Cognitive remediation therapy plus standard care versus standard care for people with schizophrenia

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of cognitive remediation therapy plus standard care in people with schizophrenia compared with standard care.

Background

Description of the condition

Schizophrenia is a serious mental disorder. It is heterogenous in terms of manifestation of symptoms and signs, age of onset, and course of illness, with a lifetime risk of 1% (Fanous 2005; Jablensky 2000). The incidence risk ratio for men to develop schizophrenia in comparison to women is about 1.42 (Aleman 2003). Schizophrenia can be characterised by 'positive' symptoms, such as delusions and hallucinations, and 'negative' symptoms, such as lack of affect and behavioural dysfunction (APA 2013). Some people with schizophrenia may also manifest mild to severe cognitive deficits such as decline in spatial working memory and executive functioning which, in themselves, can create or at least be part of intrapersonal and interpersonal difficulties such as poor social and occupational functioning (Green 1996; Green 2000).

These cognitive deficits were identified by psychiatrists/neurologists of the late 19th century Pick and Kraepelin, who initially defined schizophrenia as 'dementia praecox', as the people under their care exhibited a rapid cognitive disintegration that had usually begun in late adolescence or early adulthood (Berrios 2003). Cognitive dysfunction may be evident in early phases of the illness and may predate onset (Bortolato 2015; Cannon 2000; David 1997; Jones 1994; Russell 1997).

The cognitive deficits found in people with schizophrenia are also heterogenous. Not all people with schizophrenia show the same cognitive deficits, and they may vary through the course of the disorder (Bora 2017; Fioravanti 2005; Heaton 2001; Kremen 2004). These deficits can also manifest in people with schizophrenia with preserved general intellectual abilities, suggesting that cognitive deficits may be core manifestations of the illness (Faraone 2001). However, many people with schizophrenia show a significant decline in full‐scale intelligence quotient (IQ), suggesting that cognitive deficits may be secondary to general intellectual decline (Hedman 2013; Heinrichs 1998). Deficits in executive function, spatial working memory, verbal memory, and learning have been consistently reported in people with schizophrenia (Bora 2017; Hoff 2005; Kravariti 2007; Piskulic 2007). Some of these deficits are independent of general intellectual deficits, while others seem to correlate. Table 1 provides an explanation of the respective cognitive functions, while Table 2 presents studies that have investigated cognitive deficits in people with schizophrenia with or without general intellectual decline.

Table 1.

Definitions of cognitive functions (executive function, memory, attention/concentration)

Cognitive functions	Definition and explanation
Executive function	Definition: A cognitive process that refers to the initiation and planning of rational behaviour (e.g. the initiation and planning of all behaviours that are needed to visit the supermarket)
	Explanation: This involves formulation of goals, generation of multiple response alternatives, choosing and initiating goal‐directed behaviours, correcting and modifying behaviours when conditions change, and persisting in the face of distraction (Baddeley 1986).
Memory	Definition: A cognitive ability that refers to the ability to encode and retrieve information
	Three basic types of memory
	1. Sensory memory: a system that stores information for less than a quarter of a second (250 ms)	2. Short‐term memory or working memory: a system that stores information for a few seconds up to 30 minutes	3. Long‐term memory: Long‐term memory stores more information and for longer periods of time and is subdivided into episodic, semantic, and procedural memory (Baddeley 1992; Baddeley 2001; Tulving 1983).
	Explanation: Sensory memory involves visual sensory or iconic and echoic sensory memory. Short‐term memory is used when dialling a new telephone number with seven digits. We hold these digits for a while but will forget them very soon if someone is talking to us or the line is busy. Short‐term memory holds about 7 ± items. Visuo‐spatial working memory is a component of working memory with the input and control from the central executive (Baddeley 1986). These tasks may require central executive resources such as the manipulation of information, while others may require only online maintenance of information and do not require input of the central executive (Repovs 2006). Long‐term memory is split into: procedural memory: learning and storage of physical skills (e.g. driving a car); semantic memory: organised knowledge about words and verbal symbols, their meaning, and the relationships among them; and rules, formulas, and algorithms that are used for the manipulation of symbols, concepts, and relationships; episodic memory: knowledge acquired through experience, but that involves temporal or spatial aspects of events. Long‐term memory involves: encoding of information; storage of information; and retrieval of information.
Attention/ concentration	Definition: A cognitive process of selectively concentrating on one aspect of the environment while ignoring other things
	Explanation: Sustained attention or vigilance refers to the capacity to remain focused and alert in order to detect and respond to changes in external stimuli over a period of time; it is considered a component of executive function (Braff 2004; Lezak 2004).

Table 2.

Studies of cognitive deficits in people with schizophrenia with or without general intellectual decline

Year	Studies	Participants	Testing	General intellectual decline
1999	Laws 1999	Chronic Patients	Executive function as measured with the Wisconsin Card Sorting Test	Yes
2000	Bilder 2000	People in first episode	Memory tasks, executive function such as perseverative responses, rapid mental flexibility	Yes
2000	Bilder 2000	People in first episode	Memory tasks	No
2000	Weickert 2000	Chronically ill and non‐chronically ill people	Executive function	Profound IQ decline IQ > 90
2001	Heaton 2001	Outpatients	Delayed verbal recall (verbal memory)	Unclear
2004	Hill 2004	People in first episode	Retrieval (verbal memory)	No
2005	Hoff 2005	People in first episode	Delayed verbal recall (verbal memory), cognitive inhibition (executive function)	Yes
2005	Joyce 2005	People in first episode and chronically ill people	Spatial working memory (executive function)	No
2006	Chan 2006	People naive to medication in first episode	Sustained attention (executive function)	No
2007	Kravariti 2007	Adolescent in first episode, chronically ill people with adolescent‐onset schizophrenia	Verbal memory and planning abilities, attention/mental flexibility	Yes
2007	Piskulic 2007	People in first episode and chronically ill people	Spatial working memory (executive function)	No
2007	Simon 2007	People at high risk, people in first episode	Verbal memory	No

IQ: intelligence quotient

Description of the intervention

Cognitive remediation in schizophrenia is an approach that aims to restore the impaired cognitive function that so damages life skills and employability for people with schizophrenia, but the cost‐effectiveness of this intervention is unclear (Patel 2010). The UK's clinical guidelines are being hampered by currently unclear definitions of cognitive remediation, poor reporting and research design (NICE 2014).

1. Difficulties in definition

There has been an effort to provide a single and focused definition of cognitive remediation in people with schizophrenia, but doing so has proved problematic. For example, cognitive remediation has been defined as "the therapeutic process of increasing or improving an individual’s capacity to process and use incoming information so as to allow increased functioning in everyday life. This includes methods to train and restore cognitive function and compensatory techniques" and/or as "a behavioral training based intervention that aims to improve cognitive processes (attention, memory, executive function, social cognition or meta‐cognition) with the goal of durability and generalization" (as cited in Barlati 2013). However, the label 'cognitive remediation' has been applied to many interventions with different methodologies.

2. History

Cognitive remediation therapy (CRT) was developed by Ann Delahunti and Rodney Morice in 1993 to improve cognitive impairments in people with schizophrenia (Delahunti 1993; Delahunti 2002; Wykes 2006; Wykes 2011). Although in neuropsychological terms a more appropriate term would be 'cognitive rehabilitation' or 'cognitive intervention', the term 'remediation' is described in the Oxford Dictionaries 2017 as ''The action of remedying something, in particular of reversing or stopping environmental damage", and it is this term that is employed for this type of therapy (Oxford Dictionaries 2017).

The initial Delahunti and Morice version of the programme was reformulated by Til Wykes in London by adding a meta‐cognitive component in therapy and the use of errorless and scaffolding techniques (Wykes 2006). The meta‐cognitive aspect of the programme refers to the effort of the therapist to teach the patient to know when and how to use particular strategies for learning and problem‐solving given their cognitive limitation (scaffolding). This approach takes place within an errorless learning approach according to which as each skill is taught the patient is given a prompt or cue immediately following an instruction in order to prevent any chance for incorrect response.

3. Overview

The first version of the programme, and the one upon which this review is based, was entitled Frontal/Executive Program and was targeted specifically at activating frontal and prefrontal brain areas. The programme consisted of three modules such as cognitive flexibility, working memory, and planning. Overall, the programme was offered individually, using mainly paper and pencil tasks and was based on a cognitive strategy instruction (Delahunti 1993; Delahunti 2002).

The cognitive shift module consists of a package of six to eight training sessions of one hour targeting cognitive inflexibility and attention difficulties. The module requires the capacity to effectively engage and disengage from a particular cognitive set. It is practiced with visual, conceptual, and motor information. The therapist uses verbal instructions as a cue and aims to make the patient pay attention to all stimuli, to ask the person to identify what the current set is, and to show if their performance speed is appropriate.

The working memory module consists of two parts. Both parts consist of eight sessions of one hour and are used for several weeks. Part A includes a series of working memory tasks, while Part B includes additional exercises to Part A tasks and emphasises sequencing and dual tasks. The module targets executive processes that are central to memory control such as attention, sequencing, working simultaneously with multiple tasks, delayed verbal and visual memory information. People with schizophrenia work with as many as two to five information sets at a time.

The planning module aims to improve cognitive functioning through the use of cognitive strategies such as active coding, sequencing, and chunking, using internal and external verbal mediation in multitasking performance. The main aim of this module is to help people to organise information, to plan goals and subgoals, to generate cognitive strategies and self control. The first part consists of 12 one‐hour sessions, while the second part involves eight training sessions.

4. Working categories

On the basis of available published studies there are prevalent approaches of CRT in people with schizophrenia. There are treatments that aim to do the following.

4.1 Improve cognitive functions

4.1.1 Improve cognitive functions plus psychosocial dysfunctions such as social skills training

An example of this is integrated psychological therapy (IPT) (Brenner 1992; Brenner 1994; Roder 2006). Integrated psychological therapy is undertaken in groups, and the improvement of cognitive functions involves attention, social cognition, communication skills, social skills, and interpersonal problem‐solving.The main aim of IPT is the treatment of neurocognitve deficits while also targeting the improvement of social behaviour through social skills training.

4.1.2 Focusing on attention, memory, and problem‐solving and on improving social cognition with the practice of social interactions in real‐life interactions

An example of this is cognitive enhancement therapy (CET) (Hogarty 1999a; Hogarty 1999b). The training targets cognitive functions and is done individually and assisted with computer programs, while the social cognition training is done in groups through structured exercises and the practice of social interactions in real‐life situations. The aim of CET is the rehabilitation of cognitive deficits and the improvement of social cognition.

4.1.3 Focusing on attention, memory, and executive function and on targeting the improvement of clinical symptoms

Some studies also examine the effect of CRT programmes on clinical symptoms of patients, suggesting that there is a reduction in symptoms after the implementation of CRT. However, the effect of such programmes seems to be small (effect size 0.28) (McGurk 2007). Similarly, Cella 2017 reported small‐to‐moderate effect sizes of the benefits of CRT in treating negative symptoms in people with schizophrenia.

4.2 Remediate cognitive impairments by targeting executive functions

This focuses specifically on cognitive flexibility, working memory, and planning. Examples are CRT as developed by Delahunti (Delahunti 1993; Delahunti 2002), and reformulated by Wykes (Wykes 2006). Cognitive remediation therapy is undertaken individually using mainly paper‐and‐pencil tasks. Wykes emphasises meta‐cognition and the use of errorless learning and scaffolding and is based on cognitive strategy instruction.

We think that the prevalence of use of these approaches is small and know of no surveys of practice. A few clinical centres use these time‐ and skill‐intensive approaches as part of their treatment goals. These centres of excellence have pioneered this experimental procedure.

How the intervention might work

Cognitive deficits in psychiatric disorders are prevalent, but the pattern of cognitive deficits in schizophrenia is substantially different. Cognitive deficits in people that exhibit schizophrenia in adult life manifest in early childhood and adolescence prior to the onset of clinical symptoms (Keefe 2007; Cannon 2002). However, people who develop affective disorders do not manifest cognitive deficits until their affective symptoms appear (Cannon 2002). Additionally, people with schizophrenia continue to show cognitive deficits even with the remission of clinical symptoms, while people with bipolar disorders show a different pattern, such as a) a remission of cognitive deficits as their affective symptoms remit (Griffin 1993), and b) the persistence of cognitive deficits even after the remission of symptoms is related to the pathophysiology of the illness such as a long illness duration, a higher number of manic episodes, and prior psychotic symptoms (Martínez‐Arán 2004; Robinson 2006).

There is increasing evidence that the cognitive deficits that are core manifestations of schizophrenia are caused by changes in brain plasticity (neuroplasticity) throughout development. 'Neuroplasticity' refers to the ability of the brain to reorganise itself by forming new neural connections through experience/learning. Neuroplasticity allows the neurons in the brain to compensate for injury or disease and adjust their activities in response to new learning. Although the exact mechanism that underlies cognitive deficits in schizophrenia has not yet been identified, there is evidence that the cognitive deficits are due to abnormal neuroplasticity, specifically disconnectivity within neural networks (Friston 1998; Stephan 2006; Daskalakis 2008; Pomarol‐Clotet 2008). A meta‐analysis showed that people with schizophrenia not only failed to activate the dorsolateral prefrontal cortex when performing working memory tasks (working memory is a subsystem of executive function), a process known as hypofrontality, they also showed increased activation in other brain regions such as in the anterior cingulated and left frontal pole regions compared to healthy controls, suggesting that abnormal activation patterns in people with schizophrenia are not restricted to one brain area only (Glahn 2005).

As neuroplasticity underlies functional recovery in a range of clinical conditions such as brain injury and stroke, researchers have started to investigate neuroplasticity as a target treatment of cognitive deficits in people with schizophrenia. Clinical improvement in stroke and brain injury has been associated with changes at the cellular level and the functional connectivity of relevant neural networks (Cramer 2011). Overall, therapies that employ brain plasticity aim to restore or improve functional and structural changes in the brain after injury. Physical rehabilitation targets the functional improvement of the motor system after injury, while cognitive rehabilitation treatments, through training of learning processes, aim to mitigate cognitive deficits by improving the structure and function of the brain via neuroplasticity.

Animal studies and studies on aging adults show that in order for neuroplasticity to take place, mainly to induce the creation of new synaptic structures, a process known as 'synaptogenesis':

1. training (learning) should be repetitive and of sufficient duration in order to lead to structural changes in the brain (Muller 2002). The sufficient duration of cognitive training and its positive effect on the remediation of cognitive deficits in people with schizophrenia is supported by a study showing that the longer the duration of cognitive training, the better the improvement in verbal learning and memory, processing speed, and functional outcome (Fisher 2009)

2. cognitive training should target firstly sensory and simple cognitive functions, and then move on to complex cognitive functions. It is worth noting that some evidence shows that improvement in sensory functions leads to improvements in higher cognitive functions such as working memory in healthy aging adults, suggesting that sensory functions may be important targets for the treatment of cognitive functions (Berry 2010); and

3. the monitoring of performance and the gradual increase of task difficulty is of utmost importance.

Cognitive remediation approaches have been developed in psychiatric disorders and more recently in schizophrenia. Cognitive remediation therapy is one type of rehabilitation treatment that is used in the mitigation of cognitive deficits in people with schizophrenia on the basis of neuroplasticity. The aim of CRT is to improve cognitive deficits in people with schizophrenia by targeting several cognitive domains with the goal of improving social functioning. The initial programme developed by Delahunti 1993, known as the Frontal/Executive Program, was based on a processing model and uses tasks that aim to activate the frontal and prefrontal neural brain systems. Increased activation of these brain systems is expected to lead to an improved executive function, as the frontal and prefrontal neural brain systems have been associated with executive function processes. The activation of brain repair mechanisms can lead to neurobiological changes and ultimately improved cognition (Lezak 2004).

Why it is important to do this review

Cognitive remediation is a time‐ and skill‐intensive experimental therapy that aims to improve social functioning. Its effectiveness is unclear in terms that are meaningful to people with the illness, carers, or policymakers. Our knowledge of existing studies suggests methodological variability, that any effects of cognitive remediation on global cognition are small, and that these remediation approaches have the strongest effect on social functioning (McGurk 2007; Wykes 2011). If possible, producing workable definitions exploring the effects of methodological variability, as well as the effects on clinically understandable outcomes, will be of value.

Schizophrenia is treated using pharmacological and psychological approaches. First‐ and second‐generation antipsychotics target positive symptoms, but they have a modest, if any, effect on cognitive deficits in people with schizophrenia (Hill 2010; Mishara 2004 ; Davidson 2009; Keefe 2007). Additionally, the effect of cognitive remediation approaches is small to moderate (McGurk 2007), and it is costing the UK's National Health Service (NHS) more than all of cancer care (Mangalore 2007). These observations, and the emerging evidence of the potential of treatment of cognitive deficits through improvement of the structure and the function of the brain via neuroplasticity, make the study of cognitive remediation in people with schizophrenia important and urgent.

Objectives

To assess the effects of cognitive remediation therapy plus standard care in people with schizophrenia compared with standard care.

Methods

Criteria for considering studies for this review

Types of studies

We will consider all relevant randomised controlled trials. We will include randomised trials meeting our inclusion criteria and reporting usable data. We will consider trials that are described as 'double blind' ‐ in which randomisation is implied ‐ and include or exclude these trials once we have carried out a sensitivity analysis (see Sensitivity analysis). We will exclude quasi‐randomised studies, such as those that allocate intervention by alternate days of the week. Where people are given additional treatments as well as CRT, we will only include data if the adjunct treatment is evenly distributed between groups and it is only CRT that is randomised.

Types of participants

People with a diagnosis of schizophrenia and in a stable state, diagnosed by any criteria, irrespective of gender or race. Most people in each study should fall into the category of 'adult' (age 17 to 65 years).

As we are interested in ensuring that information is as relevant to the current care of people with schizophrenia as possible, we propose to clearly highlight the current clinical state (acute, early postacute, partial remission, remission) as well as the stage (prodromal, first episode, early illness, persistent) and whether the studies primarily focused on people with particular problems (e.g. negative symptoms, treatment‐resistant illnesses).

Types of interventions

1. Cognitive remediation therapy (CRT)

We will include trials where CRT is based on the model developed by Delahunti and colleagues in conjunction with the components described below (Delahunti 1993; Delahunti 2002).

For a study to be included the CRT must clearly reflect:

• a cognitive‐neuropsychological rehabilitation model (an intervention based on cognitive models of an impaired processing system for assessment and treatment, highlighting restoration of cognitive function and not compensation).

Examples of this are retraining approaches that address specific cognitive functions such as executive function (specifically cognitive flexibility, working memory, and planning) and aim to retrain people in problem‐solving or goal management skills via practice and cognitive exercises. Specifically, this is the CRT of Delahunti and not its reformulation with emphasis on meta‐cognition.

Also, for this review, the following criteria must clearly be evident:

• the intervention should have been performed in a clinical setting by a qualified clinical psychologist and/or neuropsychologist or with postgraduate experience/qualification in CRT;

• the CRT was either a paper‐and‐pencil format or a computerised format; and

• the length of therapy should be from 36 to 40 sessions, and each session should be a duration of 1 hour.

We will classify as 'well‐defined' an intervention that targets restoration of cognitive function.

2. Standard care

We anticipate everyone in both groups to be given standard care defined as the care a participant would normally receive. This can include antipsychotic drugs and other pharmacological agents plus a range of additional therapies such as supportive counselling and cognitive behavioural therapy, administered by a multidisciplinary team such as clinical psychologists, psychiatrists, occupational therapists.

Where participants are given other treatments in addition to CRT or standard care, we will only include data if the adjunct treatment is evenly distributed between groups.

Types of outcome measures

Also, for this review, the following criteria for outcomes must clearly be evident.

• The studies controlled for the mediating effect of age.

• Studies assessing general intellectual ability (IQ) or, at least, pre‐morbid IQ, and controlling for its mediating effect versus studies that have not assessed IQ or, at least, pre‐morbid IQ, and not controlling for its mediating effect (see Sensitivity analysis).

• Studies assessing cognitive function and providing pretreatment and after‐treatment scores.

We aim to divide all outcomes into short term (less than six months), medium term (six to 12 months), and long term (over 12 months).

We will endeavour to report binary outcomes recording clear and clinically meaningful degrees of change (e.g. global impression of much improved, or more than 50% improvement on a rating scale, as defined within the trials) before any others. We will thereafter list other binary outcomes and then those that are continuous.

Primary outcomes

1. Social functioning

1.1 Clinically important change in social functioning ‐ as defined by each of the studies

2. Cognitive functioning

2.1 Clinically important change in general cognitive functioning ‐ as defined by each of the studies 2.2 Clinically important change in specific aspects of cognitive functioning ‐ as defined by each of the studies

3. Adverse effects/events

3.1 Clinically important adverse effects

Secondary outcomes

1. Social functioning

1.1 Any change in social functioning ‐ as defined by each of the studies 1.2 Average endpoint or change score on social functioning scale ‐ as defined by each of the studies 1.3 Substantial improvement/no improvement in target function ‐ as defined by each of the studies (e.g. social skills)

2. Cognitive functioning

2.1 General

2.1.1 Any change in cognitive functioning ‐ as defined by each of the studies 2.1.2 Average endpoint or change score cognitive functioning scale

2.2 Specific

2.2.1. Any change in specific aspects of cognitive functioning ‐ as defined by each of the studies 2.2.2. Average endpoint or change score on specific aspects of cognitive functioning scale

3. General functioning

3.1 General

3.1.1. Clinically important change in general functioning ‐ as defined by each of the studies, including working ability 3.1.2 Average endpoint or change score on general functioning scale

3.2 Specific

3.2.1 Clinically important change in specific aspects of functioning, such as life skills ‐ as defined by each of the studies 3.2.2 Any change in educational status ‐ as defined by each of the studies 3.2.3 Any change in employment status ‐ as defined by each of the studies

4. Mental state

4.1 General

4.1.1 Clinically important change in general mental state ‐ as defined by each of the studies 4.1.2 Any change in general mental state ‐ as defined by each of the studies 4.1.3 Average endpoint or change score on general mental state scale

4.2 Specific

4.1 Clinically important change in specific symptoms ‐ as defined by each of the studies (positive, negative, affective, cognitive symptoms of schizophrenia) 4.2 Any change in specific symptoms ‐ as defined by each of the studies (positive, negative, affective, cognitive symptoms of schizophrenia) 4.3 Average endpoint or change score specific symptom scale

5. Adverse effects/events

5.1 General adverse effects

5.1.1 At least one adverse effect/event 5.1.2 Average endpoint/change scores adverse effect scales

5.2 Specific adverse effects ‐ clinically important ‐ as defined by each of the studies

5.2.1 Categorised into classes (anticholinergic, cardiovascular, central nervous system, gastrointestinal, endocrine, haematology, hepatitic, metabolic, movement disorders, various other, death ‐ all causes)

6. Global state

6.1 Clinically important change in global state (clinical response as defined by the individual studies, e.g. global impression of much improved, or more than 50% improvement on a rating scale) 6.2 Relapse ‐ as defined by each of the studies 6.3 Any change in global state 6.4 Average endpoint or change score global state scale

7. Service use

7.1 Use of other medications 7.2 Admitted to hospital 7.3 Time in hospital

8. Satisfaction with care (recipients of care or carers) (including subjective well‐being and family burden)

8.1 Recipient

8.1.1 Clinically important change in satisfaction ‐ as defined by each of the studies 8.1.2 Recipient of care satisfied/not satisfied with treatment 8.1.3 Recipient of care average endpoint or change score on satisfaction scale

8.2 Carers (including health professionals)

8.2.1 Clinically important change in satisfaction ‐ as defined by each of the studies 8.2.2 Carer satisfied/not satisfied with treatment (general impression of carer/other) 8.2.3 Carer average endpoint or change score on satisfaction scale

9. Leaving the study early

9.1 For any reason 9.2 Due to inefficacy 9.3 Due to adverse effect

10. Behaviour

10.1 General

10.1.1 Clinically important change in general behaviour ‐ as defined by each of the studies 10.1.2 Any change in general behaviour ‐ as defined by each of the studies 10.1.3 Average endpoint or change score general behaviour scale

10.2 Specific

10.2.1 Clinically important change in specific aspects of behaviour ‐ as defined by each of the studies, e.g. aggression, violence, social behaviour, work 10.2.2 Any change in specific aspects of behaviour ‐ as defined by each of the studies, e.g. aggression, violence, social behaviour, work 10.2.3 Average endpoint or change on specific aspects of behaviour scale

11. Economic outcomes

11.1 Costs due to treatment, as defined by each of the studies 11.2 Total direct and indirect costs 11.3 Average change in total cost of medical and mental health care

'Summary of findings' table

We will use the GRADE approach to interpret findings and GRADEpro GDT to export data from our review to create a 'Summary of findings' table (Schünemann 2011). These tables provide outcome‐specific information concerning the overall certainty of evidence from each included study in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on all outcomes we rate as important to patient care and decision‐making. We aim to select the following main outcomes for inclusion in the 'Summary of findings' table.

1. Social functioning: clinically important change in social functioning ‐ as defined by each of the studies

2. Cognitive functioning: clinically important change in general cognitive functioning ‐ as defined by each of the studies

3. Cognitive functioning: clinically important change in specific aspects of cognitive functioning, i.e. spatial working memory, verbal memory, and learning ‐ as defined by individual studies as one summative score

4. Adverse effects/events: clinically important adverse effects

5. General functioning: clinically important change general function ‐ as defined by individual studies

6. Global state: clinically important change in global state ‐ as defined by individual studies

7. Economic outcome

If data are not available for these pre‐specified outcomes but are available for ones that are similar, we will present the closest outcome to the pre‐specified one, but take this into account when grading the finding.

Search methods for identification of studies

Electronic searches

Cochrane Schizophrenia Group’s Study‐Based Register of Trials

The Information Specialist will search the register using the following search strategy:

(*Cognitive Attention Training* OR *Cognitive Behavior Social Skills Training* OR *Cognitive Differentiation Training* OR *Cognitive Enhancement* OR *Cognitive Function Training* OR *Cognitive Rehabilitation* OR *Cognitive Remediation* OR *Cognitive Retraining* OR *Cognitive Skills Training* OR *Cognitive Strategy Training* OR *Cognitive Tasks Training* OR *Cognitive Training*) in Intervention Field of STUDY

In such study‐based register, searching the major concept retrieves all the synonyms and relevant studies because all the studies have already been organised based on their interventions and linked to the relevant topics.

This register is compiled by systematic searches of major resources (including AMED, BIOSIS, CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings (see Group’s Module). There is no language, date, document type, or publication status limitations for inclusion of records into the register.

Searching other resources

1. Reference searching

We will inspect references of all included studies for further relevant studies.

2. Personal contact

We will contact the first author of each included study for information regarding unpublished trials. We will note the outcome of this contact in the 'Characteristics of included studies' or 'Characteristics of studies awaiting classification' tables.

Data collection and analysis

Selection of studies

Review authors AP, BU, and EK will independently inspect citations from the searches and identify relevant abstracts. AP will independently re‐inspect a random 20% sample of these abstracts to ensure reliability of selection. Where disputes arise, we will acquire the full report for more detailed scrutiny. AP will then obtain and inspect full reports of the abstracts or reports meeting the review criteria. BU and EK will re‐inspect a random 20% of these full reports in order to ensure reliability of selection. Where it is not possible to resolve disagreement by discussion, we will attempt to contact the authors of the study concerned for clarification.

Data extraction and management

1. Extraction

Review author BU will extract data from all included studies. In addition, to ensure reliability, AP will independently extract data from a random sample of these studies comprising 10% of the total. We will attempt to extract data presented only in graphs and figures whenever possible, but will include only if two review authors independently obtain the same result. In multicentre studies, where possible we will extract data relevant to each centre. Any disagreements will be discussed and decisions documented. If necessary, we will attempt to contact authors through an open‐ended request in order to obtain missing information or for clarification. AP will help clarify issues regarding any remaining problems, and we will document these final decisions.

2. Management

2.1 Forms

We will extract data onto standard, predesigned, simple forms.

2.2 Scale‐derived data

We will include continuous data from rating scales only if:

• the psychometric properties of the measuring instrument have been described in a peer‐reviewed journal (Marshall 2000);

• the measuring instrument has not been written or modified by one of the trialists for that particular trial; and

• the instrument should be a global assessment of an area of functioning and not subscores which are not, in themselves, validated or shown to be reliable. However, there are exceptions; we will include subscores from mental state scales measuring positive and negative symptoms of schizophrenia.

Ideally, the measuring instrument should either be i.) a self report or ii.) completed by an independent rater or relative (not the therapist). We realise that this is often not reported clearly; we will note in the 'Description of studies' section whether or not this is the case.

2.3 Endpoint versus change data

There are advantages of both endpoint and change data: change data can remove a component of between‐person variability from the analysis; however, calculation of change needs two assessments (baseline and endpoint), which can be difficult to obtain in unstable and difficult‐to‐measure conditions such as schizophrenia. We have decided to primarily use endpoint data, and only use change data if the former are not available. If necessary, we will combine endpoint and change data in the analysis, as we prefer to use mean differences (MDs) rather than standardised mean differences (SMDs) throughout (Deeks 2011).

2.4 Skewed data

Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non‐parametric data, we will apply the following standards to relevant continuous data before inclusion.

For endpoint data from studies including fewer than 200 participants:

• when a scale starts from the finite number zero, we will subtract the lowest possible value from the mean, and divide this by the standard deviation (SD). A value lower than one strongly suggests that the data are skewed, and we will exclude these data. If this ratio is higher than one but less than two, there is the suggestion that the data are skewed; we will enter these data and test whether their inclusion or exclusion would change the results substantially. Finally, if the ratio is larger than two we will include these data, because it is less likely that they are skewed (Altman 1996; Higgins 2011a);

• if a scale starts from a positive value (such as the Positive and Negative Syndrome Scale (PANSS), which can have values from 30 to 210) (Kay 1986), we will modify the calculation described above to take the scale starting point into account. In these cases skewed data are present if 2 SD > (S − S min), where S is the mean score and 'S min' is the minimum score.

Please note: we will enter all relevant data from studies of more than 200 participants in the analysis irrespective of the above rules, because skewed data pose less of a problem in large studies. We will also enter all relevant change data, as when continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether or not data are skewed.

2.5 Common measurement

To facilitate comparison between trials we aim, where relevant, to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week, or per month) to a common metric (e.g. mean days per month).

2.6 Conversion of continuous to binary

Where possible, we will make efforts to convert outcome measures to dichotomous data. This can be done by identifying cut‐off points on rating scales and dividing participants accordingly into 'clinically improved' or 'not clinically improved'. It is generally assumed that if there is a 50% reduction in a scale‐derived score such as the Brief Psychiatric Rating Scale (BPRS) (Overall 1962), or the PANSS (Kay 1986), this could be considered as a clinically significant response (Leucht 2005a; Leucht 2005b). If data based on these thresholds are not available, we will use the primary cut‐off presented by the original authors.

2.7 Direction of graphs

Where possible, we will enter data in such a way that the area to the left of the line of no effect indicates a favourable outcome for CRT. Where keeping to this makes it impossible to avoid outcome titles with clumsy double‐negatives (e.g. 'not un‐improved'), we will report data where the left of the line indicates an unfavourable outcome and note this in the relevant graphs.

Assessment of risk of bias in included studies

Review authors AP and BU will independently assess risk of bias using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions to determine trial quality (Higgins 2011b). This set of criteria is based on evidence of associations between potential overestimation of effect and the level of risk of bias of the article that may be due to aspects of sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting, or the way in which these 'domains' are reported.

If the raters disagree, the final rating will be made by consensus with the involvement of another member of the review group. Where details of randomisation and other characteristics of trials are inadequate, we will attempt to contact study authors to obtain further information. We will report non‐concurrence in quality assessment, but if disputes arise regarding the category to which a trial is to be allocated, this will be resolved by discussion.

We will note the level of risk of bias in both the text of the review, figures, and the 'Summary of findings' table/s.

Measures of treatment effect

1. Binary data

For binary outcomes, we will calculate a standard estimation of the risk ratio (RR) and its 95% confidence interval (CI), as it has been shown that RR is more intuitive than odds ratios and that clinicians tend to interpret odds ratios as RR (Boissel 1999; Deeks 2000). Although the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH), with their CIs, are intuitively attractive to clinicians, they are problematic to calculate and interpret in meta‐analyses (Hutton 2009). For binary data presented in the 'Summary of findings' table/s, where possible we will calculate illustrative comparative risks.

2. Continuous data

For continuous outcomes, we will estimate MD between groups. We prefer not to calculate effect size measures (SMD). However, if scales of very considerable similarity are used, we will presume that there is a small difference in measurement, and will calculate effect size and transform the effect back to the units of one or more of the specific instruments.

Unit of analysis issues

1. Cluster trials

Studies increasingly employ 'cluster randomisation' (such as randomisation by clinician or practice), but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intraclass correlation in clustered studies, leading to a unit of analysis error whereby P values are spuriously low, CIs unduly narrow, and statistical significance overestimated (Divine 1992). This causes type I errors (Bland 1997; Gulliford 1999).

Where clustering has been incorporated into the analysis of primary studies, we will present these data as if from a non‐cluster randomised study, but adjust for the clustering effect.

Where clustering is not accounted for in primary studies, we will present data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. We will attempt to contact first authors of studies to obtain intraclass correlation coefficients for their clustered data and adjust for this by using accepted methods (Gulliford 1999).

We have sought statistical advice and have been advised that the binary data from cluster trials presented in a report should be divided by a 'design effect'. This is calculated using the mean number of participants per cluster (m) and the intraclass correlation coefficient (ICC): thus design effect = 1 + (m − 1) * ICC (Donner 2002). If the ICC is not reported, we will assume it to be 0.1 (Ukoumunne 1999).

If cluster studies have been appropriately analysed and intraclass correlation coefficients and relevant data documented in the report taken into account, synthesis with other studies will be possible using the generic inverse variance technique.

2. Cross‐over trials

A major concern of cross‐over trials is the carry‐over effect. This occurs if an effect (e.g. pharmacological, physiological, or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, participants can differ significantly from their initial state at entry to the second phase, despite a wash‐out phase. For the same reason, cross‐over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both carry‐over and unstable conditions are very likely in severe mental illness, we will only use data from the first phase of cross‐over studies.

3. Studies with multiple treatment groups

Where a study involves more than two treatment arms, we will present the additional treatment arms in comparisons if relevant. If data are binary, we will simply add these and combine within the two‐by‐two table. If data are continuous, we will combine data following the formula in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). Where additional treatment arms are not relevant, we will not reproduce these data.

Dealing with missing data

1. Overall loss of credibility

At some degree of loss of follow‐up, data must lose credibility (Xia 2009). We choose that, for any particular outcome, should more than 50% of data be unaccounted for, we will not reproduce these data or use them within analyses. If, however, more than 50% of data in one arm of a study are lost, but the total loss is less than 50%, we will address this within the 'Summary of findings' table/s by downgrading quality. Finally, we will also downgrade quality within the 'Summary of findings' table/s should the loss be 25% to 50% in total.

2. Binary

In the case where attrition for a binary outcome is between 0% and 50% and where these data are not clearly described, we will present data on a 'once‐randomised‐always‐analyse' basis (an intention‐to‐treat analysis). Those participants leaving the study early are all assumed to have the same rates of negative outcome as those who completed, with the exception of the outcomes of death and adverse effects. For these outcomes, the rate of those who stay in the study ‐ in that particular arm of the trial ‐ will be used for those who did not. We will undertake a sensitivity analysis testing how prone the primary outcomes are to change when data only from people who completed the study to that point are compared to the intention‐to‐treat analysis using the above assumptions.

3. Continuous

3.1 Attrition

We will use data where attrition for a continuous outcome is between 0% and 50%, and data only from people who complete the study to that point are reported.

3.2 Standard deviations

If SDs are not reported, we will attempt to obtain the missing values from the study authors. If these are not available, where there are missing measures of variance for continuous data, but an exact standard error (SE) and CIs available for group means, and either P value or t value is available for differences in mean, we can calculate SDs according to the rules described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). When only the SE is reported, SDs are calculated by the formula SD = SE * √(n). The Cochrane Handbook for Systematic Reviews of Interventions presents detailed formulae for estimating SDs from P, t, or F values, CIs, ranges, or other statistics (Higgins 2011a). If these formulae do not apply, we will calculate the SDs according to a validated imputation method that is based on the SDs of the other included studies (Furukawa 2006). Although some of these imputation strategies can introduce error, the alternative would be to exclude a given study’s outcome and thus to lose information. Nevertheless, we will examine the validity of the imputations in a sensitivity analysis that excludes imputed values.

3.3 Assumptions about participants who left the trials early or were lost to follow‐up

Various methods are available to account for participants who left the trials early or were lost to follow‐up. Some trials only present the results of study completers; other trials use the method of last observation carried forward (LOCF); while more recently, methods such as multiple imputation or mixed‐effects models for repeated measurements (MMRM) have become more of a standard. While the latter methods seem to be somewhat better than LOCF (Leon 2006), we feel that the high percentage of participants leaving the studies early and differences between groups in their reasons for doing so is often the core problem in randomised schizophrenia trials. We will therefore not exclude studies based on the statistical approach used. However, by preference we will use the more sophisticated approaches, that is we will prefer to use MMRM or multiple imputation to LOCF, and we will only present completer analyses if no intention‐to‐treat data are available at all. Moreover, we will address this issue in the 'Incomplete outcome data' item of the 'Risk of bias' tool.

Assessment of heterogeneity

1. Clinical heterogeneity

We will consider all included studies initially, without seeing comparison data, to judge clinical heterogeneity. We will simply inspect all studies for participants who are clearly outliers or situations that we had not predicted would arise; where found, we will discuss such situations or participant groups.

2. Methodological heterogeneity

We will consider all included studies initially, without seeing comparison data, to judge methodological heterogeneity. We will simply inspect all studies for clearly outlying methods that we had not predicted would arise and will discuss any such methodological outliers.

3. Statistical heterogeneity

3.1 Visual inspection

We will inspect graphs visually to investigate the possibility of statistical heterogeneity.

3.2 Employing the I² statistic

We will investigate heterogeneity between studies by considering the I² statistic alongside the Chi² P value. The I² statistic provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2003). The importance of the observed value of I² depends on the magnitude and direction of effects as well as the strength of evidence for heterogeneity (e.g. P value from Chi² test, or a confidence interval for I²). We will interpret an I² estimate greater than or equal to 50% and accompanied by a statistically significant Chi² statistic as evidence of substantial heterogeneity per the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). When substantial levels of heterogeneity are found in the primary outcome, we will explore reasons for the heterogeneity (Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). These are described in the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011). We are aware that funnel plots may be useful in investigating reporting biases, but are of limited power to detect small‐study effects. We will not use funnel plots for outcomes where there are 10 or fewer studies, or where all studies are of similar size. In other cases, where funnel plots are possible, we will seek statistical advice in their interpretation.

Data synthesis

We understand that there is no closed argument for preference for use of fixed‐effect or random‐effects models. The random‐effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This often seems to be true to us, and the random‐effects model takes into account differences between studies, even if there is no statistically significant heterogeneity. However, there is a disadvantage to the random‐effects model, in that it puts added weight onto small studies, which are often the most biased ones. Depending on the direction of effect, these studies can either inflate or deflate the effect size. We choose to use the fixed‐effect model for all analyses.

Subgroup analysis and investigation of heterogeneity

We will investigate the effects of CRT in different subgroups of people for our primary outcomes of interest, or failing that, the outcomes nearest to those identified as being of primary interest.

1. Subgroup analyses

We will examine the effects of CRT on people with schizophrenia who manifested severe cognitive deficits as against moderate as against mild cognitive deficits at baseline.

Cognitive functioning is:

• within normal limits if performance scores are within one‐fifth of an SD of the normative standards;

• mildly impaired if scores fall between 0.2 and 0.5 SDs below the normative standards;

• moderately impaired if scores fall between 0.5 and 0.8 SDs below the normative standards; and

• is severely impaired at 0.8 or more SD below the normative standards (Cohen 1988).

2. Investigation of heterogeneity

We will report if inconsistency is high. Firstly, we will investigate whether data have been entered correctly. Secondly, if data are correct, we will inspect the graph visually and remove outlying studies successively to see if homogeneity is restored. For this review we have decided that should this occur with data contributing to the summary finding of no more than 10% of the total weighting, we will present data. If not, we will not pool these data and will discuss any issues. We know of no supporting research for this 10% cut‐off, but are investigating the use of prediction intervals as an alternative to this unsatisfactory state.

When unanticipated clinical or methodological heterogeneity is obvious, we will simply state hypotheses regarding this heterogeneity for future reviews or versions of this review. We do not anticipate undertaking analyses relating to this.

Sensitivity analysis

We will investigate the sensitivity of our primary findings to our assumptions about key methodological issues and definitions of CRT.

1. Methodological issues

1.1 Implication of randomisation

We aim to include trials in a sensitivity analysis if they are described in some way that implies randomisation. For primary outcomes, if the inclusion of these trials does not result in a substantive difference, they will remain in the analyses. If their inclusion does result in statistically significant differences, we will not add the data from these lower‐quality studies to the results of the higher‐quality trials, but will present these data within a subcategory.

1.2 Assumptions for lost binary data

Where assumptions must be made regarding participants lost to follow‐up (see Dealing with missing data), we will compare the findings of the primary outcomes when we use our assumption compared with completer data only. If there is a substantial difference, we will report results and discuss them, but continue to employ our assumption.

Where assumptions must be made regarding missing SD data (see Dealing with missing data), we will compare the findings of primary outcomes when we use our assumption compared with complete data only. We will undertake a sensitivity analysis to test how prone our results are to change when completer data only are compared to the imputed data using the above assumption. If there is a substantial difference, we will report results and discuss them, but continue to employ our assumption.

1.3 Risk of bias

We will analyse the effects of excluding trials that are judged to be at high risk of bias across one or more of the 'Risk of bias' domains (implied as randomised with no further details available, allocation concealment, blinding, and outcome reporting) for the meta‐analysis of the primary outcome. If the exclusion of trials at high risk of bias does not alter the direction of effect or the precision of the effect estimates substantially, then we will include relevant data from these trials.

1.4 Imputed values

We will undertake a sensitivity analysis to assess the effects of including data from trials where we use imputed values for ICC in calculating the design effect in cluster randomised trials.

If we note substantial differences in the direction or precision of effect estimates in any of the sensitivity analyses listed above, we will not pool data from the excluded trials with the other trials contributing to the outcome, but will present them separately.

1.5 Fixed‐effect and random‐effects

We will synthesise data using a fixed‐effect model; however, we will also synthesise data for the primary outcome using a random‐effects model to evaluate whether this alters the significance of the results.

2. Intervention

2.1 Delivery

We will investigate for the primary outcomes whether participants who were treated with CRT using a computerised format had a clearly different outcome to people treated using a paper‐and‐pencil format.

What's new

Date	Event	Description
10 May 2018	Amended	New authors are being sought to take over this protocol.

Contributions of authors

Alexandra Pentaraki: is guarantor of the review. Alexandra conceived, designed, co‐ordinated the review, and wrote the study protocol. She also provided a clinician's and methodological perspective.

Bello Utoblo: helped write the protocol.

Eleni Maria Kokkoli: helped write the protocol.

Sources of support

Internal sources

• University of Liverpool Online Programs (in partnership with Laureate Online Education), UK.

  Employs lead author Alexandra Pentaraki.

• King's College London, UK.

  Employs lead author Alexandra Pentaraki.

• Leeds Beckett University, Leeds, UK.

  Review author Bello Utoblo is a student at this university.

• Brain Matters Institute, Greece.

  Supports lead author Alexandra Pentaraki.

External sources

• No sources of support supplied

Declarations of interest

Alexandra Pentaraki is a clinical psychologist who specialises in neuropsychology and psychotherapy, and is a founder and director of Brain Matters Institute.

Bello Utoblo: none known.

Eleni Maria Kokkoli: none known.

Notes

New authors are being sought to take over this protocol.

Withdrawn from publication for reasons stated in the review