the answer lies in trauma, social dysfunction or social determinants or that those with schizophrenia should be allowed to determine what treatment they want or need when their brains are so impacted that they become delusional, have the negative symptoms of lack of motivation and pleasure and cognitive losses?

It’s nice that they care but first they should get more information before they start telling us what should be done. I wonder if they realize that the poor souls they see pushing their shopping carts full of junk while mumbling to themselves could be helped or the increasing number of pan handlers at traffic lights also do not need to be there.

I’m not being paternalistic but compassionate in suggesting that they need help and understanding – the help of the best medication and supports that science has developed to date. We give that to Alzheimer’s patients – a disease not dissimilar to schizophrenia. In fact, more progress has been made in pharmaceutical agents for schizophrenia than has been made for Alzheimer’s. In 1987, I wrote a book on Alzheimer’s and nothing much has changed since then. One drug that slows the cognitive decline but does not alter the eventual outcome has been around for a few years. Recently, a very expensive new drug was approved by the FDA but that is mired in controversy. Turns out it does nothing and the FDA has been implicated in encouraging its approval despite negative results in trials. Just Friday, another new drug was approved that only moderately slows cognitive decline in very early stages at an estimated cost of $25,000 a year.

If the “woke folks” were to do with Alzheimer’s what they do with schizophrenia, they would be telling families to allow their cognitively impaired relatives to live like they wish and to decide what if any treatment they want. Imagine if demented grandma was allowed to retain her basic human rights to refuse living in a dementia home and could simply wander the streets and potentially freeze to death as some who have wandered off have done.

Where is the freedom in that?



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