Introduction

Is Schizophrenia a Real Disease?

few months ago, a woman suffering from post-partum depression threw Washington, D.C. into a panic before being shot to death by police. A week before that, a person who believed that electromagnetic radiation was controlling his brain shot and killed twelve people at the Washington Navy Yard. These and similar incidents have prompted calls for increased attention to mental illness. Dr Keith Ablow writes:

The reason we are seeing a surge of violent mentally ill people (and I believe we are witnessing this rising tide) is that we have systematically dismantled the mental health care system in America so completely that it is now routine for psychotic people thinking of killing others to be treated by entry level social workers in community mental health centers, turned away from emergency rooms or discharged from hospital inpatient units if they simply promise not to murder anyone and sent home from court or jail after committing violent acts clearly connected to underlying psychiatric illness.

But there's a problem here. Inpatient treatment for a psychiatric disorder is quite different from inpatient treatment for a physical disorder. If you have a heart condition, for example, you can walk out any time as doctors say “AMA” (against medical advice).

That is not true for psych patients. For them, inpatient treatment is another term for involuntary confinement. Back when I was doing research in Bethesda, Maryland, we had some colleagues who worked in the clinical center next to us. Looking for their lab one day, I got off on the wrong floor where they had the psych ward. I was surprised to learn that there are no door handles on the inside. You can get in easily enough, but it's not so easy to get back out.

So what Ablow and others are talking about is involuntary confinement of people who have not yet committed a crime. That's serious stuff. Locking people up and forcibly treating them is a tempting solution. But which people? To be justified, the decision would have to be based on a solid diagnosis based on objective clinical tests. So far, for mental disorders, there simply is no such thing. Millions have been spent on research trying to find ways of diagnosing schizophrenia, with no success.

Excessive institutionalization also can create problems. Knowing that the legal system might excuse them for their behavior if they can be declared insane may well be a powerful motivation for criminals to falsely claim that the neighbor's dog told them they must sauté the postman in Béarnaise sauce. It could also lead to increased stigmatization of these disorders, as people become afraid that expressing unusual ideas will land them in an inescapable prison.

In the legal arena, we often hear the following argument: if a person believes he or she is doing something ordinary, like basting a turkey, when instead they're really doing something horrific, can they be held responsible? This is a difficult question, but it is also a straw man argument: the problem is that we have no way of knowing what another person really believes and experiences. And that is why we have so much trouble defining schizophrenia.

Defining schizophrenia

So, what is schizophrenia? In view of the rising tide of calls to “institutionalize” people (which means, essentially, to imprison them and pump them full of behavior-suppressing drugs), this question becomes urgent. One of the most basic principles of our legal system is that although mental states can be an exculpating factor, we punish behavior, not beliefs or mental states. Making health care more available is a desirable goal. But if we imprison people for having abnormal thoughts and crazy ideas, as is implied by some commentators, we could end up with a system like that in the Soviet Union, where people were committed to psychiatric institutions for political dissent.

Most popular descriptions, such as those at www.schizophrenia.com, assert that schizophrenia is a disease of the brain. Five main lines of evidence are typically adduced for this idea:

1. Gray matter deficits found in treated and untreated patients.
2. Enlarged ventricles, which is basically the same thing.
3. White matter hyperintensities in the amygdala, which is the part of the brain responsible for the so-called “fight-or-flight” response and emotional memory.
4. Impaired cognitive function, which means memory difficulties and problems with information processing.
5. Impaired awareness and decreased prefrontal lobe function, as shown by PET scans.

Now, up front I have to say I am an Alzheimer's disease researcher, not a schizophrenia researcher. To me, those MRI scans and PET scans of schizophrenia patients are clearly showing evidence of mild dementia—that is, loss of neurons.

Loss of neurons is prima facie evidence of neurocognitive impairment. A classic case of how cognitive impairment might be confused with psychiatric illness was found in one taxi driver who suddenly started seeing “demons.” It turned out that these hallucinations started immediately after he installed a new carpet in his cab. The carpet was found to be emitting toxic vapors to which he had been exposed continuously during working hours. Eliminating the carpet eliminated his hallucinations, and he went back to his normal job of cheating foreigners, swerving in front of bicycles, and swearing at all the other drivers, with no after-effects.

There are many other similarities between schizophrenia and Alzheimer's disease. Alzheimer patients don't just forget things. They often have delusions. They hallucinate. They have seizures. They often insist that things that are logically impossible are true. They can be paranoid and aggressive. Occasionally they become violent (although this is more common in frontotemporal dementia, in which the damage is focused more in the frontal lobes). In fact, about 50% of Alzheimer patients have psychotic symptoms such as delusions and hallucinations [11].

In other types of dementia, we observe the same thing. Approximately 60-70% of patients with Lewy body dementia and Parkinson's disease dementia have visual hallucinations and delusions [12]. There are some differences in the nature of the hallucination from one disease to the next, but they are all signs of a brain that is struggling to make sense of the world, but failing because its ability to process information is impaired.

Causes

In earlier times, schizophrenia was thought to be caused by an imbalance in neurotransmitters such as dopamine. However, recent research points more to the idea that what we would call “mild dementia” is an integral part of schizophrenia. For example, Ingo Fromman et al. of the Rheinische Friedrich-Wilhelms-University in Bonn, Germany found that patients in the so-called late prodromal stage were impaired in memory, executive control, and processing speed [1]. These are all functions that are impacted by loss of neuronal function. Yulia Zaytseva et al. of the Moscow Research Institute of Psychiatry obtained similar results, and proposed that “cognitive remediation,” which addresses the neurological deficits, is the most appropriate strategy for such patients [2].

Cognitive remediation would focus on synapses. Synapses, which are the connection points between neurons, are affected by neurotrophic factors such as nerve growth factor and BDNF, and by a multitude of brain proteins and brain peptides such as netrin, Wnt, transforming growth factor-beta (TGF-β), and tumor necrosis factor-alpha (TNF-α) [3]. We don't fully understand how these molecules work together, so only time will tell what benefits this research will produce.

However, a few psychiatrists, notably Thomas S. Szasz, have made a strong case that there is, in fact, no such thing as schizophrenia or, for that matter, any mental disorder. A century of research, he says, has failed to identify a cause or provide an objective diagnosis for any of them. The fact that there are many websites and articles devoted to affirming that schizophrenia is real is proof that the question is still open for scientific debate. But this raises the question: if there is no such thing as schizophrenia, what on earth is wrong with all those so-called crazy people?

There was a report about ten years ago about how a big drug company called Janssen Pharmaceutica, which is now part of Johnson & Johnson R&D, created a virtual reality project that supposedly gives people an idea. In the simulation, you walk through an ordinary drugstore, but instead of an ordinary shopping trip where you stand in line peacefully for an hour or so listening to Muzak and having the pharmacist ignore you, all the people just glare at you the whole time, and women protect their children from you when you walk through the aisle.

So is this what schizophrenia is like? A case of being really stressed out, angry, and therefore being hated and ostracized from society? If so, we would have to say it is not a disease, but a social phenomenon.

Symptoms

Another symptom is supposedly hearing inner voices. But again, as Thomas Szasz pointed out, “It is not an accident that in all of psychiatric literature, there is not a single account of voices that command a schizophrenic to be especially kind to his wife.”

No one can say whether these “voices” are qualitatively different from the “small voice” that religious people claim to have, or the inner voice we all have, which tells us right from wrong. In normal people, it is clearly just one's own brain speech-planning activity. Does this become an auditory hallucination in patients? We don't know for sure.

With the rise of molecular biology a few years ago, we saw many discoveries of genes that correlate with “susceptibility“ to disorders such as depression and schizophrenia. These papers usually went to great lengths to emphasize that it is only a correlation, not a cause, and susceptibility might only mean the person is susceptible to brain injury, nothing more. But those subtleties were often lost when reported in the media.

It seems to me that a temporary, partial dysfunction of the temporal or frontal lobe could radically affect a patient's idea of how the world works, by forcing the flow of information in the brain to take a different path. The patient might appear paranoid or delusional, believing things about the world that make no sense. Until the brain manages to re-wire itself, the patient's world must seem like an unending bad dream.

You may have experienced this yourself many times without realizing it. When a person is tired, they can experience bizarre fleeting thoughts that, if expressed, would sound crazy. But these thoughts disappear almost immediately, and they're impossible to remember because they can't be integrated into your worldview. No amount of effort can retrieve these ideas. However, if you experienced them because of brain injury or extreme stress, they could last for months or years—long enough for you to express them and, perhaps, get locked up.

There are many other hypotheses, some more plausible than others, but none of which should be categorically ruled out. One is that solanine, a toxic glycoalkaloid found in unripe potatoes, causes schizophrenia. Another is that a protein called neuroregulin 1 is at fault. Other hypotheses include viruses, environmental toxins, and Toxoplasma gondii, a parasitical disease acquired from cats [4, 5]. In support of this theory is the finding that antipsychotic drugs such as haloperidol and valproic acid are as effective against the effects of toxoplasmosis as anti-T. gondii drugs [6].

These hypotheses are controversial, but they illustrate the fundamental dilemma: are we really comfortable with the idea of locking away cat ladies or people who eat too many potatoes? Such could well be a side-effect of any rush to enact new legislation to solve the problem of subway pushings.

Antipsychotic drugs

The fact that drugs can alleviate the symptoms doesn't help with our understanding, either. Tranquilizer drugs undoubtedly can suppress the feelings of rage that psychotics experience. But this does not mean that they are affecting the course of the disease. They may only be suppressing the behavior.

Fluphenazine, an antianxiety drug which blocks D2 dopamine receptors, has been used for over 50 years as an antipsychotic. Yet a recent meta-analysis [7] of seven randomized controlled trials revealed that there is no significant difference between oral fluphenazine and placebo in important outcomes, such as global state. Fluphenazine, along with many newer drugs, however, does have well known adverse effects, called extrapyramidal symptoms, which can range from acute dystonic reactions to tarditive diskinesia and Parkinsonism [8]. Thus, the dopamine hypothesis, which was never entirely satisfactory, is desperately looking for a replacement.

Diagnosis

Since we do not have a clear idea what causes schizophrenia, or even whether it is a real disease, it should not be a big surprise that it is difficult to diagnose accurately.

This isn't only the case for neuropsychiatric disorders. Alzheimer's disease researchers have the same problem. While the patient is alive, the only way of diagnosing Alzheimer's is by cognitive testing. It has been shown that these tests are only about 50% accurate, except in the very late terminal stages. The fact that it's so hard to know whether a patient really has the disease we're studying makes it frustratingly difficult to identify the cause.

In Alzheimer's disease, the sobering fact is that only reliable way of diagnosing the disease is by performing an autopsy after the patient dies from it. With schizophrenia we don't know whether the diagnosis is 50% accurate, 100%, or 0%—or even whether it is really a disease at all.

This seriously hampers research, because the diagnosis is made by behavioural examination alone. The symptoms are compared to a list like those found in the DSM-5. There is no objective, scientific way of proving whether a patient is really schizophrenic. The fact that the DSM continually revises its diagnostic criteria [4, 9] means that our understanding of this disorder is still in flux.

Conclusion

Based on the above, I propose that schizophrenia is a dementia-like syndrome. Not otherworldly craziness like you see in the movies, but a partial loss of function that may or may not be temporary. Does that make it a disease? I guess that depends on your definition.

In a subject with mild dementia (which can have a multitude of causes, from childhood physical head trauma to toxic substances), the patients' coping mechanisms would start to fail, and their contact with society and ability to deal with people and manipulate them would progressively deteriorate. There is undoubtedly an emotional component to it, with fear, rage, and suspicion that accumulate from the patients' inability to obtain the desired responses from their social environment. These build up inside a person who is cognitively impaired, and therefore unable to process them rationally, until they explode in something like a subway pushing that seems inexplicable to others.

If this is true, it's no wonder it's so difficult to diagnose. It's probably inaccurate to call it a “disease” at all. The term schizophrenia should be abandoned, like so many terms before it have been, and replaced with something that more closely reflects something that can be measured—perhaps something like “mild dementia and acute stress disorder.” Before that can happen, though, we need to know a lot more about it.

Others have made similar suggestions. Michał Harciarek and colleagues at the University of Gdansk suggested that schizophrenia and frontotemporal dementia have a shared cause [10]. They point out that not only are there similarities in symptoms, but there is also familial co-morbidity. These two disorders are so similar that each is sometimes mistakenly diagnosed as the other, or as both occurring simultaneously. Just as with autism, there may be many different diseases that are lumped together as the same disorder.

In practical terms, it means that excusing violent acts by schizophrenics is hard to justify. But it is even harder to justify institutionalizing nonviolent ones, when no objective diagnostic criteria exist and the only effective treatment is drugs that can produce what many ex-patients have described as a zombie-like state. The question we should be asking is not just “What is the best way to protect society?” but also “What is the best way to help the patient?”

Finally, to those who advocate locking psychotics up and forcing them to undergo treatment to prevent them from committing violent acts, it is worth mentioning this: locking someone up is a profoundly political act. We should be mindful of our lack of understanding, careful what we wish for, and conservative about the institutions we create.

Full disclosure: despite the picture above, I am not really a dolphin.

References

[1] Schizophr Bull. 2011 Jul;37(4):861-73. Neuropsychological profiles in different at-risk states of psychosis: executive control impairment in the early--and additional memory dysfunction in the late--prodromal state. Frommann I, Pukrop R, Brinkmeyer J, Bechdolf A, Ruhrmann S, Berning J, Decker P, Riedel M, Möller HJ, Wölwer W, Gaebel W, Klosterkötter J, Maier W, Wagner M.

[2] Biomed Res Int. 2013;2013:819587. Neurocognitive Functioning in Schizophrenia and during the Early Phases of Psychosis: Targeting Cognitive Remediation Interventions. Zaytseva Y, Korsakova N, Agius M, Gurovich I.

[3] Front Synaptic Neurosci. 2013 Sep 18;5:6. Growth factors in synaptic function. Poon VY, Choi S, Park M.

[4] Psychiatr Clin North Am. 2012 Sep;35(3):557-69. The nosology of schizophrenia: toward DSM-5 and ICD-11. Tandon R.

[5] Toxoplasma gondii and schizophrenia. Torrey EF, Yolken RH. Emerg Infect Dis. 2003 Nov;9(11):1375-80. Review.

[6] Proc Biol Sci. 2006 Apr 22;273(1589):1023-30. Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour. Webster JP, Lamberton PH, Donnelly CA, Torrey EF.

[7] Schizophr Bull. 2013 Sep 26. [Epub ahead of print] Fluphenazine (Oral) Versus Placebo for Schizophrenia. Matar HE, Almerie MQ, Sampson S.

[8] Nurse Pract. 1992 Nov;17(11):56, 62-4, 67. Extrapyramidal symptoms are serious side-effects of antipsychotic and other drugs. Blair DT, Dauner A.

[9] Curr Psychiatry Rep. 2013 Nov;15(11):409. Defining Psychosis: The Evolution of DSM-5 Schizophrenia Spectrum Disorders. Bhati MT.

[10] Int Rev Psychiatry. 2013 Apr;25(2):168-77. Schizophrenia and frontotemporal dementia: shared causation? Harciarek M, Malaspina D, Sun T, Goldberg E.

[11]. Biol Psychiatry. 2013 Oct 5. pii: S0006-3223(13)00773-7. Psychosis in Alzheimer's Disease. Murray PS, Kumar S, Demichele-Sweet MA, Sweet RA.

[12]. Drugs Aging. 2013 Aug;30(8):603-11. Neuropsychiatric symptoms in patients with dementias associated with cortical lewy bodies: pathophysiology, clinical features, and pharmacological management. Ballard C, Aarsland D, Francis P, Corbett A.