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 an individual locked in a dark institution, constantly plagued by non-existent voices and vivid hallucinations. Even as a final year BSc Biology student with a neuroscience research placement under my belt, I too was guilty of this reflex association. Upon skimming through project titles on FindaPhD.com, the word “schizophrenia” jumped out of the page. My excitement was sparked as I envisaged myself unravelling the intricacies of psychosis. As I examined the project title more closely, I admittedly experienced a minor surge of disappointment: the research was interested in targeting the cognitive deficits of schizophrenia. Cognitive deficits? I was unaware that cognition was significantly impaired in schizophrenia patients. And even if it was, did these symptoms really warrant extensive investigation? Surely, in the context of a disorder characterised by multimodal hallucinations and debilitating delusions, cognitive difficulties shouldn’t be an urgent therapeutic priority.

The failure of current antipsychotics

A few hours of literature research and an interview with my PhD supervisor later, my appreciation of schizophrenia had been completely transformed.

Fortunately for our hypothetical institutionalised patient, modern antipsychotic drugs combating ‘positive’, psychotic symptoms have allowed many individuals to successfully function and flourish within their communities. So why, my supervisor pointed out to me, do so many schizophrenia patients still fail to achieve independent living, find employment and form relationships? Even more alarmingly, why are rates of symptomatic relapse so high? By the end of our conversation, I was convinced: the answer lies in the debilitating cognitive disturbances suffered by individuals, too often overlooked by research and – crucially – neglected by current drug therapies.

Cognitive impairment in schizophrenia: an unmet clinical need

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, institutionalisation and advancement in cognition assessment tools. In particular, patients struggle in areas of verbal learning, processing speed and working memory.

Cognitive functioning in schizophrenia has been subjected to decades of research. However, the true impact of cognition upon disease outcomes has only recently come to light. A plethora of studies have drawn links between poor cognitive performance and impaired psychosocial functioning. One might argue that this is a rather obvious association. But why does it matter? Closer consideration reveals the enormous impact this has on daily life: if a schizophrenia patient is unable to perform hygiene-related tasks and keep up with their medications, they have little hope of finding employment or successfully integrating into community living.

As recently as January 2020, research has emphasised the detrimental effects of poor cognition. An Ecuadorian study conducted at the psychiatric Kennedy Hospital used the SCIP (Screening of Cognitive Deterioration in Psychiatry) tool alongside questionnaires assessing quality of life and sociodemographic status to reveal the inverse relationship between cognitive impairment and quality of life as perceived by the patient.

Even considering the impact of untreated cognitive symptoms upon 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 and a substantial waste of resources. As if the significance of cognitive impairment had not been sufficiently demonstrated, a Swedish study following over 500 schizophrenia patients made the staggering finding that executive function independently predicted premature death.

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 – located on neurons in the brain, these receptors mediate signalling crucial for learning and memory functions. One such medication is memantine, which has shown some promise in schizophrenia patients.

Unfortunately, using pharmacological treatments to improve cognition is far from straightforward. It is critical to remember that these patients still rely upon antipsychotics 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? This is where cognitive remediation therapy comes in. Using behavioural training, this technique is not only shown to improve performance across numerous cognitive domains, but also delay the relapse of symptoms.

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. The game plan is clear: find this drug, roll it out to patients and the problem will be solved.

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 behavioural therapies allowing one patient to thrive may be completely unsuccessful in another. Encouragingly, current efforts are directed toward identifying patients most likely to benefit from certain treatment strategies, using biological indicators or ‘biomarkers’.

In the world of science, it is all too easy to become immersed in the daily frustrations and unsolved mysteries of research and forget why one is even investigating a particular disorder. As a colleague in neuroscience R&D at Eli Lilly once said to me: “in every meeting, there should always be a chair reserved for the most important person in the room. And that person is the patient.”

There is an undeniably long way to go before schizophrenia patients will be able to make a complete recovery, with a low risk of relapse and a satisfactory quality of life. But recognising cognition as the wrongly neglected aspect of schizophrenia is certainly a step in the right direction.

References:

J, Avila, Villacrés L, Rosado D, and Loor E. ‘Cognitive Deterioration and Quality of Life in Patients with Schizophrenia: A Single Institution Experience’Cureus 12, no. 1 (25 January 2020).

Molina, Juan, and Ming T. Tsuang. ‘Neurocognition and Treatment Outcomes in Schizophrenia’. In Schizophrenia Treatment Outcomes: An Evidence-Based Approach to Recovery, edited by Amresh Shrivastava and Avinash De Sousa, 35–41. Cham: Springer International Publishing, 2020.

Schaefer, Jonathan, Evan Giangrande, Daniel R. Weinberger, and Dwight Dickinson. ‘The Global Cognitive Impairment in Schizophrenia: Consistent over Decades and around the World’Schizophrenia Research 150, no. 1 (October 2013): 42–50.

Evans, Jovier D., Robert K. Heaton, Jane S. Paulsen, Barton W. Palmer, Thomas Patterson, and Dilip V. Jeste. ‘The Relationship of Neuropsychological Abilities to Specific Domains of Functional Capacity in Older Schizophrenia Patients’. Biological Psychiatry 53, no. 5 (1 March 2003): 422–30.

Semkovska, Maria, Marc-André Bédard, Lucie Godbout, Frédérique Limoge, and Emmanuel Stip. ‘Assessment of Executive Dysfunction during Activities of Daily Living in Schizophrenia’. Schizophrenia Research 69, no. 2–3 (1 August 2004): 289–300.

Tsai, G. E. ‘Ultimate Translation: Developing Therapeutics Targeting on N-Methyl-d-Aspartate Receptor’Advances in Pharmacology (San Diego, Calif.) 76 (2016): 257–309.

Thomas, Michael L., Michael F. Green, Gerhard Hellemann, Catherine A. Sugar, Melissa Tarasenko, Monica E. Calkins, Tiffany A. Greenwood, et al. ‘Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia’JAMA Psychiatry 74, no. 1 (1 January 2017): 37–46.

Trapp, Wolfgang, Michael Landgrebe, Katharina Hoesl, Stefan Lautenbacher, Bernd Gallhofer, Wilfried Günther, and Goeran Hajak. ‘Cognitive Remediation Improves Cognition and Good Cognitive Performance Increases Time to Relapse–Results of a 5 Year Catamnestic Study in Schizophrenia Patients’. BMC Psychiatry 13 (9 July 2013): 184.

Helldin, Lars, Fredrik Hjärthag, Anna-Karin Olsson, and Philip D. Harvey. ‘Cognitive Performance, Symptom Severity, and Survival among Patients with Schizophrenia Spectrum Disorder: A Prospective 15-Year Study’. Schizophrenia Research 169, no. 1–3 (December 2015): 141–46.

 

This article was originally published on the PLOS ECR Community website on 21st February 2020.

Images in text

  1. Schizophrenia – Jo Skinner Photography at flickr.com
  2. White Matter Might Matter – Stefan Sommer, ETH Zurich SNSF at flickr.com

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