Reduced paraoxonase 1 activities may explain the comorbidities between temporal lobe epilepsy and depression, anxiety and psychosis

doi:10.5498/wjp.v12.i2.308

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World Journal of Psychiatry

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World J Psychiatry. Feb 19, 2022; 12(2): 308-322
Published online Feb 19, 2022. doi: 10.5498/wjp.v12.i2.308

Table 1 Sociodemographic and clinical data of healthy controls and patients with temporal lobe epilepsy and patients with psychosis, depression and anxiety due to temporal lobe epilepsy (mean ± SD)

Variables	HC¹	TLE²	TLE + PSY³	TLE + DEP⁴	TLE + ANX⁵	F/X²	df	P value
Age (yr)	37.4 (12.8)	40.0 (12.8)	37.9 (10.5)	39.0 (10.7)	37.0 (8.2)	0.34	4/141	0.849
Sex (♂/♀)	10/30	11/16	13/14	4/21	5/22	10.31	4	0.036
BMI (kg/m²)	24.0 (4.3)	24.1 (4.0)	23.5 (3.7)	23.9 (4.3)	22.4 (4.3)	0.79	4/140	0.535
Married (No/Yes)	26/14	18/9	20/7	20/5	15/11	3.58	4	0.466
Education (yr)	14.2 (4.9)²^,³^,⁴^,⁵	11.4 (4.7)¹	9.4 (4.4)¹	10.3 (5.4)¹	10.8 (4.5)¹	5.14	4/141	0.001
TUD (No/Yes)	38/2	24/3	23/4	21/4	23/4	Ψ = 0.136	-	0.607
Frequency seizures	-	29.1 (84.7)	19.1 (40.7)	8.0 (17.0)	9.7 (11.0)	0.99	3/89	0.402
Age onset TLE (yr)	-	17.8 (12.6)	12.2 (10.1)	17.6 (8.9)	16.1 (8.8)	1.75	3/100	0.162
Hx Aura (No/Yes)	-	6/21	5/22	7/18	8/19	1.15	3	0.766
Hx Postictal confusion (No/Yes)	-	8/19	10/16	9/16	11/15	0.97	3	0.808
Hx Status epilepticus (No/Yes)	-	24/3³	14/11²	21/4	13/9	10.75	3	0.013
Seizure control	-	7/8/8	7/8/8	5/4/0	5/5/10	Ψ = 0.309	-	0.307
BPRS	18.3 (1.1)²^,⁵	23.6 (3.3)¹^,³^,⁴^,⁵	41.3 (5.9)¹^,²^,⁴^,⁵	32.9 (6.7)¹^,²^,³^,⁵	29.4 (50.)¹^,²^,³^,⁴	115.64	4/141	< 0.001
HAM-D	0.6 (2.0)²^,⁵	4.8 (2.5)¹^,⁴^,⁵	5.8 (2.9)¹^,⁵	19.8 (4.9)¹^,²^,³^,⁵	10.3 (3.8)¹^,²^,³^,⁴	145.21	4/140	< 0.001
HAM-A	2.6 (5.4)²^,⁵	7.8 (3.9)¹^,³^,⁴^,⁵	11.6 (6.7)¹^,²^,³^,⁵	18.9 (8.8)¹^,²^,³^,⁵	23.8 (5.4)¹^,²^,³^,⁴	59.69	4/141	< 0.001
MMSE	28.3 (2.4)²^,⁵	25.1 (4.4)¹^,³	22.4 (5.4)¹^,²^,⁴^,⁵	25.7 (2.4)¹^,³	25.8 (8.9)¹^,³	11.06	4/140	< 0.001

^1-5Results of post-hoc comparisons among the five diagnostic groups.

¹Indicates HC and “1” associated with column figures indicates that this value is different from HC.

²Indicates TLE and “2” associated with column figures indicates that this value is different from TLE.

³Indicates TLE + PSY and “3” associated with column figures indicates that this value is different from TLE + PSY.

⁴Indicates TLE + DEP and “4” associated with column figures indicates that this value is different from TLE + DEP.

⁵Indicates TLE + ANX and “5” associated with column figures indicates that this value is different from TLE + ANX.

BMI: Body mass index; TUD: Tobacco use disorder; Control seizures: Seizure free and fairly and poorly controlled seizures; BPRS: Brief Psychiatric Rating Scale; HAM-D: Hamilton Depression Rating Scale; HAM-A: Hamilton Anxiety Rating Scale; MMSE: Mini Mental State Examination; HC: Healthy controls; TLE: Temporal lobe epilepsy; TLE: TLE without ant psychiatric comorbidities; TLE + PSY: Psychotic Disorder due to TLE; TLE + DEP: Mood Disorder due to TLE with depressive features; TLE + ANX: Anxiety Disorder due to TLE.

Table 2 Results of multivariate general linear model analysis examining the differences between diagnostic groups (diagnosis), namely healthy controls, temporal lobe epilepsy with and without comorbidities including depression, psychosis, and anxiety

Tests	Dependent variables	Exploratory variables	F	df	P value	Partial Eta squared
	All 4 biomarkers
Multivariate	CMPAase	Diagnosis	6.49	16/410	< 0.001	0.158
	Arylesterase	Sex	1.22	4/134	0.306	0.035
	Res CMPAase	Age	0.61	4/134	0.654	0.018
	Res Arylesterase	BMI	1.07	4/134	0.375	0.031
Between-subject effects	CMPAase	Diagnosis	28.06	4/137	< 0.001	0.450
	Res CMPAase	Diagnosis	26.60	4/137	< 0.001	0.437
	Arylesterase	Diagnosis	11.31	4/137	< 0.001	0.248
	Res Arylesterase	Diagnosis	16.90	4/137	< 0.001	0.330

Diagnosis: Five diagnostic groups, namely Psychotic Disorder due to temporal lobe epilepsy (TLE), Mood Disorder due to TLE with depressive features, Anxiety Disorder due to TLE, “Pure TLE” (without any comorbidities) and healthy controls. PON1: Paraoxonase; CMPAase: 4-(chloromethyl)phenyl acetate hydrolysis; Res: Residualized (after regression on PON1 genotype); BMI: Body mass index.

Table 3 Model-generated estimated marginal means of paraoxonase 1 levels in healthy controls and patients with temporal lobe epilepsy and psychosis, depression and anxiety due to temporal lobe epilepsy

Variables	HC¹	TLE²	TLE + PSY³	TLE + DEP⁴	TLE + ANX⁵
CMPAase (U/mL)	42.1 (1.3)²^,³^,⁴^,⁵	28.5 (1.6)¹	24.5 (1.6)¹	24.8 (1.7)¹	27.3 (1.7)¹
Res CMPAase (z scores)	1.041 (0.128)²^,³^,⁴^,⁵	-0.196 (0.150)¹	-0.545 (0.163)¹	-0.545 (0.163)¹	-0.375 (0.159)¹
Arylesterase (U/mL)	212.4 (9.0)²^,³^,⁴^,⁵	156.4 (10.5)¹	144.2 (10.4)¹	143.7 (11.4)¹	137.3 (11.2)¹
Res Arylesterase (z scores)	0.920 (0.140)²^,³^,⁴^,⁵	-0.193 (0.163)¹	-0.425 (0.162)¹	-0.400 (0.177)¹	-0.434 (0.174)¹

^1-5Results of post-hoc comparisons among the five diagnostic groups.

¹Indicates HC and “1” associated with column figures indicates that this value is different from HC.

²Indicates TLE and “2” associated with column figures indicates that this value is different from TLE.

³Indicates TLE + PSY and “3” associated with column figures indicates that this value is different from TLE + PSY.

⁴Indicates TLE + DEP and “4” associated with column figures indicates that this value is different from TLE + DEP.

⁵Indicates TLE + ANX and “5” associated with column figures indicates that this value is different from TLE + ANX.

TLE: Temporal lobe epilepsy; TLE: TLE without psychiatric comorbidities; TLE + PSY: Psychotic Disorder due to TLE; TLE + DEP: Mood Disorder due to TLE with depressive features; TLE + ANX: Anxiety Disorder due to TLE; HC: Healthy controls; PON1: Paraoxonase; CMPAase: 4-(chloromethyl)phenyl acetate hydrolysis; Res: Residualized values after regression on PON1 genotype.

Table 4 Measurement of paraoxonase enzymatic activity in healthy controls and subgroups of temporal lobe epilepsy patients

PON1 activities	HC	Pure TLE	F	df	P value	Partial eta squared
CMPAase (U/mL)	42.8 (1.7)	28.8 (1.9)	30.61	1/62	< 0.001	0.331
Arylesterase (U/mL)	215.4 (10.8)	156.4 (12.2)	13.47	1/62	0.001	0.178
		MTS
CMPAase (U/mL)	41.7 (1.5)	25.6 (1.2)	81.44	1/100	< 0.001	0.449
Arylesterase (U/mL)	209.8 (9.4)	139.4 (7.5)	36.98	1/100	< 0.001	0.270
		Pure MTS
CMPAase (U/mL)	42.2 (1.8)	27.3 (2.6)	22.61	1/52	< 0.001	0.303
Arylesterase (U/mL)	213.0 (10.8)	139.5	14.65	1/52	< 0.001	0.220

Data are results of univariate general linear model analysis and are shown as model-generated marginal estimated mean (SE) values after covarying for age, sex and body mass index. Pure TLE: Temporal lobe epilepsy without any psychiatric comorbidity; MTS: Established mesial temporal lobe sclerosis (thus including psychiatric comorbidities); Pure MTS: Established mesial temporal lobe sclerosis without any psychiatric comorbidity; TLE: Temporal lobe epilepsy; HC: Healthy controls; MTS: Mesial temporal sclerosis.

Table 5 Results of multiple regression analysis with rating scales as dependent variables and paraoxonase status as explanatory variables

Dependent variables	Explanatory variables (model)	β	t value	P value	F model	Df	P value	Partial Eta squared
BPRS	CMPAase	-0.444	-6.09	< 0.001	29.35	2/143	< 0.001	0.291
BPRS	Education	-0.213	-2.93	0.004	29.35	2/143	< 0.001	0.291
Psychosis	CMPAase	-0.260	-3.20	0.002	9.56	2/143	< 0.001	0.118
Psychosis	Education	-0.167	-2.06	0.041	9.56	2/143	< 0.001	0.118
Negative symptoms	Education	-0.329	-4.52	< 0.001	12.75	4/141	< 0.001	0.226
	Sex	-0.329	-4.29	< 0.001
	Res CMPAase	-0.189	-2.56	< 0.011
	Age	-0.172	-2.30	0.023
HAM-D	CMPAase	-0.347	-4.51	< 0.001	11.95	4/140	< 0.001	0.254
	Education	-0.231	-3.02	0.003
	Overdominant model	-0.227	-3.06	0.003
	Sex	0.170	2.31	0.023
Suicidal ideation	Dominant model	0.354	4.61	< 0.001	13.21	2/143	< 0.001	0.156
Suicidal ideation	Res CMPAase	-0.173	-2.26	0.025	13.21	2/143	< 0.001	0.156
Physiosomatic symptoms	CMPAase	-0.349	-4.47	< 0.001	19.94	1/144	< 0.001	0.122
PMR	Education	-0.386	-5.13	< 0.001	14.75	4/141	< 0.001	0.295
	Sex	-0.252	-3.54	0.001
	Res CMPAase	-0.243	-3.36	0.001
	Age	-0.186	-2.53	0.013
HAM-A	CMPAase	-0.350	-4.80	< 0.001	12.93	2/143	< 0.001	0.153
HAM-A	Sex	0.163	2.10	0.037	12.93	2/143	< 0.001	0.153
Psychopathology index	CMPAase	-0.430	-5.83	< 0.001	19.94	3/141	< 0.001	0.298
	Education	-0.250	-3.41	0.002
	Overdominant model	-0.148	-2.07	0.040
MMSE	Education	0.593	9.09	< 0.001	54.48	2/142	< 0.001	0.434
MMSE	CMPAase	0.175	2.69	0.008	54.48	2/142	< 0.001	0.434

BPRS: Brief Psychiatric Rating Scale; HAM-D: Hamilton Depression Rating Scale; HAM-A: Hamilton Anxiety Rating Scale; MMSE: Mini Mental State Examination; PMR: Psychomotor retardation; Res CMPAase: Residualized (after regression on PON1 genotype); CMPAase: 4-(chloromethyl)phenyl acetate hydrolysis; Dominant and overdominant model: PON1 Q192R genotype models.

Citation: Michelin AP, Maes MHJ, Supasitthumrong T, Limotai C, Matsumoto AK, de Oliveira Semeão L, de Lima Pedrão JV, Moreira EG, Kanchanatawan B, Barbosa DS. Reduced paraoxonase 1 activities may explain the comorbidities between temporal lobe epilepsy and depression, anxiety and psychosis. World J Psychiatry 2022; 12(2): 308-322
URL: https://www.wjgnet.com/2220-3206/full/v12/i2/308.htm
DOI: https://dx.doi.org/10.5498/wjp.v12.i2.308