Association of Plasma Neurexin-3 with Severity of Schizophrenia

Introduction

Schizophrenia is a chronic mental illness accompanied by a disturbance in the thought process and emotional responsiveness. ¹ Schizophrenia is associated with complications such as cognitive dysfunction, suicide and an increased risk of premature mortality.^{2, 3}

Synaptic dysfunction is known to play a key role in the development of neuropsychiatric disorders, including schizophrenia and bipolar disorder. ⁴ Previous studies have documented altered plasma levels and single-nucleotide polymorphisms of markers of synaptic plasticity and their relation to the severity of schizophrenia.^{5, 6}

Neurexins are transmembrane proteins that bind to neuroligins and mediate the formation and maturation of synapses. ⁷ Neurexin signaling is known to be altered in several psychiatric disorders, including schizophrenia. ⁸ Deletion of neurexin-1 is reported to increase the risk of schizophrenia by reducing neuronal activity and neurotransmitter release.^{9, 10} Earlier studies have documented altered neurexin-3 levels in psychiatric disorders. Cerebrospinal fluid (CSF) neurexin-3 levels were found to be reduced in major depressive disorders. ¹¹ Plasma neurexin-3 levels were reported to increase and to be associated with cognitive scores in patients with bipolar disorders. ¹² Neurexin-3 gene polymorphism has been investigated in schizophrenia and was found to be associated with the risk of schizophrenia. ¹³ Since data about plasma neurexin-3 levels are lacking in schizophrenia, the present study was undertaken to investigate plasma neurexin-3 levels and their relation to the severity of schizophrenia.

Methods

This case-control study comprised 216 schizophrenia patients (age—20–50 years), diagnosed based on DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, edition-5) criteria and 216 controls. Participants with medical disorders, inflammatory disorders and active substance use were excluded. Institute Ethics Committee (IEC/2018/523) approval was obtained. Written consent was obtained from all the participants of the study. The Positive and Negative Syndrome Scale (PANSS) ¹⁴ was used to analyse schizophrenia severity. Based on the PANSS score, schizophrenia patients were divided into mild illness (PANSS = 30–58), moderate illness (PANSS = 59–74) and marked illness (PANSS = >75).

Results

The clinical characteristics and neurexin-3 levels in schizophrenia cases and controls are shown in Table 1. Neurexin-3 levels were significantly reduced in schizophrenia cases compared to controls (p < .001).

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Table 1.

Clinical Characteristics and Neurexin-3 Levels in Schizophrenia Cases and Controls.

Sr No	Characteristics	Controls (n = 216)	Schizophrenia Cases (n = 216)	p
1	Age (years)	36 ± 8	35 ± 9	.232
2	Drug naive		93
3	Drug free		123
4	Disease duration (years)	–	3 (1–7)
5	Neurexin-3 (pg/mL)	564.70 (427.14–1,055.8652)	379.33 (210.72–526.740)	<.001

Table 2 shows the correlation of neurexin-3 with PANSS scores and the duration of the disease. Neurexin-3 was positively associated with negative symptom score (p = .037), general psychopathological score (p = .025) and total PANSS score (p = .019) in schizophrenia cases. There was no significant association between neurexin-3 and disease duration.

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Table 2.

Correlation of Neurexin-3 with Disease Severity Score in Schizophrenia.

Parameters	Neurexin-3	p
Age	–0.007	.918
Duration of disease	–0.009	.899
Positive symptom score	0.098	.152
Negative symptom score	0.142	.037
General Psychopathological Score	0.153	.025
Total PANSS score	0.160	.019

Note: PANSS: Positive and Negative Syndrome Scale.

Table 3 shows the neurexin-3 levels and disease duration in schizophrenia subgroups based on PANSS scores. Neurexin-3 was significantly increased (p < .05), and disease duration (p < .05) was significantly reduced in schizophrenia patients with marked illness compared to those with mild illness.

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Table 3.

Plasma Neurexin-3 and Duration of Disease in Schizophrenia with Mild, Moderate, Marked and Severe Illness.

Parameter	Schizophrenia with Mild Illness (PANSS: 30–58) (n = 107)	Schizophrenia with Moderate Illness (PANSS: 59–74) (n = 54)	Schizophrenia with Marked Illness (PANSS: >75) (n = 55)
Neurexin-3	348.8 (13–2,602)	407.3 (10–2,646)	415.1 (122–4,008)*
Duration of disease	4 (0–20)	3 (0–20)	2 (0–15)*

Notes: *p < .05 compared to mild illness. PANSS: Positive and Negative Syndrome Scale.

Discussion

Neurexin-3 is a marker of synaptic plasticity and is known to play a role in the pathophysiology of schizophrenia. ¹⁵ An earlier study from the Chinese Han population has documented an association between single-nucleotide polymorphisms of the neurexin-3 gene and weight gain in schizophrenia patients treated with risperidone. ¹³ Altered plasma neurexin-3 levels were reported in bipolar disorder, ¹² but there are no data regarding neurexin-3 levels in schizophrenia.

In the current study, neurexin-3 levels were significantly reduced in schizophrenia cases compared to controls (p < .001). When subgroup analysis was performed on schizophrenia patients based on PANSS scores, we found that around 50% (n = 107) had mild illness (PANSS = 30–58), 25% (n = 54) had moderate illness (PANSS = 59–74), and 25% had marked illness (PANSS = >75). Neurexin-3 was significantly increased (p < .05) in schizophrenia patients with marked illness compared to those with mild illness. It was positively associated with negative symptom score (p = .037), general psychopathological score (p = .025) and total PANSS score (p = .019) in schizophrenia cases. There was no significant association between neurexin-3 and disease duration. Even though the mechanism through which neurexin-3 is related to the severity of schizophrenia is not known, it can be speculated that altered neurexin-3 levels may affect the formation, maturation and functioning of synapses, ⁷ resulting in synaptic dysfunction, which may increase the severity of schizophrenia.

The main limitation of the study is that the effect of anti-psychotics on neurexin-3 levels was not analysed. Other types of neurexins were not analysed due to financial constraints.

Conclusion

We conclude that neurexin-3 is reduced in schizophrenia and positively associated with PANSS scores, suggesting that reduced neurexin-3 levels lead to the severity of schizophrenia. Further studies are needed to analyse neurexin-3 gene expression in schizophrenia and its association with disease severity.