Written by Jessica Brown

March 2020

Cognition in Schizophrenia

A missing piece of the therapeutic puzzle

What kind of mental image springs to mind upon reading the word ‘schizophrenia’? Many envisage individuals locked in dark institutions, plagued by non-existent voices and vivid hallucinations. Fortunately, modern antipsychotic drugs combating these ‘positive’ symptoms have allowed many patients to successfully function within their communities. So, why do so many schizophrenia patients still fail to achieve an independent living, find steady employment, and form meaningful relationships? Even more alarmingly, why are rates of symptomatic relapse so high? One possibility lies in the debilitating cognitive disturbances suffered by patients, too often overlooked by research and – crucially – neglected by current therapies. 

 

Schizophrenia is a staggeringly heterogeneous disorder, with symptoms manifesting very differently in each patient. Amidst this variety, cognitive deficits are a consistent feature, persisting independently of circumstances such as medication and institutionalization. In particular, patients struggle with verbal learning, processing speed, and working memory. But do these impairments really have a major impact? 

 

The average lifespan of a schizophrenia patient is approximately 20 years shorter than the normal population. Although this statistic is often attributed to suicide, a Swedish study following over 500 schizophrenia patients made the staggering finding that executive function independently predicted premature death. 

 

Schizophrenia is not all about hallucinations and erratic behavior, the cognitive aspects of this disorder deserve a closer look.

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Cognitive Impairment In Schizophrenia: An Unmet Clinical Need

Compared to psychotic symptoms, the cognitive aspects of schizophrenia have previously attracted less research interest. Querying the Web of Science database for articles including the title terms “cognition” and “schizophrenia” generates 1460 records, whereas an identical search for “psychosis” and “schizophrenia” gives a total of 2149. However, in the past decade, the number of cognition-focused publications has steadily risen. This recent surge in research interest reflects a dawning recognition of the correlation between cognition and disease outcomes. One might argue that this is a rather obvious association, but closer consideration reveals the enormous impact this has on daily life: if a patient with schizophrenia is unable to perform hygiene-related tasks and keep up with their medications, they have little hope of finding employment or successfully integrating into their community. 

 

This is a particularly pressing issue in underdeveloped countries, home to 90% of people with schizophrenia, and where 50% of diagnosed patients cannot access adequate treatment. In many such areas, however, research interest is lacking. A study published in January 2020 was the first in Ecuador to investigate the consequences of schizophrenia in terms of cognitive impairment and life quality. The research, conducted at the psychiatric Kennedy Hospital, revealed an inverse relationship between cognitive impairment and quality of life as perceived by the patient. 

 

Even considering the impact of untreated cognitive symptoms upon a patient‘s quality of life, it is still reasonable to pose the question: so what? The sad reality is that for many patients, cognitive difficulties make antipsychotic drugs a futile intervention, leading to symptomatic remission. Not only is such failed recovery disappointing from a medical perspective, on a financial level, it also represents a substantial waste of time and resources.  

 

Therapeutic Intervention: A Multi-pronged Approach

In the face of such alarming data, it is unsurprising that the cognitive deficits of schizophrenia have become an urgent therapeutic target. But how can cognition be elevated? 

 

Amongst the most promising interventions are drugs targeting NMDA receptors which are crucial for learning and memory functions. One such medication is memantine, which has shown some promise in schizophrenia patients, particularly as an adjunctive treatment. Indeed, clinical trials conducted in December 2019 revealed memantine augmentation of standard antipsychotic treatment improved verbal memory, learning, verbal letter fluency, and working memory in individuals with chronic schizophrenia.

 

Unfortunately, using pharmacological treatments to improve cognition is far from straightforward. One major challenge is that most of these patients still rely upon antipsychotic drugs to manage positive symptoms, which often interfere with the activity of cognition-targeting drugs. Even without this complication, is it rational to expect a single-target approach to be effective in treating such a complex, multi-faceted disorder? The failure of numerous drug compounds at clinical trial stages is attributed to the limited target range of these agents, manipulating a single neurotransmitter or receptor class. In reality, the etiological underpinnings of schizophrenia likely extend beyond one specific disruption to fundamental ‘wiring’ defects on a greater scale, and this should be appreciated by therapeutic interventions.

 

This is where cognitive remediation therapy comes in. A 5-year study showed that computer-assisted cognitive training could improve attention, memory, problem-solving skills. But do these alterations foster long-term clinical benefits? In fact, those individuals with good post-test cognitive performance (in verbal memory an executive functioning) showed a longer time to relapse. 

 

Early administration of these therapies could even alter the disease trajectory. Not only are at-risk patients receiving cognitive rehabilitation less likely to transition into a full pathological state, but comparable techniques administered to rats throughout adolescence induced cognitive improvements that persisted into adulthood. If previously failed drug compounds were delivered alongside cognitive enrichment programmes, would this block the progression of schizophrenia? Excitingly, many researchers argue that this is possible. 

 

Concluding Thoughts

As scientists, I believe we are often drawn to the “one size fits all” approach: current medicine is geared toward identifying a “magic bullet” to target a single, disease-causing agent. Sadly, as research continues to search for successful schizophrenia treatment strategies, one thing is becoming painstakingly clear: one size does not fit all. A particular cocktail of drugs and behavioral therapies allowing one patient to thrive may be completely unsuccessful in another. Whilst simply improving cognition is unlikely to alleviate psychotic symptoms, similarly, a patient receiving pharmacotherapy alone is unlikely to undergo the enduring, large-scale elevations in cognitive plasticity required for complete functional recovery. 

 

Encouragingly, current efforts are directed toward identifying patients most likely to benefit from certain strategies, using biological indicators or ‘biomarkers’. Despite the need for such therapeutic tailoring, targeting cognition should clearly form a core component of any treatment package.

 

There is a long way to go before schizophrenia patients will be able to make a complete recovery, with a low risk of relapse and satisfactory quality of life. To facilitate comprehensive symptomatic improvements, it is vital that research considers the complete consequences of a schizophrenia diagnosis, from financial deprivation and social exclusion to the cognitive barriers impairing daily functioning. Such a shift in perspective is unlikely to occur overnight, but recognizing cognition as the wrongly neglected aspect of schizophrenia may be a step in the right direction.

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