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COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA: THE “BIG” UNMET NEED

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    Cognitive dysfunction is one of the big unmet needs in schizophrenia said Peter Falkai, as he opened the ‘Thinking clearly with schizophrenia – is cognitive impairment the obstacle holding your patients back?’ satellite symposium held at the 34th European Congress on Neuropsychopharmacology.
     
    The objectives of the symposium were three-fold, said Prof. Falkai, who is Professor and Chairman of the Department of Psychiatry and Psychotherapy at the Ludwig-Maximilians-University Munich, Germany. The first objective was to get a perspective of the reality of living with cognitive impairment due to schizophrenia and to really appreciate the impact that this has on the quality of life of the patient, their carers and family members.
     
    Then, from a more practical and clinical point of view, the aim was to look at how cognitive impairment affects patients’ functional abilities and what clinicians can do to identify the signs and symptoms and manage these accordingly. Finally, said Prof. Falkai, the aim was to look at the future of managing cognitive impairment in patients with schizophrenia, going beyond the management of psychosis. 

    Challenges of living with cognitive impairment from the patient perspective

    Martine Frager Berlet, who knows only too well what it is like to live with someone challenged by cognitive impairment due to schizophrenia, gave the first presentation. Mrs. Frager Berlet, who is a member of the French patient advocacy association UNAFAM, conveyed her personal opinions on how adaptive behaviour might help those living with schizophrenia to better understand the various support on offer, to appreciate why certain tasks they need to do may be beneficial to them, and understand about their illness and its treatment.
     
    What could better cognition mean for patients and families?
     
    From the patient and family perspective, Mrs. Frager Berlet said that the ideal outcome of any medicine or intervention aimed at improving patients’ cognition would hopefully result in them being able to respond more rationally to situations. Furthermore, the goal would be to enable a better understanding of each other, better anticipation of what will happen next, and a better ability to plan. Moreover, the intervention should ideally help those living with schizophrenia to express their feelings rather than keep silent. Mrs. Frager Berlet noted that not all cognition deficits are acute, and it can be difficult for them to understand other people’s intentions. It can be difficult for loved ones to envisage projects, bring them to life, and continue with them, Mrs. Frager Berlet said, but it can be made much easier if they and those caring for them can all understand each other better.
     
    Unfortunately, Mrs. Frager Berlet observed that people with schizophrenia often refuse to accept offers of help and support, failing to recognize that they could benefit. Everyday tasks, such as shopping, cooking, cleaning, making phone calls, writing emails, or making and keeping appointments, can pose challenges and not be seen as something that needs greater attention or is important. Moreover, patients may fail to link how completing a task will improve their quality of life and miss the point that improved cognition could help them to understand the importance of these tasks. All in all, improved cognition results in better functioning of the brain, Mrs. Frager Berlet said, enhanced self-confidence, and control over emotions, thus providing a brighter future for patients, families, and carers.

    Cognitive impairment from a physician’s perspective

    Next, consultant psychiatrist Dr. Nagore Penades of NHS Greater Glasgow and Clyde in Scotland, UK, looked at how physicians can best approach cognitive impairment in people with schizophrenia. She focussed her presentation on five key questions to get the audience thinking:  1) Is treating the positive symptoms of schizophrenia enough? 2) Is the treatment of psychosis all about antipsychotics? 3) How do we measure functioning and how do we know if it is improving? 4) How can we improve functioning, and 5) what can we do right now with what is available to us?
     
    Addressing her first question, Dr. Penades observed that managing positive symptoms alone was probably not enough to improve the quality of life and functioning of patients. There is enough evidence available now to show that negative symptoms contribute more than positive symptoms to the impaired quality of life and poor functioning seen in people with schizophrenia, she said.1 Indeed, one in five people with schizophrenia will experience at least one negative symptom, such as affective flattening, poverty of speech, and a lack of will to anything.1
     
    Importantly, specific cognitive deficits are seen in the large majority of people with schizophrenia, Dr. Penades said. This may include problems with attention, executive function, or learning new verbal information, for example, but there is a lot of heterogeneity among patients. 2,3,4
     
    When treating a patient is not all about managing the psychosis, Dr. Penades argued. Cognitive symptoms need to be addressed but there has so far been modest efficacy seen in trials of typical and atypical antipsychotics.5 While there continues to be research looking for a medication that might help, non-pharmacological approaches should not be forgotten.6
     
    How do we measure functioning and how do we know if it is improving?
     
    To answer the question about functioning, Dr. Penades said it was important to remind oneself about what is even meant by functioning. It is a broad term that encompasses people’s ability to function socially, perform everyday tasks, go to work, and feel happy and contented with their life. Cognitive functioning is also an important ingredient, she added.
     
    For good cognition, there needs to be the ability to perceive things as they are, the ability to pay attention, remember and recall past events, furthermore the ability to judge, evaluate, solve problems, make decisions, and of course above all, to communicate with others.7 On top of this, Dr. Penades said, there needs to be the opportunity to learn, to practice, to make mistakes, to improve, and start again.
     
    In terms of measurement, there are lots of scales and instruments that can be used to monitor functioning, such as the Activities of Daily Living, the Social Functioning Questionnaire, and many more, she observed. For cognitive functioning, there are several specific scales: the Weschler Adult Intelligence Scale (WAIS), The Behavioral Activation for Depression Scale (BADS), and the Matrics Consensus Cognitive Battery (MCCB).
     
    Treating cognitive symptoms, what can be done right now?
     
    Data from a large systematic review and meta-analysis have suggested that antipsychotic treatment may have some benefits on cognitive function.8 However, is important to consider the origin of the cognitive impairment Dr. Penades said. Is the impairment intrinsic, and caused by the disease itself? Is it iatrogenic, and a side effect of treatment: or is it social, caused by lack of opportunities, a lack of trial and error? She once again emphasized the individuality of the patient, and that a personalized approach should be the mainstay of treatment. For example, if a patient has an attention deficit, it is important to differentiate, select and prescribe the most suitable medication for that specific patient.
     
    Holistic approach and taking baseline assessments
     
    In concluding, Dr. Penades looked at how psychiatry practice had changed in the past 20 years. She queried if a holistic approach to managing patients had been lost. Rarely are baseline assessments of patients’ social or cognitive function made, which is perhaps something physicians could now consider when managing their patients in the future. Her takeaway message was to understand the root of the problem, target it, and remember to take a baseline assessment.

    What does the future hold for managing cognitive symptoms?

    A holistic approach to managing patients is paramount, agreed Philip Harvey, Professor of Psychiatry and director of the Division of Psychology at the University of Miami Miller School of Medicine in Florida, United States.  Managing patients is about addressing all the symptom domains and while cognition is important, functional capacity, negative symptoms, and impaired self-assessment all need to be addressed.
     
    Pharmacological treatments: the old and the new

    Unawareness of illness and lack of insight has been studied for many years, Prof. Harvey added, but research into awareness of functional and cognitive abilities is rather newer. Unfortunately, none of the currently available treatments have really had much of an effect in this regard.8,9
     
    While efforts have been made to try to develop new pharmacological approaches, such as trialing nicotinic agonists, adrenergic agonists, cholinesterase inhibitors, histamine receptor antagonists, steroids, or phosphodiesterase inhibitors, none have yielded very impressive results in enhancing cognitive functioning.10-12
    Design issues are a possible reason why these early trials have failed Prof. Harvey suggested.
     
    Cognitive remediation works
     
    There is evidence, however, that cognitive remediation works, said Prof. Harvey. Plus, if cognitive training and rehabilitation interventions are used together, the success of these interventions increases markedly.13,14 Cognitive training allows patients to execute skills that are already in their repertoire, he explained, but the important thing to keep in mind is that cognitive training does not teach functional skills.14
     
    Another strategy is adding long-acting injectable treatment to cognitive training and skills training, said Prof. Harvey. This may lead to a more substantial gain when compared to adding oral antipsychotic medications, he suggested.28 It is also important to keep in mind that clinical stability may be a prerequisite for being able to engage adequately in these rehabilitation-type interventions, he said.14
     
    Additive effects of interventions
     
    Prof. Harvey further observed that combining interventions may have additive effects; just like adding cognitive training onto skills training, adding a pharmacological boost may lead to better outcomes. For this purpose, amphetamine, guanfacine, and a novel antidepressant vortioxetine have been used. Pharmacological augmentation could also be applied to social skills training, in the same way, Prof. Harvey suggested.15,16
     
    Maybe it is time to start thinking about treating severe mental illness like we treat high blood pressure or cardiac disease, commented Prof. Harvey, where it is not seen to be a problem to use multiple medications from different classes because they all have slightly different targets. 14
     
    Assessing patients in the moment
     
    People with schizophrenia can find self-assessment challenging, said Prof. Harvey, noting that there is a disconnect between patient-reported functioning and clinician-rated functioning. This may lead to a reduced willingness to engage in treatment. Why would you get cognitive training if you don’t have any cognitive or functional challenges? Patients may overestimate their functional capabilities, and this requires close attention and alternative strategies.
     
    Being asked to remember a month later can be particularly challenging for someone with schizophrenia and who may have cognitive deficits. One solution may be to assess patients at the moment or while they are experiencing or doing something, said Prof. Harvey. There are several ways to do momentary assessments: people can be contacted via a smart device and asked: “Where are you?” “Who are you with?” “What are you doing?”; or another option is to use passive measurement like GPS to see if the people are where they say they are and engaging in certain behaviours.
     
    Prof, Harvey concluded by pointing out that a thorough assessment of what someone’s functional abilities are, what their functional goals are, and what their current skills are, is critical to develop a personalized treatment plan.

    References

    1. Tsapakis EM, Dimopoulou T, Tarazi FI. Clinical management of negative symptoms of schizophrenia: An update. Pharmacol Ther. 2015;153:135–47.
    2. Stahl SM. Stahl’s Essential Psychopharmacology, 4th ed., 2013. Cambridge University Press.
    3. Kitchen H, Rofail D, Heron L, et al. Cognitive impairment associated with schizophrenia: a review of the humanistic burden. Adv Ther. 2021;29:148–62.
    4. Mosiolek A, Gierus J, Koweszko T, et al. Cognitive impairment in schizophrenia across age groups: a case-control study. BMC Psychiatry. 2016;16:37.
    5. Miyamoto S, Miyaje N, Fleischhacker WW, et al. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psyhiatry 2012;17:1206–27.
    6. Sinkeviciute I, Begemann M, Prikken M, et al. Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis. NPJ Schizophr. 2018;4:22.
    7. Bowie CR, Harvey PD. Cognitive deficits and functional outcome in schizophrenia[SF1] . Neuropsychiat Dis Treat. 2006;2:531–6.
    8. Hsu WY, Lane H-Y, Lin C-H. Medications used for cognitive enhancement in patients with schizophrenia, bipolar disorder, Alzheimer’s disease, and Parkinson’s disease. Front Psychiatry 2018;9:91.
    9. Husa AP, Moilanen J, Murray GK, et al. Lifetime antipsychotic medication and cognitive performance in schizophrenia at age 43 years in a general population birth cohort. Psychiatry Res. 2017;247:130­­–8.
    10. Sinkeviciute I, Begemann, M., Prikken, M, et al. Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis. NPJ Schizophr. 2018;4:22.
    11. Recio-Barbero M, Segarra R, Zabala A, et al. Cognitive enhancers in schizophrenia: a systematic review and meta-analysis of alpha-7 nicotinic acetylcholine receptor agonists for cognitive deficits and negative symptoms. Front Psychiatry. 2021;12:631589.
    12. Haig GM, Bain E, Robieson W, et al. A randomized trial of the efficacy and safety of the H3 antagonist ABT-288 in cognitive impairment associated with schizophrenia. Schizophr Bull. 2014;40:1433–42.
    13. Turner DT, McGlanaghy E, Cuijpers P, et al. A meta-analysis of social skills training and related interventions for psychosis. Schizophr Bull. 2018;44:475–91.
    14. Harvey PD, Bowie, McDonald CR, et al. Evaluation of the efficacy of BI 425809 pharmacotherapy in patients with schizophrenia receiving computerized cognitive training: methodology for a double-blind, randomized, parallel-group trial. Clin Drug Investig. 2020;40:377–85.
    15. Swerdlow NR, Tarasenko M, Bhakta SG, et al. Amphetamine enhances gains in auditory discrimination training in adult schizophrenia patients. Schizophr Bull. 2017;43:872–80.
    16. Harvey PD, Sand M. Pharmacological augmentation of psychosocial and remediation training efforts in schizophrenia. Front Psychiatry. 2017;8:177.

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