Cognitive Remediation Interventions in Schizoaffective Disorder: A Systematic Review

Background: Patients with schizoaffective disorder (SAD) suffer from cognitive impairment, which negatively influences their functionality. Cognitive remediation (CR) interventions have been shown to be effective in patients with schizophrenia (SZ) and bipolar disorder (BD), but evidence in SAD is limited so far. The aim of this study is to systematically review the published data on CR interventions, either in neurocognition or social cognition, in patients with SAD. Methods: We conducted a comprehensive, computerized literature search using terms related to CR interventions in psychotic and affective disorders, and particularly in SAD. Pubmed, Embase, and Web of Knowledge databases were used up to February 28th, 2018 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search returned 2672 articles of which four were finally selected meeting the inclusion criteria. Results: Cognitive Enhancement Therapy, computerized Cognitive Remediation Therapy and Cognitive Training showed positive results in subsamples of patients with SAD regarding neurocognition and functioning in comparable terms to patients with schizophrenia as well as in a greater extent in quality of life. Benefits in social cognition were also described when Social Cognition Interaction Training was considered in patients with SAD. Conclusions: CR interventions seem to improve neurocognition and social cognition in patients with SAD as well as functioning and quality of life. However, further randomized controlled trials on CR interventions with an optimized design focusing on selected sample of patients with SAD are imperative.


INTRODUCTION
Cognitive impairment is highly prevalent in several mental disorders, especially in those presenting with psychotic symptoms (1)(2)(3)(4)(5). Therefore, a neuropsychological examination of patients with psychiatric disorders has been progressively integrated in the elementary assessment of these patients (6,7). Cognitive impairment has been widely studied in patients with schizophrenia (SZ), who usually exhibit some cognitive dysfunction preceding the illness onset (8). The most prevalent impaired cognitive domains in these patients are attention, processing speed, working memory, and problem solving (9)(10)(11). Cognitive impairment is also common in bipolar disorder (BD) even during euthymia (12)(13)(14)(15). Although a subgroup of patients with BD may present some mild cognitive deficits before illness onset or even a higher cognitive performance than healthy population, most patients present an average cognitive performance until the first episode (16)(17)(18). After illness onset, cognitive performance in BD declines in particular in the domains of attention, verbal learning and memory, and executive functions according to clinical severity and number of relapses (8,13,19). Therefore, in general terms, there are many similarities between SZ and BD including scope of cognitive domains (20,21).
First descriptions on cognitive performance of patients with schizoaffective disorder (SAD) come from studies with mixed samples of patient with SAD and SZ (22)(23)(24). Later, comparisons on the cognitive performance between SAD and SZ were also published (25)(26)(27)(28)(29)(30)(31)(32)(33). On the one hand, studies suggested that both groups of patients might present a similar pattern of neurocognitive impairment, especially in memory, executive functions, cognitive flexibility, reasoning, and problem solving (25)(26)(27)(28). On the other hand, subsequent studies described less severity of neurocognitive impairment in patients with SAD compared to patients with SZ (29)(30)(31)(32)(33). Concerning social cognition, patients with SAD displayed a higher performance on tasks related to the Theory of Mind (ToM) compared to patients with SZ (32). When comparing the neurocognitive performance between patients with SAD and BD, poorer execution in verbal memory and occupational functioning has been detected in patients with SAD (4). All in all, these findings evidence the cognitive heterogeneity in patients with SAD (31,34) and place this disorder in an intermediate position in terms of cognitive performance between SZ and BD although possibly closer to SZ (35). In terms of structural neuroimaging abnormalities, SAD also resembles more SZ than BD (36).
Since cognitive impairment is related to a worse clinical course and poor functional outcome (3,(37)(38)(39)(40), it needs to be considered as a therapeutic clinical target in order to improve both psychosocial functioning and quality of life of patients with SAD (41)(42)(43)(44). Nowadays some studies have suggested that social cognition may explain more functional outcome variance than neurocognition and that is why social cognition has been increasingly considered as another important treatment target (45,46). Cognitive remediation (CR) interventions in psychiatric disorders are psychological or pharmacological based approaches (42). Concerning pharmacological treatments in affective and psychotic disorders, evidence so far suggests only a small effect on cognitive improvement; several drugs with potential procognitive effects are currently being investigated (47,48). With regards to psychological approaches, CR interventions have been developed to improve cognitive processes such as attention, memory, executive function, social cognition, and metacognition (Cognitive Remediation Experts Workshop, April, 2010) (49,50).
The evidence of CR in neurocognition and social cognition in patients with SAD mainly stems from mixed sample studies, generally of patients with SAD and SZ or in fewer cases patients with SAD and BD (51). Although there are no studies focused exclusively on analyzing the efficacy of cognitive interventions in samples composed by patients with SAD, a systematic review about cognitive rehabilitation on patients with SAD as well as affective disorders hinted an improvement on the level of cognitive performance after completion of cognitive remediation in patients with SAD (52). The data of SAD in this study were determined by estimated pooled effect size (ES) weighted for the percentage of patients with SAD. Potential changes in other outcomes apart from cognition, such as social cognition, psychosocial functioning, and quality of life were not analyzed. According to the lack of knowledge of CR interventions in patients with SAD, we aimed to systematically review the evidence on CR interventions in neurocognition, social cognition, psychosocial functioning, and quality of life in patient with SAD exclusively and describe their possible benefits in these particular patients.

METHODS
This systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines (53).

Data Sources and Search Terms
A comprehensive literature search of CR interventions in SAD was conducted by three authors independently (EL, BS, and IG) using the search terms in Pubmed, Embase, and Web of Science electronic databases from inception to February 28th, 2018.
Reference list of individual papers were also examined to identify any additional relevant studies.

Study Inclusion Criteria
Records were reviewed using the following inclusion criteria: (1) Published studies (randomized clinical trials and follow-up cohort studies) about cognitive interventions targeted at improving cognitive skills, functioning, or quality of life which reported results about the sample or subsample of patients with SAD with at least 2 timing outcomes measures; (2) number or proportion of cases diagnosed with SAD in the sample; (3) diagnoses of SAD according to DSM-III, DSM-III-R, DSM-IV, DSM-IV-TR, DSM-5, ICD-9, or ICD-10; (4) no language restrictions were applied in this review; (5) no comparator group was imperative.

Study Exclusion Criteria
The exclusion criteria applied were: (1) meta-analyses, systematic or narrative reviews, single cases, cases series, study protocols, letters to the editor, editorials, debate articles, opinion papers or congress abstracts; (2) interventions not involving CR interventions; (3) trials without identifying the number of participants with SAD; (4) studies without concrete outcomes about patients with SAD.

Procedures and Data Extraction
Articles were selected based on title and abstract and, when necessary, on examination of the full text to assess its relevance. After elimination of duplicated sources, the full texts of the potentially eligible studies were considered. References were also reviewed to identify further possible studies of interest. Most existing articles on this subject about patients with psychosis and BD were reviewed, since in many cases the sample was mixed and the diagnosis of SAD was not detected in the search.
Extracted information was synthesized in two tables. In Table 1 Table 2 the characteristics of the interventions applied according to the following structure: (a) intervention; (b) target; (c) duration; (d) setting: individual or group intervention; and (e) type: computer assisted or non-computer assisted sessions.

RESULTS
Using the aforementioned keywords, the search returned 2672 records (Figure 1). The literature search identified 554 potentially relevant studies. After excluding studies that did not include or describe the sample of patients with SAD and their outcomes, four papers were identified according to the inclusion criteria (54)(55)(56)(57).
The sample consisted of 73 patients with SAD out of 216 ( Table 1).Two studies were performed in USA (55,57), one in Germany (56), and one in Spain (54). The average study global sample size was 54 (SD 22.4) participants ranging from 32 to 89 patients. 58.3% of participants were men with a mean age of 38.1 (SD = 9.2) years. Three studies reported participants illness duration (54, 55, 57) which ranged from 3.2 to 30 years with a mean duration of 16.6 (SD 13.9) years. The average percentage of patients with SAD in the four studies was 33.8% in a range from 10.8 to 44%. The study with the largest sample of SAD was carried by Twamley et al. (57) with a sample of 39 patients. The interventions carried out in each study are described in Table 2.
Lewandowski et al. (55) compared a group that received Cognitive Enhancement Therapy (CET) with another group that received Enriched Supportive Therapy (EST) as a control group in a randomized controlled trial. The total sample included 20 patients with SAD and 38 with SZ. The authors conducted a secondary analysis comparing cognitive outcomes in patients with SAD and SZ with positive findings for CET in both diagnoses. The authors did not find a significant influence of the diagnosis on the relationship between improvement and treatment condition for the domains of processing speed, neurocognition, cognitive style, social cognition, social adjustment, or symptoms. Moreover, they described significant benefits for CET vs. EST for both SAD and SZ in withingroup analysis: social cognition (SAD d = 1.69, SZ d = 1.68); social adjustment (SAD d = 1.36, SZ d = 1.65); and symptoms (SAD d = 1.00, SZ d = 0.68); all p < 0.045. In patients with SZ, CET produced significant improvement over EST in neurocognition (d = 0.46, p = 0.025) and cognitive style (d = 1.08, p = 0.009), however only trend-level effects were observed among patients with SAD (d = 0.52, p = 0.089 and d = 0.99, p = 0.098, respectively). No significant effect of the diagnosis on clinical improvement was found, with the exception of a significant reduction on depressive and anxious symptoms in patients with SAD (p = 0.019). This may be due to higher levels of anxiety and depression at baseline in this group of patients.
The computerized Cognitive Remediation Therapy (cCRT) is the intervention used in the study by Scheu et al. This study sample included 10 patients with SAD and 22 with SZ. After 4 weeks, the authors observed a significant improvement in the neurocognitive performance that involved attention memory, strategy, numeracy and visuo-motor skills in patients with SAD and SZ (56). No significant differences were found in improvement rates between both diagnostic groups. There was no significant correlation between improvement rates and the number of attended training sessions, but better improvement rates were linked to a higher total number of completed tasks (r = 0.36, p < 0.05). Correlation analyses revealed no significant relationship between any of the baseline cognitive or symptom measures and improvement rates. Cognitive improvements on processing speed and verbal memory were associated with higher baseline scores on the general PANSS and total PANSS (r = −0.44, p < 0.05; r = −0.45, p < 0.01, respectively), while improvements on Trail Making Test A were related to higher scores in the positive PANSS (r = −0.43, p < 0.05). Higher scores in the PANSS scores indicated worse clinical state.
Twamley et al. (57) studied the efficacy of Cognitive Training (CT) and Standard Pharmacotherapy (SP) compared to SP alone in a mixed sample of 39 patients with SAD, 45 with SZ and 5 with psychosis not otherwise specified. Patients showed a significant improvement in attention (p = 0.049), verbal memory (p = 0.017), and negative symptoms severity (p = 0.002) at 3-month follow-up and in verbal memory (p = 0.039), prospective memory (p = 0.050), functional capacity (p = 0.004), negative symptoms severity (p = 0.025), and self-reported quality of life (p = 0.004) at 6-month follow-up. Results of cognitive outcomes were not available according to diagnoses. However, patients with SAD showed a significant improvement in subjective perception of quality of life at 6 months compared to patients with SZ (p = 0.03) (57). At 3-month follow-up, improvement in digit span forward and in Hopkins Verbal Learning Test (HVLT) were associated with higher levels of negative symptoms severity at baseline (r = 0.45, p = 0.045; r = 0.50, p = 0.025, respectively). Moreover, improvement in   No evidence for between-group effects on any clinical outcome was found.
The risk of bias was assessed in all eligible studies as recommended by the Cochrane Collaboration (58). However it was difficult to determine due to the heterogeneity of the study design and because the focus of this systematic review was beyond the main objectives of the selected articles.

DISCUSSION
Despite the scarce number of studies on the topic, there is evidence, although limited, of the effectiveness of CR interventions in patients with SAD. CET, cCRT, and CT showed positive results in cognition in the subsample of patients with SAD considering neurocognitive or functional parameters as well as outcomes related to quality of life. Benefits in social cognition were also described when SCIT as well as CET were considered in patients with SAD.
These results are in line with previous bibliography on the issue. Regarding neurocognition, Anaya et al. (52) described in their meta-analysis that CR interventions showed positive effects on cognition at post-intervention in patients with SAD as well as in patients with affective disorders with an ES of 0.32. Interestingly, the authors pointed out that the effect of CR interventions increased when the meta-analysis was limited to studies that included exclusively patients with SAD, obtaining a pooled ES weighted for the percentage of patients with SAD of 0.41. In addition, we also have found some evidence that schizoaffective patients could improve in specific measures of social cognition, social adjustment, symptoms and quality of life after receiving a CR intervention.
It is worth commenting on the studies that presented a relevant percentage of patients with SAD in the sample but did not specifically mention results of the subsample of patients with SAD. Considering neurocognition, In a subsequent article (59) of the one included in this systematic revision, Twamley et al. described general improvement in cognitive domains considering the entire sample. In another study with 53% of the sample diagnosed with SAD (60), computerassisted cognitive rehabilitation showed greater improvement in neurocognitive performance, specifically in verbal memory and attention, and negative symptoms compared to a wait-list control group. Regarding social cognition, a recent systematic review that included studies with samples of patients with SAD and SZ (61) stated that interventions in social cognition could improve several domains related to affect recognition, ToM and social perception. However, the effect on attributional style and the relationship between improvement in social cognition and functioning were unclear. All in all, CR interventions in neurocognition and social cognition seem to be effective in the psychotic spectrum.
Whether patients diagnosed with SAD benefit from CR interventions more than SZ or less than BD is still open to question. Lewandowski et al. published the results of CET between patients with SAD and SZ in a subanalysis of a previous study (55,62). Although positive results were described in both groups, a lower benefit of the treatment was observed in the cognitive performance of patients with SAD compared to those with SZ. This may be due to a ceiling effect since patients diagnosed with SZ present more cognitive impairment compared to patients diagnosed with SAD. The evidence suggests that the wider the cognitive impairment at baseline, the greater benefits can be obtained with CR interventions. It may be due to the fact that there is more room for improvement or because of an increased motivation (57). Nevertheless, in the study performed by Scheu et al. (56), outcomes of patients with SAD did not differ from those observed in patient with SZ, being positive in both disorders. Thus, despite the cognitive heterogeneity (31,34), SAD may be placed in an intermediate position in terms of neurocognitive performance between SZ and BD although possibly closer to SZ (35).
There is controversy about how basal clinical state may impact on the results of CR and how CR may influence the clinical state. With regard to the former, on one hand, Wykes et al. (63) reported in a meta-analysis focused on CR in patients with SZ that the benefits were more significant in less symptomatic patients. On the other hand, Twamley et al. (57) found an association between higher levels of negative symptoms and greater benefits, and between higher levels of positive symptoms and greater improvement in functional capacity. Therefore, they consider that the presence or severity of symptoms should not be an exclusion criterion for these interventions. Other authors consider that the severity of positive or negative symptoms does not predict the rate of improvement (19,56,64). Considering the latter, the two meta-analyses by Wykes  Another issue of debate is the right moment to provide CR interventions. Some authors suggest that the younger the patients, the more they benefit from CR interventions (63,(66)(67)(68)70). On the contrary, the two major meta-analysis in the literature about CR interventions concluded no relationship between these two variables or that the older the patients, the better outcomes of CR interventions (63,65). Twamley et al. pointed out that older patients achieved more improvement, specifically in prospective memory (57). The concept of cognitive reserve may provide an explanation for the discrepancy in these results since it reflects the capacity of the brain to endure neuropathology and successfully complete cognitive tasks (69). Moreover, cognitive reserve has been found as a significant predictor of cognitive and psychosocial functioning in patients with SZ and BD (70)(71)(72). Another key issue in CR interventions relates to the relationship between number of sessions and the obtained benefits. The meta-analysis carried out by Wykes et al. (63) and the study of Scheu et al. (56) did not reveal any association between the aforementioned variables. Last but not least, the drop-out ratio is another matter of concern in CR interventions. Twamley et al. (57) analyzed who was more likely to drop out in their randomized controlled trial of CT in which 57.30% of the patients completed the therapy while 31.46% did not start it and 11.24% withdrew. Those who completed CT had more formal education and lower antipsychotic doses than had dropouts with no CT exposure, but the groups did no otherwise differ. In Lewandowski et al. (55) and Lahera et al. (54) studies, the frequencies of dropouts were 20.6 and 19.1%, respectively.
As a summary, Lewandowski et al. (55) obtained small effects on neurocognition in the group of SAD, vs. medium effects in the group of SZ. However, patients with SAD improved more in symptomatology after cognitive treatment. In this study, a similar improvement in the functionality of both groups was obtained. On the other hand, Scheu et al. (56) did not find differences in improvement rates when comparing patients with SAD and SZ. Lahera et al. (54) did not find differences after treatment when compared patients with SAD and BD, considering that the sample included four patients with SAD. Twamley et al. (57) did not report group differences but more improvement in subjective quality of life at 6 months in SAD compared to patient with SZ.
Despite data gathered in this systematic review seems to support a positive effects of CR interventions in SAD, these results should be interpreted with caution. First of all, the samples of the four reviewed studies are restricted to small subsamples of patients diagnosed with SAD within a wider sample of patients diagnosed mostly with SZ or BD. Although we only consider articles that studied the concrete subsample of SAD, the obtained results stem from post-hoc analyses, which are not always aligned with the aim of the primary objective of the study and therefore may increase false positive results. Moreover, the heterogeneity of the design of the reviewed CR interventions should be beared in mind. This heterogeneity could partly explain discrepancies among results from these studies.
In this systematic review, scarce studies on CR interventions in SAD were found. However, available data support that CR interventions may improve neurocognition and social cognition in this group of patients. Subsequently, functioning and quality of life on this population may also benefit from improving the daily life of patients with SAD. So as to confirm this hypothesis, further randomized controlled trials on CR interventions with an optimized design and selected sample of patients with SAD are urged.

AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

ACKNOWLEDGMENTS
CMB would like to thank the Departament de Salut de la Generalitat de Catalunya for the PERIS grant (SLT002/16/00331).
IG is supported by the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness of Spain [Juan Rodés Contract (JR15/00012) and a grant (PI16/00187)] integrated into the Plan Nacional de I+D+I and cofunded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER).
EV thanks the support of the Spanish Ministry of Economy and Competitiveness (PI15/00283) integrated into the Plan Nacional de I+D+I y cofinanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER); CIBERSAM; and the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya to the Bipolar Disorders Group (2017 SGR 1365) and the project SLT006/17/00357, from PERIS 2016-2020 (Departament de Salut). CERCA Programme/Generalitat de Catalunya.
AM-A thanks the support of the Spanish Ministry of Economy and Competitiveness (PI15/00330) integrated into the Plan Nacional de I+D+I y cofinanciado por el ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER); CIBERSAM) and the project SLT006/17/00177, from PERIS 2016-2020 (Departament de Salut). CERCA Programme/Generalitat de Catalunya.