The moderating role of COMT gene rs4680 polymorphism between maladaptive metacognitive beliefs and negative symptoms in patients with schizophrenia

Abstract

Background

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 explaining mechanisms of this association are still less known and poorly understood. This study aims to bridge this knowledge gap by testing the hypothesis that COMT rs4680 variants will act as moderators in the relationship between certain metacognitive domains and negative symptoms’ severity.

Method

A cross-sectional study was carried-out during the period between February and March 2024. A total of 115 biologically unrelated Arab (Lebanese) patients with schizophrenia were included.

Results

After controlling for sex and duration of illness as a potential confounder, moderation analyses showed that the AG genotype of the COMT rs4680 served as a significant moderator between maladaptive metacognitive beliefs about cognitive confidence (i.e. lack of confidence in memory) and negative symptoms. In non-carriers of the COMT rs4680 AG genotype, lower cognitive confidence (i.e., more “lack of cognitive confidence”) is significantly associated with greater negative symptoms.

Conclusion

Findings suggest that metacognition may be a relevant treatment target in the management of negative symptoms particularly in non-carriers of the COMT rs4680 AG genotype. Therefore, genetic testing could potentially be used to match patients with metacognitive interventions that are more likely to be effective in supporting recovery from negative symptoms.

Introduction

Negative symptoms are a group of symptoms that 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 negative symptoms in people with schizophrenia spectrum disorders [16, 21, 22]. Several previous studies also showed that a worse efficiency in metacognitive skills from 6 to 36 months after baseline assessment was predictive of greater negative symptoms [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, 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 between metacognition and negative symptoms

The role of COMT in negative symptoms

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.

The role of COMT in metacognition

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, the present study proposes to test the hypothesis 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]. Moreover, earlier studies have mainly considered total scores across multiple domains of metacognition. Since metacognition is multidimensional in its nature, it is important to explore whether each metacognitive subdomain has a unique influence on negative symptoms [49]. 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.

Method

Sample and procedure

A total of 115 biologically unrelated Arab (Lebanese) patients with schizophrenia were included in this cross-sectional study has been conducted during February and March 2024. The target sample was set as inpatients of the Psychiatric Hospital of the Cross, Jal Eddib (suburbs of the capital Beirut), Lebanon. The latter is a private hospital that delivers tertiary care for psychiatric patients that has 950 beds. Services provided include long and short stay and outpatient psychiatric clinics [50]. A recent study showed that between 2018 and 2022, a total of 2533 patients was admitted, with a mean duration of the global length of the stay was 28.35 ± 26.57 days, with a range between 2 and 300 and a median of 21.00 days [50]. Patients with the following inclusion criteria were eligible to participate: (1) age of 18 years and over, (2) with a schizophrenia disorder diagnosis following the DSM-5 criteria [35], (3) institutionalized in the above-mentioned long-stay hospital for more than one year (detailed description of the study population can be found elsewhere [51, 52]), (4) remitted and clinically stable (as defined by Fleischhacker et al. [53], patients “were required to be symptomatically stable, as judged by the treating physician, be receiving a stable dose of an antipsychotic drug for at least 4 weeks before the survey and be in good general physical health”).

Genotyping

To analyze the rs4680 polymorphism of the COMT gene, Thermo Scientific GeneJET Genomic DNA Purification Kit (Thermo Fisher Scientific Inc.) was used to isolate DNA from patients’ blood. DNA quantification was done using the NanoDrop spectrophotometer (Thermo Fisher Scientific Inc.).

For all SNP genotyping, The TaqMan^® Drug Metabolism Genotyping Assay (ABI: Applied Biosystems Inc., Foster City, CA, USA) was used according to the standard manufacturer’s protocol. DNA samples of known genotypes were used in every reaction as positive controls. The PCR reaction was conducted in a 25 µl reaction volume, containing 11.25 µl DNA sample (20ng), 12.5 µl PCR master mix, and 1.25 µl primer pairs and probes. A pre-incubation at 95 °C for 10 min was used to activate the Hot-Start DNA polymerase and denature DNA. It was followed by 50 amplification cycles consisting of a denaturation phase at 92 °C for 15 s and an extension phase at 60 °C for 90 s. The probe fluorescence signal was detected using the Bio-Rad CFX96 Real-Time PCR System.

Measures

Sociodemographic and clinical information

Data were gathered during a face-to-face interview of around 30 min with all participants. The questionnaire consisted of a first section containing information on socio-demographics, including age, gender, education level (Primary, secondary, university), marital status (single, married, separated, divorced, widowed), duration of illness (in years), and duration of hospitalization (in years).

The self-evaluation of negative symptoms scale (SNS)

The SNS is a 20-item scale that assesses negative symptoms through five dimensions: emotional withdrawal, social withdrawal, avolition, alogia, and anhedonia [54]. Each item is scored on a three-point Likert-type scale, ranging from 0 (strongly disagree) to 2 (strongly agree). Higher total scores (0–40) reflect more severe negative symptoms. The Arabic version of the SNS was used [55], with a Cronbach alpha value of.85. The SNS was chosen because it specifically measures several possible dimensions of negative symptoms by self-rating. This is valuable and relevant, as most patients with schizophrenia are shown to be incapable of accurately reporting their negative symptoms in semi-structured interviews [56, 57]. Self-reporting was found to identify some clinical information on negative symptoms that are detected and analysed by patients themselves, and that are not necessarily recognized by interviewers in hetero-evaluation [58]. In addition, the SNS was found to allow patients to better express their loss of emotion and deficits in motivation, regardless of depressive symptoms [54, 59, 60].

The 30-item Metacognitions Questionnaire (MCQ-30)

The MCQ-30 is composed of 30 items that evaluate maladaptive metacognitive beliefs through five domains: Negative beliefs, Cognitive self-consciousness, Need to control thoughts, Positive beliefs about worry, and (Lack of) Cognitive confidence [13]. Each item is rated on a four-point Likert scale from 1 (Disagree) to 4 (Agree). Higher total sub-scores refer to greater level of the corresponding domain. The Arabic validated version of the MCQ-30 was used in this study [61]. It yielded a Cronbach alpha ranging from 0.72 to 0.97 for the different sub-scores in the present sample.

Statistical analysis

The SPSS software v.26 was used for the statistical analysis. The negative symptoms score was considered normally distributed, with normality verified since the skewness and kurtosis values for each item of the scale varied between − 1 and + 1 [62]. Student’s t-test was used to compare two means, the ANOVA test to compare three means, and the Pearson test to correlate the impulsivity scores with other continuous variables. The moderation analysis was conducted using PROCESS MACRO (an SPSS add-on) v.3.4 model 1, taking the polymorphism rs4680 as a moderator between emotional intelligence and impulsivity. Interaction terms were probed by examining the association of one predictor with impulsivity at the mean, 1 SD below the mean and 1 SD above the mean of the moderator. Results were adjusted over all variables that showed a p < .25 in the bivariate analysis. P < .05 was deemed statistically significant.

Results

One hundred fifteen patients enrolled in the study, with all characteristics of the patients summarized in Table 1.

Table 1.

Sociodemographic and other characteristics of the patients (n = 115)

Gender
Male	73 (63.5%)
Female	42 (36.5%)
Education
Primary	28 (24.3%)
Complementary	43 (37.4%)
Secondary	30 (26.1%)
University	14 (12.2%)
Cigarette smoking
No	28 (24.3%)
Yes	87 (75.7%)
Cannabis lifetime use
No	105 (91.3%)
Yes	10 (8.7%)
Rs4680 polymorphism*
Genotype AA	34 (32.1%)
Genotype AG	44 (41.5%)
Genotype GG	28 (26.4%)
Age (years)	57.64 ± 10.41
Age at onset of schizophrenia	25.32 ± 7.76
Duration of hospitalization (years)	3.73 ± 4.82
Duration of illness (years)	32.17 ± 11.54
Impulsivity	22.70 ± 4.08
Emotional intelligence	37.93 ± 8.42

*Numbers do not add the total N because of missing values

Bivariate analysis

Significantly higher negative symptoms scores were found in females compared to males (Table 2). Moreover, higher cognitive confidence was significantly associated with higher negative symptoms (Table 3).

Table 2.

Bivariate analysis of factors associated with negative symptoms (SNS scale score)

	Mean ± SD	t / F	df /df1,df2	p
Sex		-5.36	111	< 0.001
Male	9.63 ± 6.44
Female	16.61 ± 7.04
Education		1.86	3,109	0.141
Primary	14.70 ± 8.42
Complementary	11.43 ± 7.05
Secondary	12.17 ± 7.28
University	9.43 ± 6.10
Cigarette smoking		1.15	111	0.253
No	13.59 ± 7.48
Yes	11.71 ± 7.42
Cannabis lifetime use		0.96	111	0.339
No	12.37 ± 7.40
Yes	10.00 ± 7.94
Rs4680 polymorphism		0.48	2,102	0.618
Genotype AA	11.67 ± 7.41
Genotype AG	13.20 ± 6.78
Genotype GG	11.86 ± 8.61

Numbers in bold indicate significant p values

Table 3.

Pearson correlation matrix

	1	2	3	4	5	6	7	8	9	10
1. Negative symptoms (SNS scores)	1
2. Age	0.08	1
3. Age of schizophrenia onset	0.11	0.17	1
4. Duration of hospitalization	0.01	0.07	− 0.17	1
5. Duration of illness	0.03	0.73***	− 0.46***	0.04	1
6. Cognitive confidence	0.34***	− 0.01	0.06	− 0.13	− 0.01	− 0.35***	1
7. Positive beliefs	− 0.02	− 0.30**	− 0.19*	0.01	− 0.20*	− 0.07	0.03	1
8. Cognitive self-consciousness	− 0.18	− 0.14	− 0.03	0.15	− 0.15	0.39***	− 0.35***	0.20*	1
9. Negative beliefs	0.13	− 0.22*	− 0.18	− 0.09	− 0.07	− 0.17	0.06	0.43***	0.15	1
10. Needs to control thoughts	− 0.08	− 0.23*	0.06	0.07	− 0.25**	0.28**	− 0.04	0.21*	0.31**	0.36***

*p < .05; **p < .01; ***p < .001; numbers in the table refer to Pearson correlation coefficients r

Moderation analysis

The results of the moderation analyses are shown in Table 4. After controlling for sex and duration of illness, the interaction of cognitive confidence by rs4680 genotype AG was significantly associated with negative symptoms. In patients not having the rs4680 genotype AG, higher cognitive confidence was significantly associated with higher negative symptoms (Fig. 1).

Table 4.

Moderation analysis

	a. Genotype AG vs. AA*				b. Genotype GG vs. AA*
	Beta	t	p	95% CI	Beta	t	p	95% CI
Model 1: Cognitive confidence as an independent variable
Cognitive confidence	0.47	3.42	0.001	0.20; 0.75	0.23	1.74	0.085	− 0.03; 0.49
Genotype	7.57	2.60	0.011	1.79; 13.35	-3.34	-1.01	0.316	-9.91; 3.23
Interaction cognitive confidence by genotype	− 0.49	-2.23	0.028	− 0.92; − 0.05	0.20	0.83	0.408	− 0.28; 0.68
Model 2: Positive beliefs as an independent variable
Positive beliefs	0.03	0.19	0.852	− 0.29; 0.35	− 0.16	-1.16	0.249	− 0.44; 0.12
Genotype	5.84	1.94	0.055	− 0.13; 11.98	-2.20	− 0.62	0.538	-9.25; 4.85
Interaction positive beliefs by genotype	− 0.37	-1.53	0.128	− 0.84; 0.11	0.13	0.44	0.664	− 0.45; 0.70
Model 3: Cognitive self-consciousness as an independent variable
Cognitive self-consciousness	− 0.29	-1.64	0.104	− 0.64; 0.06	− 0.21	-1.36	0.176	− 0.52; 0.10
Genotype	− 0.68	− 0.13	0.895	-10.77; 9.42	1.11	0.18	0.861	-11.34; 13.55
Interaction cognitive self-consciousness by genotype	0.13	0.47	0.638	− 0.43; 0.69	− 0.10	− 0.28	0.780	− 0.77; 0.58
Model 4: Negative beliefs as an independent variable
Negative beliefs	0.17	1.03	0.307	− 0.16; 0.50	− 0.001	− 0.01	0.995	− 0.32; 0.32
Genotype	4.97	1.56	0.121	-1.33; 11.27	-2.60	− 0.75	0.452	-9.43; 4.23
Interaction negative beliefs by genotype	− 0.33	-1.15	0.255	− 0.89; 0.24	0.20	0.62	0.537	− 0.44; 0.84
Model 5: Need to control thoughts as an independent variable
Need to control thoughts	− 0.01	− 0.05	0.959	− 0.41; 0.39	− 0.34	-1.83	0.070	− 0.71; 0.03
Genotype	9.87	2.21	0.030	0.99; 18.74	-6.53	-1.33	0.185	-16.24; 3.18
Interaction Need to control thoughts by genotype	− 0.58	-1.87	0.064	-1.20; 0.04	0.42	1.22	0.225	− 0.26; 1.10

*Reference group; numbers in bold indicate significant p values

Fig. 1.

Moderation of the effect of the Metacognition domain “Cognitive confidence” on negative symptoms by the COMT rs4680 genotypes

Discussion

This is the first study investigating the moderating role of the COMT rs4818 polymorphism in the relationship between metacognition and negative symptoms and after controlling for possible confounders, the first examination of this relationship using a specific measure of negative symptoms and considering each metacognition domain separately, and the first inclusion of people diagnosed with schizophrenia originating from an Arab country of the Middle East. Moderation analyses showed that, in our patients with schizophrenia, the AG genotype of the COMT rs4680 served as a significant moderator between maladaptive metacognitions about cognitive confidence and negative symptoms.

After controlling for sex and duration of illness as a potential confounder, our results showed that the COMT rs4680 AG genotype significantly moderated the relationship between a specific maladaptive metacognitive belief, i.e. the lack of cognitive confidence, and negative symptoms. This metacognitive dimension refers to a distrust of one’s perception, attention, and memory. Consistent with our results, previous studies indicated that low cognitive confidence is more frequently exhibited by people at risk of developing psychosis compared to healthy controls [63, 64]. In addition, evidence drawn from an extensive literature supports that impaired metacognition is associated with greater negative symptoms in people with schizophrenia spectrum disorders [16, 21, 22, 65–69]. However, when considering each metacognition subdomain separately in relation to summed measures of negative symptoms, findings show more inconsistencies, with around or below 50% significance observed across studies for all metacognition subdomains [11]. Indeed, in agreement with our findings, previously reported relationships between metacognition subscales and negative symptoms found a range of significant and non-significant associations [69, 70]. This calls into question whether considering metacognition as a single-scored construct could obscure the differential relationships of its subtypes with negative symptoms, and suggests that future studies need to examine the different metacognitive domains and how each of these might impact negative symptoms before drawing any clear conclusion about this relationship [11].

The study hypothesis was partly supported, showing a significant moderating effect of the COMT rs4680 AG genotype on the association between lack of cognitive confidence and negative symptoms. An interaction between genotype and metacognition impacted negative symptoms in a positive direction, such that non-carriers of the COMT rs4680 AG genotype showed more severe negative symptoms in the presence of lack of cognitive confidence. Our results suggest that the effects of metacognitive beliefs may be moderated by genetic factors that exist as a biological foundation for individually varying negative symptom expression. In other words, findings suggest that COMT polymorphism, which transforms from valine (or allele G) to methionine (or allele A), is likely to affect the expression of negative symptoms based on the metacognitive profiles of patients. The human COMT gene is present on human chromosome 22q11, which is a region closely related to induced high enzymatic activity, resulting in lower dopamine levels in the prefrontal cortex [71]. The “revised dopamine hypothesis” proposes hypoactive dopamine transmission in the PFC and hyperactive dopamine transmission in the mesolimbic areas in patients with schizophrenia [72], with negative symptoms resulting from reduced dopaminergic activation in the PFC [73]. More specifically, the Met-allele (A) gives rise to lower COMT activity, lower phasic dopamine release, and higher tonic dopamine levels, leading in turn to more negative symptoms [74]. There is other empirical evidence that carriers of the COMT rs4680 A allele [75] and the AA genotype showed greater improvement in negative symptoms following antipsychotic treatment, compared to carriers of the COMT rs4680 GG genotype. The COMT rs4680 genotype is also one of the major enzymes involved in noradrenaline [38] metabolism in the PFC, which have both been implicated in metacognition [40, 76] and negative symptoms [73]. Additionally, research indicated that genetic variations in the COMT gene are closely connected to cognition [33, 45, 77] and to response to cognitive interventions [46, 47] in patients with schizophrenia spectrum disorders. However, there is to date insufficient or inconclusive evidence on the link of COMT rs4680 with cognition and negative symptoms, with non-significant associations having also been observed [78]. Altogether, the current results suggest that COMT genotype may improve our understanding of the development and maintenance of negative symptoms, and inform the tailoring of interventions for effectively relieving them in schizophrenia-spectrum patients. Nevertheless, more studies are still needed to elucidate the mechanisms underlying the role of COMT in psychopathology in patients with schizophrenia.

Study limitations

There are some limitations to be recognized and addressed in future studies. First, the design was cross-sectional, which prevents from concluding that metacognitive beliefs contributed to the development of patients’ negative symptoms. Future studies with a longitudinal design may confirm the causal investigation of these variables. Second, the study included chronic inpatients who were in a long-stay and under antipsychotic treatment, which can limit the representativeness of our sample. Further studies including outpatients, those in acute phases, and those at earlier stages of the disease are needed before conclusions can be generalized to all patients diagnosed with schizophrenia. Third, the possible influence of antipsychotic medication on metacognition or negative symptoms was not considered in the context of the present study. Another limitation consists of the lack of other clinical or cognitive assessments, such as the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), or the MATRICS Consensus Cognitive Battery (MCCB). Finally, negative symptoms were measured using a self-report scale. Although this method of assessment was shown to be reliable in detecting negative symptoms [58], future studies should consider using diagnostic interviews and clinician-rated measures, as self-ratings could be affected by patients’ cognitive abilities.

Clinical implications and future research directions

These limitations aside, our study has valuable practical implications. The findings showed that COMT rs4680 moderated the relationship between metacognition and negative symptoms. Particularly, patients with schizophrenia who do not carry the SNP COMT rs4680 AG genotype were more likely to be affected by metacognition impairments (i.e. a lack of cognitive confidence) and produce more severe negative symptoms. This suggests that integrated intervention and prevention programs that consider both genetic and individual cognitive factors simultaneously are needed to improve negative symptoms in schizophrenia. Our analyses provide more evidence to support the significant relationship between metacognition and negative symptom scores, which calls for further development and evaluation of treatments targeting maladaptive metacognitive beliefs in people with severe and/or persistent negative symptoms [25]. An example of interventions that can be tested in our context and population is the Metacognitive Reflection and Insight Therapy (MERIT)s [79], which demonstrated effectiveness in improving metacognitive functioning and reducing symptoms in persons with schizophrenia [80–82]. In addition, it is suggested that metacognition may be a relevant treatment target in the management of negative symptoms particularly in non-carriers of the COMT rs4680 AG genotype. Therefore, genetic testing could potentially be used to match patients with metacognitive interventions that are more likely to be effective in supporting recovery from negative symptoms.

Conclusion

This study sought to advance our comprehension of the intricate nature and mechanisms underlying the relationship between metacognition and negative symptoms. Findings indicated that the role of the COMT gene rs4680 polymorphism in moderating this relationship was supported. This suggests that genetic testing can pave the way for more effective and personalized interventions, tailored to the unique needs of each patient based on their metacognitive and genetic profile. In particular, interventions targeting metacognition, while taking various COMT genotypes into account, may fill a gap in treatment needs of patients with negative symptoms, and facilitate efforts towards improvements in clinical and functional outcomes. Future experimental genomic studies are warranted to confirm our findings.

Author contributions

FFR, EEH, AAL and SH designed the study; FFR drafted the manuscript; GK, NH, MEM and RAK collected the data; SH carried out the analysis and interpreted the results; all authors reviewed the paper for intellectual content, reviewed the final manuscript and gave their consent.

Funding

None.

Data availability

All data generated or analyzed during this study are not publicly available due the restrictions from the ethics committee. Reasonable requests can be addressed to the corresponding author (SH).

Declarations

Ethics approval and consent to participate

Ethics approval for this study was obtained from the ethics committee at the Psychiatric Hospital of the Cross. A digital informed consent was obtained from all subjects and/or their legal guardians for study participation and was considered equivalent to receiving a written informed consent. All methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.