Prolidase activity in adult bipolar disorder patient: a case - control study

Background: Bipolar disorder is one of the major neuropsychiatric illnesses. It is responsible for 6.8% of disability-adjusted life years among all mental disorders. Few studies have evaluated the biochemical basis of bipolar disorder. Prolidase is an enzyme that degrade extracellular matrix into proline. In stress condi�on, prolidase by releasing proline maintain ATP genera-on, redox state, apoptosis and cell prolifera�on. The rela�onship between serum prolidase with bipolar disorder was inves-gated in this study. Methods: A case - control study was conducted at the Department of Laboratory Medicine in collabora�on with the Department of Psychiatry of Bangabandhu Sheikh Mujib Medical University, Dhaka from March 2021 to February 2022. Thirty-ﬁve pa�ents with bipolar disorder type I consis�ng of 15 euthymic and 20 manic pa�ents were enrolled in the study according to the availability of pa�ents as cases. Thirty-ﬁve age - and sex-matched healthy individuals were recruited from the Department of Laboratory Medicine as controls. Serum prolidase level was measured in cases and controls using venous blood. Results: Serum prolidase level was signiﬁcantly higher in cases than controls ( P =0.021). There was no signiﬁcant diﬀerences was observed between euthymic and manic pa�ents ( P =0.629). Signiﬁcant posi�ve correla�on was found between Young Mania Ra�ng Scale severity score and serum prolidase level ( P =0.001). Conclusion: Serum prolidase ac�vity may be associated with bipolar disorder. This needs further corrobora�on because our sample size


INTRODUCTION
Bipolar disorder is a chronic progressive psychiatric illness characterized by an episode of mania, hypomania and depression interspersed with euthymia. 1 Around the world, 46 million people had bipolar disorder in 2017. 2 In South Asia, the prevalence of bipolar disorder is 0.6%, 3 which is similar to the prevalence (0.5%) in Bangladesh. 4 Research findings suggest that men and women have equal frequencies of bipolar disorder around the world. 5 The diagnosis of bipolar disorder is based upon clinical interview. Due to disease heterogeneity, accurate diagnosis of bipolar disorder is difficult. It may take 10 years on average for a person to be correctly diagnosed with bipolar disorder. 6 There is a need to find out a reliable peripheral blood biomarker.
A recent study showed that serum prolidase activity may have a role in bipolar disorder pathogenesis. 7 Measuring the level of serum prolidase may be helpful to predict the disease. A review of literature identified 20 protein analytes with excellent predictive performance for bipolar disorder. 7 The panel had a good predictive performance to identify misdiagnosed bipolar disorder and a fair to good predictive performance to differentiate between bipolar patients and controls. 7 Three analytes of this panel belong to structurally related family of protease which are matrixmetalloproteinase that play important role in extracellular matrix degradation. 7 Prolidase is a

Prolidase activity in adult bipolar disorder patient: a casecontrol study
Methods: A case -control study was conducted at the Department of Laboratory Medicine in collabora on with the Department of Psychiatry of Bangabandhu Sheikh Mujib Medical University, Dhaka from March 2021 to February 2022. Thirty-five pa ents with bipolar disorder type I consis ng of 15 euthymic and 20 manic pa ents were enrolled in the study according to the availability of pa ents as cases. Thirty-five age -and sex-matched healthy individuals were recruited from the Department of Laboratory Medicine as controls. Serum prolidase level was measured in cases and controls using venous blood.
Results: Serum prolidase level was significantly higher in cases than controls (P=0.021). There was no significant differences was observed between euthymic and manic pa ents (P=0.629). Significant posi ve correla on was found between Young Mania Ra ng Scale severity score and serum prolidase level (P=0.001).
Conclusion: Serum prolidase ac vity may be associated with bipolar disorder. This needs further corrobora on because our sample size was small.

BRIEF ARTICLE
member of the matrix metalloproteinase family that degrades the extracellular matrix into proline and hydroxyproline. 8 An increased prolidase level is associated with increased proline peptides. 9 Disorder of proline metabolism was found to be associated with adult bipolar disorder. 10 The link has been also found between hyperprolinemia and the development of bipolar disorder. 11 In bipolar disorder, brain energy generation and basal metabolic rate is increased in case of mania. 12 Normal physiological processes also happen in excess in bipolar disorder such as excitotoxicity, excessive apoptotic activity and cellular senescence. 13 Proline plays a key role in maintaining cellular homeostasis and excess physiological processes such as apoptosis and autophagy in stressful condition. 14 In stressful condition, PRODH/POX enzyme is involved in generating more reactive oxygen species during oxidation of proline in mitochondrial proline cycle. 14 As a result, anti-oxidant capacity of the brain is limited. Impairment of signal transduction, neuronal plasticity and cell flexibility occurs due to lipid peroxidation of membranes by oxidative stress which is responsible for neural injury. 15 A study from Turkey suggested prolidase as a reliable diagnostic marker for adult bipolar disorder. 16 Another study also found significant higher prolidase level in bipolar disorder patients. 17 However, the relationship of prolidase with Young Mania Rating Scale (YMRS) has not been examined previously. The objective of this study was to determine association between prolidase activity with bipolar disorders. Its correlation with YMRS was also examined.

Study design
This case-control study was conducted at the 2. Prolidase level is significantly correlated with bipolar disorder severity.
3. Measurement of serum prolidase may be helpful in early detection of bipolar disorders among adults.
Sandwich-ELISA. The micro-ELISA plate was precoated with an antibody specific to human prolidase. Correlation of serum prolidase with YMRS score was determined by Spearman rank correlation co-efficient test. A probability value of less than 0.05 was considered statistically significant.

TABLE 1
shows the sociodemographic variables of the participants. Mean age of the participants was 32.9 years for cases and 36.1 years for controls, with a predominance of males(66%). The mean duration of the disease was 5.0 years. Prolidase activity in adult bipolar disorder patient 98

DISCUSSION
We report here that a higher level of serum prolidase level in adult bipolar disorder patients, compared to healthy controls. The age and sex distribution of series may not be directly comparable to many other studies [15][16][17][18][19] because of differences in study settings, subject selection and sample sizes.
Selek et al. had determined higher prolidase levels in bipolar disorder patients compared to their control group which was statistically significant (P<0.001) and consistent with current study. 16 Increased serum prolidase level in bipolar disorder was also reported by Ceylan et al. 17 , which is consistent with the findings of the present study.
Statistically significant difference of serum prolidase level was not found between euthymic and manic groups in this study (P=0.629). Selek et al. 16 in their study also did not find any significant difference of serum prolidase level among sub-group of bipolar disorder patients which is consistent with findings of the present study.
The present study found significant positive correlation of serum prolidase level with YMRS symptom score in manic patients of bipolar disorder (r= 0.87). It seems that with increase disease process, prolidase level increases. As per our knowledge, no such correlation was observed between serum prolidase level and YMRS score previously. Although prolidase correlate with YMRS score in manic patients of bipolar disorder, the correlation in euthymic and manic was not statistically significant (data not shown). A small sample size might be responsible for this. Lifestyle and dietary patterns may also affect the prolidase activity.
Measuring serum prolidase of patients in different episodes and comparison of prolidase of patients with and without treatment is needed to be performed to identify the relation of prolidase with the characteristic property of the disorder.

Limitations
The study was conducted with a small sample size. Lack of measurement of proline level alongside prolidase was also a limitation.

Conclusion
Our finding indicates that serum prolidase activity is associated with bipolar disorder. It is correlated with the YMRS symptom scores also. Prolidase activity may have a significant role with the disease activity.