Negative symptoms are a group of symptoms that reflect a loss of normal functions that are normally present—they include social withdrawal, lack of motivation, flattened emotion, alogia, and anhedonia [1]. They are commonly reported in schizophrenia, with over 50% of patients showing at least one negative symptom [2, 3]. Negative symptoms are defined by the DSM-5 as one of the key dimensions of schizophrenia [4]. They can be a persistent clinical problem for patients [5], and lead to severe disability [6] and lower rates of recovery [7], thus posing a substantial burden on patients, their relatives, the healthcare system and society. Despite their detrimental impact, negative symptoms remain to date generally unresponsive to treatment. Their identification and treatment are more challenging compared to positive symptoms [8], making them yet neglected targets for treatment [9]. Previous efforts dedicated to improving negative symptom treatments have been hampered by incomplete understanding of the mechanisms that lead to their development and maintenance [10]. Therefore, there is a clear need to enhance knowledge on the mechanisms underlying the formation and evolution of negative symptoms [11]. One potential theoretical mechanism accounting for the emergence and persistence of negative symptoms is disturbed metacognition [12].
The relationship between metacognition and negative symptoms
Metacognition, broadly defined as ‘thinking about thinking’, is often conceptualized as a multidimensional construct encompassing five core domains: 1) the belief that it is important to control one’s thoughts, especially distressing thoughts (i.e. need to control thoughts); 2) worrying understood as uncontrollable or dangerous activity (i.e. uncontrollability and danger); 3) worrying helps one to avoid future problems (i.e. Positive Beliefs about worry); 4) overthinking about one’s own thoughts (i.e. Cognitive Self-Consciousness), and 5) beliefs concerning cognitive confidence (i.e. lack of confidence in memory) [13]. There is strong evidence to support that people diagnosed with schizophrenia exhibit global metacognitive deficits that are far more pronounced than in healthy controls [14] or people with other severe medical (e.g., Human Immunodeficiency Virus [15]) and psychiatric conditions (e.g., bipolar disorder [16], depression [17], posttraumatic stress disorder [18], borderline personality disorder [19]). There is a growing amount of literature which suggests that impaired overall metacognitive functioning exhibited by individuals with psychosis is closely connected to negative symptoms.
A meta-analysis by Arnon-Ribenfeld et al. [20] indicated a significant positive association between metacognition impairment and symptomatic outcomes, and emphasized the negative effect of this association on social quality of life. Particularly, many studies conducted in different clinical settings and nations showed that metacognitive abilities are negatively related to more severe negative symptoms in people with schizophrenia spectrum disorders (e.g., [16, 21, 22]). Several prior studies also showed that a worse efficiency in metacognitive skills from 6 to 36 months after baseline assessment was predictive of greater negative symptoms (e.g., [23, 24]). An individual participant data meta-analysis including 21 data sets and 1301 people with psychosis observed a strong relationship between metacognition and summed scores of negative symptoms that was not overridden by duration of illness or disorganization, albeit it was concluded that “this relationship is more complex than is evident” [25]. More recently, a systematic review confirmed this statement, by pointing to mixed evidence and unclear relationship between disrupted metacognition and negative symptoms, with only half of the included studies having reported statistically significant findings [11].
Overall, although the positive association between impairments in metacognitive capacity and negative symptoms in people with schizophrenia spectrum disorders is widely evidenced in the literature, the underlying mechanisms of this association are still poorly understood. To date, limited theories and models have emerged as attempts to explain the pathways leading from metacognition abilities to negative symptoms. It has been proposed that metacognition may be implicated in negative symptoms by generating a fragmented comprehension of others' and one's own beliefs, intentions, and desires, which can lead, in turn, to diminished motivation secondary to a decline of the ability to reflect on what is of importance and worth pursuing. For instance, uncertainty over the intentions of others can cause discomfort and negatively impact interpersonal relationships, thereby contributing to avoidance of social interactions and a tendency to withdraw [26, 27]. Difficulties experienced in giving meaning to one’s or others’ thoughts of themselves may contribute to increased challenges in the identification of goals and the initiation of action towards them [28]. The present study proposes to contribute to the reduction of a knowledge gap regarding the mechanisms behind the relationship between metacognition and negative symptoms by investigating a new genetic factor that might be involved as a moderator, i.e. the Catechol-O-Methyltransferase (COMT) gene rs4680 polymorphism.
COMT gene rs4680 polymorphism as moderator
The COMT is a key modulator of dopaminergic transmission in the prefrontal cortex (PFC) [29]. COMT genes have multiple single nucleotide polymorphisms (SNPs), with the most commonly studied one being the rs4680 (Val/Met or G/A substitution)[30]. Because of its catalytic activity for dopamine degradation, genetic variation of the COMT has long been thought to confer susceptibility to schizophrenia and, more specifically, contribute to negative symptoms. Indeed, dysfunction of the COMT rs4680 polymorphism affects the thermostability of the mature protein, altering dopamine levels in various regions of the brain, particularly in the PFC. As the G allele is a predominant factor of higher COMT activity in the PFC, it causes a reduction in synaptic dopamine level and a disrupted prefrontal function [31]. The presence of the G allele was found to be linked to schizophrenia [32], to impairments in neuronal and cognition functions [33] and structural brain abnormalities [34] in individuals with schizophrenia. These rs4680-related alterations in brain volumes are known to be implicated in negative symptoms of schizophrenia [35]. Several studies showed a significant association between negative symptoms in schizophrenia and COMT rs4680 polymorphism. For example, the SNP rs4680 (Val/Met) present in the COMT gene showed significant association with blunted affect in a sample of unrelated Chinese individuals diagnosed with schizophrenia [36]. Madzarac et al. [37] found that the presence of the G allele or GG genotype of COMT rs4680 was associated with an increase in several dimensions of negative symptoms and anhedonia in Croatian female patients with schizophrenia.
On the other hand, since dopamine is essential in prefrontal functions, rs4680 was claimed as a key factor influencing cognitive abilities. Moreover, the COMT rs4680 polymorphism has also an important role in modulating noradrenergic neurotransmission [38], which regulate many aspects of cognition [39]. Both dopamine and noradrenaline are likely to affect metacognition [40]. The rs4680 SNP in the COMT gene is linked to decreased COMT activity and higher levels of dopaminergic stimulation of postsynaptic neurons [31], which was related to greater performance in PFC-dependent tasks, such as executive cognitive function [41], attention and cognitive flexibility [42], as well as working memory [43]. In addition, the Met-allele is linked to successful outcomes in financial decision-making [44], which requires the integrity of metacognitive processes. Findings from studies in schizophrenia-spectrum disorders indicated that genetic variability in the COMT gene was associated with cognitive functions [33, 45] and differential improvement in cognition following cognitive intervention [46, 47]. Studies specifically focusing on the COMT rs4680 (Val/Met) polymorphism showed that Val carriers exert decreased baseline cognitive abilities, whereas Met carriers show more improvement in cognitive performance after cognitive remediation [48]. Based on the aforementioned literature, it can be hypothesized that schizophrenia patients carrying certain genotypes of COMT rs4680 would have an increased likelihood of developing more severe negative symptoms under the influence of maladaptive metacognitive beliefs.
Rationale of this study
This study was designed to specifically address several gaps in the current knowledge regarding the relationships between metacognition and negative symptoms in schizophrenia. This can be crucial to further understand the mechanisms behind the development and maintenance of negative symptoms [11]. The first identified knowledge gap is scarcity of research that has specifically focused on the relationship between metacognition and negative symptoms, with negative symptoms being often measured as a covariate rather than an outcome measure [11]. Additionally, most of the previous studies on the topic had some measurement limitations, making conclusions questionable [25]—as negative symptoms were often measured by the PANSS rather than by more focused and modern tools [49, 50]. Moreover, earlier studies have mainly considered total scores across multiple domains of metacognition. Since metacognition is multidimensional in nature, it is important to explore whether each metacognitive subdomain has a unique influence on negative symptoms [51]. Finally, no studies have investigated the role of genetic variation in the relationship between metacognition and negative symptoms. By doing this in a genetically under-represented population of patients with schizophrenia of the Middle East, our study may significantly add to the existing body of knowledge regarding the interplay between metacognitive capacities and negative symptoms across genetically diverse individuals. The present study aims to test the hypothesis that COMT rs4680 variants will act as moderators in the relationship between certain metacognitive domains and negative symptoms’ severity.