Breaking boundaries


While the causes of psychiatric disorders are still not well understood, we do know that many biological dysfunctions reported in patients cut across the traditional diagnostic boundaries. Cognitive dysfunction, for example, is experienced by patients with many different psychiatric disorders and can severely impact daily life. At ECNP 2017, we were given an overview of transdiagnostic cognitive dysfunctions in psychiatric patients. In the future, the relationship between these dysfunctions and symptom-dimensions in psychiatry may move us towards new classification systems and improved treatments.

The big issue

Cognition is the big issue in psychiatric disorders

Cognition is the big issue in psychiatric disorders. This was the opening message from Prof Barbara Sahakian, University of Cambridge. She described neuropsychiatric disorders as disorders of cognition, motivation and their interaction. Many of these disorders are of neurodevelopmental origin. The brain is in development through the teenage years and into the early twenties, with the frontal lobes last to develop. It follows that mental disorders have a greater impact on the young, with about 75% of illness onset before 24 years of age.

There is a shift in mental health policy from trying to treat chronic, relapsing disorders to prevention and early detection to ensure that mental well-being is protected. Cognition is one of the proposed biomarkers for prevention and early detection, and is an important target for treatment. Cognitive manifestations in neuropsychiatric disorders include attentional biases, aberrant learning, memory impairments, dysfunctional reward systems, and lack of top down cognitive control by the prefrontal cortex.

The value of playing games

Prof Sahakian presented ‘gamification’ of cognitive training, which was designed to be fun, attention grabbing, motivating and easy to understand. She introduced us to a Wizard Memory Game that patients with schizophrenia played for 8 hours a month. These patients showed improved performance on CANTAB PAL, a test of learning and memory, as well as global assessments of functioning. Patients enjoyed playing the game, which was important for adherence and motivation.

Searching for signs

Cognitive functioning in subjects at clinical high risk for psychosis has been a research interest for Prof Paul Amminger, NHMRC Senior Research Fellow, Australia. We need to identify the patterns and severity of neurocognitive functioning in the high risk state of psychosis to enable the development of accurate risk factors for psychosis and more effective and even preventative treatments, Prof Amminger told us.

Sought to answer a few key questions regarding neurocognitive performance and its possible link with the transition to psychosis

He presented his latest findings on cognitive functioning from the NEURAPRO study - including baseline characteristics, changes over time and, crucially, applying the findings to outcome prediction. The NEURAPRO study is a multicenter, randomized controlled trial of omega-3 fatty acids and cognitive behavioural management for young people at ultra-high risk of psychotic disorders. The study included 304 ultra-high risk participants, of whom 10.5% transitioned to psychosis within 12 months. Giving fatty acids had no impact on transition rate.

They sought to answer a few key questions regarding neurocognitive performance and its possible link with the transition to psychosis, as well as functional outcome. Using the Brief Assessment of Cognition in Schizophrenia (BACS), they found that at baseline ultra-high risk subjects performed about half a standard deviation below healthy controls on three of the six domains. Subjects experienced ‘difficulty’ but could not be described as ‘deficient’.

After a median of 24 months follow-up, and taking age, gender and IQ into account, both executive functioning (Tower of London) and motor speed (Token Motor Task) predicted transition to psychosis in ultra-high risk subjects.

In terms of functional outcomes, baseline BACS was a stronger predictor than changes in BACS over time (1 to 6 months). Baseline attention and processing speed (Symbol Coding) predicted functional outcomes at 6, 12 and 24 months, after adjusting for IQ and baseline functioning.

Breaking open boxes

Cognitive dysfunction has typically been studied in groups of patients with a certain DSM diagnosis. However, within these DSM categories, cognitive test results were often heterogeneous and no specific cognitive profiles could be distinguished. In the ACROSS study, Prof Dorien Nieman, Department of Psychiatry, Amsterdam, and colleagues investigated for the first time the relationship between cognition and psychiatric symptoms across a wide range of psychiatric disorders.

The study included 893 patients (439 male) between 14 and 75 years of age (mean age 34.6 years) with a primary psychiatric diagnosis on DSM-IV axis I. All patients were assessed with the CANTAB cognitive test battery (domains included attention, learning and memory, executive functioning, spatial working memory and psychomotor speed) and validated symptom questionnaires (including depression, anxiety, OCD, anhedonia, psychosis and PTSD).

Performance on all cognitive domains was related to severity of depressive symptoms, but not to other symptom-dimensions. Energy level was the Inventory of Depressive Symptomatology item that showed the strongest relationship with cognitive functioning.

Move away from unfruitful categorisation and towards a dimensional approach

Prof Nieman concluded that to reduce the burden caused by mental illness we need to move away from unfruitful categorisation and towards a dimensional approach. We need to appreciate the individual blend of biological, social and existential factors that contribute to each patient’s burden.

An alternative approach

We are learning that the latest neurobiological, genomic and behavioural data do not align well with currently defined mental disorders, in which heterogeneous syndromes with different pathophysiological mechanisms are grouped in to one disorder. Dr Uma Vaidyanathan, Scientific Program Manager of the Research Domain Criteria (RDoC) Unit, National Institute of Mental Health (NIMH), explained how the RDoC project aims to tackle this problem. RDoC is a set of principles for research that offers an alternative strategy for approaching and studying mental disorders.

Domains may cut across multiple disorders, as does the cognitive symptoms domain

The RDoC framework is organised around basic functions, such as working memory, and the neural systems that implement them. It consists of six domains or constructs that are based on both biology and behaviour, and allow for quantitative measures of outcomes. These domains may cut across multiple disorders, as does the cognitive symptoms domain.

The number of studies exploring the RDoC matrix has grown over the past few years, especially the cognitive and motivational constructs. In terms of engagement with regulatory agencies, the FDA has stated that objections to using an alternative to DSM classification may be overcome with arguments and data to show the validity and value of targeting a particular domain.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

Symposium references
  1. Sahakian BJ, Bruhl AB, Cook J, Killikelly C, Savulich G, Piercy T, Hafizi S, Perez J, Fernandez-Egea E, Suckling J, Jones PB. The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people. Philos Trans R Soc Lond B Biol Sci. 2015 Sep 19;370(1677):20140214.
  2. Barnett JH, Blackwell AD, Sahakian BJ, Robbins TW. The Paired Associates Learning (PAL) Test: 30 Years of CANTAB Translational Neuroscience from Laboratory to Bedside in Dementia Research. Curr Top Behav Neurosci. 2016;28:449-74.
  3. Nathan P, Lim YY, Abbott R, Galluzzi S, Marizzoni M, Babiloni C, et al. Association between CSF biomarkers, hippocampal volume and cognitive function in patients with amnestic mild cognitive impairment (MCI). Neurobiol Aging. 2017 May;53:1-10.
  4. Kaser M, Deakin JB, Michael A, Zapata C, Bansal R, Ryan D, Cormack F, Rowe JB, Sahakian BJ. Modafinil Improves Episodic Memory and Working Memory Cognition in Patients With Remitted Depression: A Double-Blind, Randomized, Placebo-Controlled Study. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Mar;2(2):115-122.
  5. Goss AJ, Kaser M, Costafreda SG, Sahakian BJ, Fu CH. Modafinil augmentation therapy in unipolar and bipolar depression: a systematic review and meta-analysis of randomized controlled trials. J Clin Psychiatry. 2013 Nov;74(11):1101-7.
  6. Millan MJ, Agid Y, Brüne M, Bullmore ET, Carter CS, Clayton NS, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012 Feb 1;11(2):141-68.
  7. Nieman D. Prevention in Mental Health Care: Time for a new approach. Oxford, UK: Routledge.
  8. Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 1996 May;26(3):477-86.
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