Flipping the script

Even today, schizophrenia is most often defined by its psychotic symptoms. Have we been getting it wrong all this time?

Illustration by Joanna Beckett

Illustration by Joanna Beckett

Schizophrenia is among the most misunderstood mental illnesses, not only by the general public but also by those who treat the condition. It is widely seen foremost as a psychotic disorder, with some associated behavioural and cognitive impairments. However, it is becoming increasingly clear that these associated features are not simply sidekicks to psychosis, but are actually core to the disorder.

The Swiss psychiatrist Eugen Bleuler coined the term schizophrenia in 1908, to better describe a condition named ‘dementia praecox’ in the late 19th century. It is derived from the Greek roots schizein and phren, meaning ‘splitting mind’, intended to describe a disconnect between reality and the world in someone’s head. This should not be mistaken to mean that schizophrenia patients have split personality or multiple personalities, which is one of many inaccuracies portrayed in the popular media.

Swiss psychiatrist Eugen Bleuler, circa 1900, who coined the term schizophrenia.   Unknown photographer/Wikimedia Commons  (public domain)

Swiss psychiatrist Eugen Bleuler, circa 1900, who coined the term schizophrenia. Unknown photographer/Wikimedia Commons (public domain)

Bleuler wrote that schizophrenia had both ‘fundamental’ and ‘accessory’ symptoms. This dichotomy was refined over time, with symptoms recategorised from 1970 as either ‘positive’ or ‘negative’. Psychotic symptoms, hallucinations and delusions fall into the positive category, in that they are experiences added to normal functioning. (Hallucinations refer to false sensory experiences, such as seeing something that is not there. A delusion, on the other hand, refers to having a false belief, such as that you are being followed by secret agents.) In contrast, negative symptoms might be described as a lack of something, such as disinterest in things that should bring joy. This classification system is still used today to describe the symptoms of schizophrenia.

The criteria for diagnosing a patient with a mental illness are outlined in resources such as the Diagnostic Statistical Manual of Mental Disorders (DSM). Even in the latest edition of the DSM, published in 2013, positive symptoms are presented as schizophrenia’s pervasive feature, fitting with the public’s perception of the disorder. The DSM states that, for a person to be diagnosed with schizophrenia, they must have a clear presence of delusions, hallucinations or disorganised speech. Negative symptoms, such as diminished emotional expression, can contribute to diagnosis but are not needed.

Antipsychotic medications are the frontline of pharmacological treatment for schizophrenia. One of the first antipsychotics, chlorpromazine, was actually a repurposed anaesthetic. After the drug was found, at low doses, to make people disinterested in what was happening around them, it was tested in clinical trials during the 1950s and shown to relieve psychosis in up to 70% of schizophrenia patients. The efficacy of chlorpromazine spawned a new generation of drugs, all of which worked by blocking activity at a receptor in the brain for the neurotransmitter dopamine. However, it quickly became apparent that these drugs also caused adverse side effects, such as tremor. In response, a second generation of antipsychotics were developed and marketed as having fewer side effects. These new drugs targeted other neurotransmitter receptors, along with that for dopamine.

1960s advertisement for Thorazine, a brand of chlorpromazine, which was used to treat the psychotic symptoms of schizophrenia.   Unknown author/Wikimedia Commons  (public domain)

1960s advertisement for Thorazine, a brand of chlorpromazine, which was used to treat the psychotic symptoms of schizophrenia. Unknown author/Wikimedia Commons (public domain)

Despite advancements to reduce the side effects of antipsychotic medication, very little progress has been made in developing drugs that more effectively improve symptoms. In fact, only one drug developed in the past 60 years, clozapine, is said to provide improved relief of symptoms. More concerningly, a patient’s functional outcome — their ability to live independently, retain a job, and maintain personal relationships — can remain poor even when their psychosis is well managed. If schizophrenia is a psychotic disorder, why are these patients still impaired in their everyday lives?

Alongside the diagnostic criteria, the DSM lists features that are associated with every disorder it describes. For schizophrenia, it says that cognitive deficits are common. These include problems with language, attention, sensory information processing, and working memory — the process of remembering a piece of information for a brief period in order to achieve a specific goal. Working memory is essential for performing complex tasks, like referring to a cooking recipe and executing its steps. Compromise it and everyday life becomes difficult.

The DSM paints cognitive impairment as an epiphenomenon of schizophrenia — as a footnote to psychosis. But this approach is misguided. In fact, defining schizophrenia by psychosis may be one of the roadblocks to developing more effective drugs for this disorder.

Thankfully, a paradigm shift is occurring. Caroline Gurvich, a senior research fellow at the Monash Alfred Psychiatry Research Centre in Melbourne, says that cognitive dysfunction is increasingly regarded as a core feature of schizophrenia, occurring in about 80% of patients. However, not all people with schizophrenia show cognitive impairment. “There is a reasonable body of literature now that identifies cognitive subgroups and there appears to be a ‘relatively intact’ subgroup,” says Gurvich.

Although not all patients show cognitive deficits, some researchers have called for schizophrenia to be reconceptualised as a cognitive disorder, rather than a psychotic one. There are several lines of evidence that support this approach. In patients, we see that cognitive impairment is present before the onset of psychosis, and that it is relatively stable across the duration of illness. Further to this, and perhaps most interestingly, cognitive impairment is detectable, albeit to a lesser extent, in unaffected first-degree relatives of people with schizophrenia.

Of key interest, Gurvich says that cognitive problems are debilitating and are strongly linked a patient’s ability to function in everyday life: “For example, work or a meaningful relationship becomes very difficult with severe cognitive problems.” Cognitive symptoms persist even when other symptoms, such as psychosis, are treated. “To really improve the lives of patients with schizophrenia, it is essential that cognition is better understood and better treated,” says Gurvich.

 
Embroidery created by a schizophrenia patient, on display at the Glore Psychiatric Museum in Missouri, USA.   Cometstarmoon/Flickr  (CC BY 2.0)

Embroidery created by a schizophrenia patient, on display at the Glore Psychiatric Museum in Missouri, USA. Cometstarmoon/Flickr (CC BY 2.0)

 

There is no single cause of schizophrenia. Genetic factors are known to play a role: In the general population, about 1% of people will develop schizophrenia in their lifetime. This jumps to about 10% if a person has a parent with the disorder, suggesting that genetics contribute but are not the whole story. Environmental factors are the other piece of the puzzle. Schizophrenia has been linked to various environmental risk factors, including early-life stress, such as child abuse or neglect, and substance use.

Understanding how these risk factors change the brain to produce cognitive impairment, a process called pathophysiology, is key to developing drugs to treat these symptoms. Changes in the dopamine system can contribute to the psychotic symptoms of schizophrenia; we know this because antipsychotics target receptors in this system. Dysfunction in another neurotransmitter, glutamate, can explain not only cognitive impairment, but also the negative symptoms and the dopamine changes that lead to psychosis. Glutamate acts on several receptors in the brain; one of these, the NMDA receptor, is the same one blocked by the recreational drugs ketamine and PCP (angel dust). Early evidence implicating glutamate in schizophrenia came from reports in the 1990s that ketamine can induce delusions in healthy people. It also dampens emotions and impairs working memory, creating a complete schizophrenia-like state.

Since then, evidence has continued to mount that the NMDA receptor contributes to the pathophysiology of schizophrenia. For example, reducing the levels of this receptor in mouse brains can induce schizophrenia-like disruptions to behaviour. The symptoms of anti-NMDA receptor encephalitis, an autoimmune disease, also support this idea. In this disease, the body produces antibodies against the NMDA receptor, compromising its function. Initially, patients present with psychotic symptoms, such as hallucinations and delusions, and later go on to experience cognitive problems, such as deficits in attention. A first-hand experience of this disease was described in the autobiography Brain on Fire: My Month of Madness, which was later turned into a Netflix film.

Given all this evidence, the glutamate system has emerged as a promising target for new drugs. Several strategies have been used to increase activity at the NMDA receptor. One approach is to increase levels of glycine — a molecule that the receptor needs to function — in the brain, by blocking a receptor that takes it up into cells. Several compounds that do this have been developed and trialled in schizophrenia patients. One compound, bitopertin, was initially shown to improve negative symptoms in patients, and subsequently to improve both positive and negative symptoms in patients that were unresponsive to the currently available drugs. Unfortunately, bitopertin is no longer under development for treatment in schizophrenia after a spate of studies that failed or were deemed inconclusive.

 
Vials of the drug ketamine. During the 1990s, reports of recreational ketamine use revealed that the drug could induce schizophrenia-like symptoms in healthy people.   Psychonaught/Wikimedia Commons  (CC0 1.0)

Vials of the drug ketamine. During the 1990s, reports of recreational ketamine use revealed that the drug could induce schizophrenia-like symptoms in healthy people. Psychonaught/Wikimedia Commons (CC0 1.0)

 

Targeting glutamate is only one of several approaches now being trialled by researchers. Gurvich is exploring how stress and sex hormones contribute to cognitive dysfunction in schizophrenia, as well as how modulating hormones can enhance cognition. Oestrogen, the primary female sex hormone, is of particular interest. Human and animal studies show that oestrogen therapies enhance cognition, but this may depend on many factors, such as patient age. One drug, raloxifene, a selective oestrogen receptor modulator, has been tested in schizophrenia with some promising results.

In addition to pharmacological approaches, researchers are also developing training-based methods to improve cognition in schizophrenia patients. Cognitive remediation, for example, is a type of behavioural training that aims to improve cognitive processes, such as attention and working memory, in a long-lasting and generalisable way. For this approach, patients complete mental exercises that address certain cognitive domains, using either a drill-practice or drill-strategy format. In drill-practice, exercises are simply completed repeatedly, while in drill-strategy patients are also taught strategies that can be used to increase performance. A 2011 report assessing 38 studies that used this training in schizophrenia found it effective for improving patients’ global cognition, regardless of therapy type. But not all the evidence is positive. One 2010 study, for example, showed that, although patients improved their performance on the tasks in which they were being trained, this did not translate to improvements in general cognition or everyday functioning.

The jury is still out on whether cognitive remediation can improve cognition and functioning in schizophrenia. However, this approach does seem to work best when combined with psychosocial rehabilitation programs, such as supported employment. Although the pathophysiology of cognitive dysfunction schizophrenia remains elusive, researchers are making progress towards developing a new drug for these symptoms. Gurvich suggests that the greatest chance for improving cognition may lay in combining the two treatment strategies. “There is promise in various pharmacology and training/therapy,” she says, “and perhaps a combination of these will provide the greatest benefits in the future.”

The scientific community has recognised cognitive impairment as a core feature of schizophrenia, and not merely subsidiary to the psychosis. Treating this cluster of symptoms is key to reducing the burden of this disorder to patients and society. The next step is to change how schizophrenia is diagnosed; without greater awareness of cognitive impairment among clinicians, newly developed treatments may not be implemented effectively. Lastly, we need awareness in the media and among the general public. Patients with schizophrenia are often falsely depicted in film and television as not only psychotic, but also violent and aggressive. This sort of stigma is hurtful and needs to be changed. Breaking the violence fallacy, and depicting schizophrenia as more than a disorder of psychosis, could improve empathy and be invaluable to people living with the disorder.

Alexandre Guérin assisted the author with elements of this article. Edited by Andrew Katsis