Citation: Wang X, Zhou Yuqiu, Liu Dongwei, et al. Research progress on the characteristics of cognitive function impairment and intervention methods in different periods of schizophrenia[J] . China Journal of General Practice, 2021, 24(32): 4121-4125. DOI: 10.12114/j.issn.1007-9572.2021.01.010.
In recent years, the problem of cognitive impairment in patients with schizophrenia (SZ) has received increasing attention, and studies have shown that 85% of patients have severe and persistent cognitive impairment, which is not only a sensitive indicator of disease development, treatment response, and functional level, but also a constraint hindering social and occupational recovery [1]. However, the development of cognitive impairment in patients with SZ remains controversial, with studies suggesting a gradual decline in cognitive function as the disease progresses, and suggesting that cognitive function remains relatively stable or even slightly improved over time [2,3]. This controversy is important, first of all, can help resolve the disagreement about whether SZ is a neurodegenerative disease or a neurodevelopmental disease, the idea of neurodegenerative disease can be traced back to the German medical scientist Kraepelin's description of the disease "early-onset dementia" in 1893, that is, SZ is a chronic degenerative disease with a gradual decline in cognitive function; while the neurodevelopmental hypothesis holds that SZ involves early neurodevelopmental abnormalities, starting in the fetal period. Cognitive deficits are the result of cognitive difficulties due to abnormal brain development [4,5,6]. Second, many studies have emphasized that cognitive dysfunction is a potential intrapathic phenotype, and SZ is largely influenced by heredity, but genetic studies have not reached consistent conclusions, so studying the genetic genes of diseases through endophotypes has a significant advantage, and as an intrapathic phenotype must be qualitative (it can manifest itself regardless of whether the disease is active or not, and shows relative stability over time) [7]. To resolve this controversy, many scholars have turned to the study of the characteristics of cognitive impairment at different stages of SZ (pre-morbidity, prodromal, first stage, and chronic phase), while cognitive impairment has been established as an important therapeutic goal for improving social functioning in patients with SZ [3,8,9]. Therefore, this paper proposes to review the characteristics of cognitive impairment and the status quo of interventions in different periods of SZ.
1 Characteristics of cognitive impairment at different stages of SZ
1.1 Pre-morbidity of SZ
Studies in recent years suggest that cognitive impairment in patients with SZ may occur earlier, such as childhood [8]. Meta-analyses show that many patients diagnosed with SZ in adulthood have a 3.7 percent increased risk of SZ for every point lower childhood IQ than their peers [10,11]. There are three hypotheses of developmental deterioration, developmental defects, and developmental delay in the development of cognitive function before the onset of SZ, as shown in Figure 1 [12]. In order to test these three hypotheses, REICHENBERG et al. [12] conducted a 30-year follow-up study of 1 037 newborns, measured their cognitive function at the age of 7, 9, 11, and 13 years of cohort members, and the final symptom follow-up age was 32 years, and the results showed that 35 patients who later developed SZ had poorer cognitive performance at the measurement point than the healthy group, first in terms of language and visual knowledge acquisition, reasoning and conceptualization, and then in processing speed, attention, There is a developmental lag in terms of visuospatial problem solving ability and working memory. Recently, MOLON et al. [13] expanded the above study in time (18 months to 20 years after birth) and came up with similar research results, neither group of studies verified the hypothesis of cognitive function deterioration, indicating that the cognitive function deficit in patients with SZ before the onset of the disease is not an absolute degradation of function over time, but the individual cannot keep up with the normal rate of development, and points out that the initial defect has a strong correlation with the subsequent lagging performance, indicating that the cognitive function impairment that occurs during puberty begins in early childhood.
Fig. 1 Schematic diagram of three hypotheses of cognitive function development before the onset of schizophrenia[12]
Figure 1 Charts showing three hypotheses about the development of cognitive impairment that precede the onset of schizophrenia
1.2 SZ Prodromal Period
Patients with SZ precede a full episode of psychosis have a longer prodromal period in which individuals are called clinical high risk for psychosis (CHR) [14]. A meta-analysis of cognitive function in the CHR population showed mild to moderate impairment in most cognitive areas of CHR individuals, involving nine areas: general intelligence, word fluency, processing speed, attention, visual memory, verbal memory, working memory, executive function, and social cognition [15]. Cross-sectional studies consistently demonstrated that the degree of cognitive impairment was between the first/chronic and healthy controls, indicating that cognitive function decreased in patients with SZ during the precursor period to the initial stage, however, the clinical status of CHR was heterogeneous, and the clinical conversion rate of clinical conversion was reported to be about 30% within 2 to 3 years, which may underestimate the cognitive impairment effect in the CHR population, so the cognitive function impairment that was later converted to the SZ subgroup (CHR+) was more conducive to understanding the development of cognitive function impairment in patients with SZ [ 14，16]。 CARRIóN et al.[4] Based on horizontal studies, the MATRICS Consensus Cognitive Battery (MCCB) of the CHR+ group performed very similarly to patients with first-episode schizophrenia (FES), and similar results were found in domestic studies [9]. Data from longitudinal studies suggest that baseline cognitive impairment is more severe in the CHR+ group than in the untransformed subgroup (CHR-), particularly in the areas of attentional, working memory, and declarative memory [17]. A meta-analysis of longitudinal cognitive data from the CHR population showed that cognitive deficits in patients with CHR remained stable or even slightly improved over time during follow-up (0.5 to 7.0 years), suggesting that there was no decrease in cognitive function during the transition from CHR to psychotic disorders [5].
1.3 SZ launch period
This stage of psychotic symptoms is full-blown, and individuals at this stage are called FES. A meta-analysis of 47 studies of cognitive function in patients with FES showed moderate to severe impairment in all 10 cognitive domains assessed [18]. MCCLEERY et al. [19] made a horizontal comparison of MCCB performance in patients with the first and chronic stages, and found no significant difference in MCCB scores between patients with FES and chronic schizophrenia (CS). SOLIS-VIVANCO et al. [16] found that this was the case even in unmediated samples, suggesting that patients with SZ did not decline in cognitive function after the first episode of the disease. However, recent ZANELLI et al. [20] conducted a 10-year follow-up study on cognitive function in PATIENTS with FES, and the results showed that patients with FES had a decrease in IQ, language ability and memory decline during follow-up, indicating that patients with SZ experienced cognitive decline after the onset of the disease. However, most of the existing longitudinal studies did not support the findings of ZANELLI et al. [20], such as BERGH et al. [21] also conducted a 10-year follow-up survey of cognitive function in 171 patients with FES, and found that FES patients had slight improvements in tests such as processing speed, conversion function, and word fluency during follow-up, noting that the study did not involve specialized cognitive therapy, and a recent meta-analysis also found that cognitive function impairment in FES patients was relatively stable in the longitudinal [5]. Therefore, the available evidence suggests that patients' cognitive function remains largely stable after the first onset of the disease.
1.4 SZ chronic phase
This phase is a period of more than 5 years of duration since the first onset of illness, with severe residual symptoms, and individuals at this stage are called CS [22]. A large number of behavioral data suggest that cognitive function in patients with CS is diffuse, usually 1 to 2 standard deviations lower than healthy controls [19]. At present, most longitudinal studies do not support the idea of progressive cognitive decline in CS patients, such as SZÖKE et al. [23] Conducted a meta-analysis of longitudinal cognitive data from 53 CS patients, and the results showed that cognitive dysfunction in CS patients tended to stabilize during follow-up (average follow-up of 12 months, median 4 months). The same meta-analysis of longitudinal cognitive data in older patients with SZ found no evidence of cognitive decline in patients during follow-up (follow-up period: 1 to 6 years, average 2.21 years) [24]. However, there are views that the development trajectory of cognitive dysfunction in CS patients may be heterogeneous, such as THOMPSON et al. [25] 201 community SZ patients and 67 healthy controls were tracked for a period of 3.5 years, and the results found that the cognitive function trajectory of 50% of patients tended to be stable, 40% of patients had a slight decline, and 10% of patients had a significant decrease in patient trajectory, while pointing out that cognitive function decline was significantly related to factors such as living in foster care, severe negative symptoms and early age of onset. These findings suggest that cognitive dysfunction in most patients with CS has longitudinal stability, but that cognitive function may decline in some patients, especially in later life.
As mentioned earlier, cognitive dysfunction predates the onset of psychotic symptoms. Most of the evidence supporting cognitive decline in patients with SZ is based on horizontal indirect comparisons of different periods of the disease, in fact, cross-study comparisons based on horizontal studies have found that there is no essential difference in the pattern and degree of cognitive impairment in patients in the CHR+, FES and CS groups, but there are many methodological problems in the indirect comparison of horizontal studies, such as education level, age, etc., so longitudinal studies can better reveal the nature of cognitive dysfunction in patients with SZ in time. At present, most longitudinal studies have found no evidence that cognitive function in patients with SZ decreases with the course of the disease, but on the contrary, there will be a slight improvement, indicating that patients with SZ do not lose the ability to acquire cognition, but the rate of cognitive function growth lags behind that of healthy people, and the above results provide strong evidence for the neurodevelopmental hypothesis and intracognitive phenotype of SZ. In fact, these findings are consistent with the insights of Wang Chuanyue [6] in China, that is, cognitive deficits secondary to abnormal neural circuits lead to progressive academic difficulties in children and place them in a non-socialized and socially isolated situation, these symptoms are relabeled as primary negative symptoms after the onset of the disease, cascading behaviors deviating from the normal developmental trajectory are increasing, and repeated exposure to adverse life events, which eventually leads to dysfunction of dopamine function and the occurrence of SZ. It can be seen that SZ is a neurodevelopmental disease, and its essence may be a cognitive function disease.
It should be noted that the current research is highly heterogeneous, mainly reflected in the field and tools of cognitive function measurement, and secondly, many studies are affected by birth cohort effects (such as drugs, environmental factors, etc.), so it is not clear whether there is an occult decline in patient cognitive function, and future studies should be based on strict homogeneity, long-term follow-up and multi-point measurement, combined with horizontal and longitudinal study design, to avoid birth cohort effects, so as to better explain the potential cohort effects.
2 Intervention modalities for cognitive impairment of SZ
Psychotic symptoms have historically been the focus of treatment, and despite their effective treatment, patients have had less than satisfactory functional outcomes. Cognitive impairment may not be found to be parallel to severity, i.e., the patient's cognitive function does not improve with the disappearance of psychotic symptoms, suggesting that cognitive dysfunction is an independent core symptom of SZ and is key to disease outcome [3,20]. At present, the interventions for cognitive dysfunction in patients with SZ are mainly focused on drugs and cognitive therapy, and other promising new interventions have been reported in recent years, as follows.
2.1 Pharmacological interventions
Studies have confirmed that antipsychotic drugs (AP) can have a moderately beneficial effect on cognitive dysfunction in patients with SZ, especially second-generation antipsychotics, but at the same time AP may also aggravate cognitive dysfunction in patients, which may be related to reactive upregulation of dopamine D2 receptors, combined use of anticholinergic drugs, and long-term use of AP can also cause metabolic adverse reactions to aggravate cognitive impairment. The role of AP on cognitive function in patients with SZ is therefore controversial [3,26]. On the other hand, some scholars are committed to the research of new cognitive enhancement drugs, mainly by acting on related neurotransmitter systems (such as glutamatergic and cholinergic systems) to improve cognitive function in patients with SZ, and the current clinical results are mixed [2,3]. SINKEVICIUTE et al. [27] conducted a meta-analysis of 93 related studies, and the results showed that the drug intervention group had less effect on overall cognitive function in patients with SZ than in the placebo group, but no significant effect on any one cognitive subfield, and when considering individual neurotransmitter systems, subgroup analysis showed that drugs acting on glutamatergic and cholinergic systems had a smaller effect on working memory. Although there are some positive findings here, these findings have not been replicated in large-scale Phase III clinical trials, and existing studies have focused on glutaminergic and cholinergic systems, and lack of research on drugs that act on the dopaminergic system, so the field is still in the exploratory stage [2].
2.2 Cognitive remediation (CR)
CR is a neuropsychological training method for cognitive function defects in patients with SZ, which aims to gradually improve patients' problem-solving and information processing skills through a series of intensive trainings, so as to improve patients' cognitive function [28]. A large number of foreign studies have confirmed that CR can specifically improve the cognitive functions such as attention, memory, processing speed, and executive function of patients with SZ, showing a medium effect level and lasting for up to 2 years, and domestic studies have also achieved good results [28,29,30]. Notably, the key to these effects may lie in the neuroplasticity of the brain and the improvement of frontotemporal function associated with cognitive impairment [31]. On the other hand, studies have found that CR improves cognitive function in patients along with social function, and CR combined with drugs or other psychiatric rehabilitation measures can improve cognitive and social function of patients more than treatment alone, so it is necessary to combine CR with other interventions such as vocational rehabilitation training to maximize patient return to society [29,32,33].
2.3 Other novel therapeutic approaches
Studies of aerobic exercise and non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been reported in recent years for the treatment of cognitive deficits in patients with clinical psychosis, and many studies have included them as part of a combined CR intervention [2，34]。 FIRTH et al. [35] reviewed 10 studies of aerobic exercise in the treatment of SZ, showing that aerobic exercise can significantly improve overall cognitive function, working memory, social cognition and attention in patients with SZ, reaching a mild to moderate effect level. In addition, MERVIS et al. [36] quantitatively analyzed six studies on tDCS treatment in the dorsolateral prefrontal cortex, and the results showed that tDCS had a slight improvement in patients' working memory and attention compared with pseudo-stimulation; Xu Qing et al. [37] found that rTMS could also effectively improve cognitive function in CS patients, and found that increasing the level of brain-derived peptide neurotrophic factors may be one of its mechanisms of action. In addition, studies have found that CR, when combined with these treatment modalities, can bring different degrees of improvement to patients' cognition and certain functions [2]. However, the above studies are still relatively weak and the results of clinical studies are mixed, and the lack of specific exercise guidelines for patients with SZ and the optimal parameters of non-invasive brain stimulation therapy (treatment target, frequency, intensity, and frequency, etc.), if there is a consensus on these aspects, the above effects will be more prominent.
3 Summary
In summary, the cognitive function of patients with SZ does not decline progressively with disease progression to a large extent, and the conception of SZ shifts from neurodegenerative disease to neurodevelopmental disease, while supporting cognition as an intrapathic phenotype. It should be emphasized that cognitive impairment often precedes the onset of psychotic symptoms nearly 10 years or even earlier, is a risk factor for developing SZ, independent of psychotic symptoms, can be improved by some drugs, cognitive training and other new therapeutic methods, and can have a migration effect on the patient's social functioning, suggesting that SZ may be essentially a cognitive disease, but the existing diagnostic and classification criteria for mental illness are based on clinical symptoms and behavioral descriptions, which may be too narrow, Therefore, it is necessary to establish a new schizophrenia prevention and control strategy from the prevention and intervention of cognitive function impairment in the future, and at the same time establish a biological basis for disease diagnosis and classification based on the analysis of endophenoids.
This article literature search strategy:
#1Search "Schizophrenia"[Mesh]
#2Search （（（（（schizophrenia[Title/Abstract]） OR schizophrenias[Title/Abstract]） OR schizophrenic disorder[Title/Abstract]） OR schizophrenic disorders[Title/Abstract]） OR Schizophrenic[Title/Abstract]） OR dementia praecox[Title/Abstract]
#3 #1 OR #2
#4Search "Cognition Disorders"[Mesh]
#5Search（（（（（cognition disorders[Title/Abstract]） OR cognition[Title/Abstract]） OR cognitive neuroscience[Title/Abstract]） OR cognitive impairment[Title/Abstract]）
#6 #4 OR #5
#7 #3 AND #6
conflict of interest
There is no conflict of interest in this article.
References Abbreviated