A Effect of jwa dates adjuvant therapy on improvement of clinical symptoms and serum interleukin-1β (IL-1β) levels in schizophrenia patients

SAIDAH SYAMSUDDIN1, FIRDAUS1, ERLYN LIMOA1, IRFAN IDRIS2, SONNY TEDDY LISAL1

1Department of Psychiatry, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia; 2Department of Physiology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia.

Summary. Background. Inflammation plays a role in the etiology and pathophysiology of schizophrenia symptoms, through the effects of proinflammatory cytokines such as IL-1β. Ajwa dates are one of the non-pharmacological modalities that have anti-inflammatory and antioxidant properties. However, clinical trials are still limited in exploring the role of Ajwa dates as an adjuvant in the management of schizophrenia. Objective. To determine the effect of Ajwa dates adjuvant therapy on the improvement of clinical symptoms and serum IL-1β levels in schizophrenia patients. As well as determining the correlation between clinical symptoms and serum IL-1β levels. Methods. Quasi-experimental study with random group selection using a single blind method. The number of subjects was 60, divided into a treatment group that received risperidone 4-6 mg/day plus 7 Ajwa dates/day for 8 weeks and a control group that only received risperidone. Improvement of clinical symptoms was assessed using the PANSS score, and serum IL-1β levels were measured in the first week (baseline) and week 8, with enzyme-linked immunoassay. Results. The better improvement in clinical symptoms was observed in the treatment group. A significant decrease in serum IL-1β levels was observed in both groups after 8 weeks of therapy, but the treatment group showed a greater decrease compared to the control group. A significant correlation was found between the improvement of positive symptoms and general psychopathology symptoms with a decrease in serum IL-1β levels in the treatment group. Conclusions. Ajwa dates have an adjuvant effect on improving clinical symptoms and reducing serum IL-1β levels through their anti-inflammatory properties in schizophrenia patients receiving risperidone therapy.

Key words. Ajwa dates, IL-1β, PANSS, risperidone, schizophrenia.

Effetto della terapia adiuvante con datteri Ajwa sul miglioramento dei sintomi clinici e dei livelli sierici di interleuchina-1β (IL-1β) nei pazienti schizofrenici.

Riassunto. Introduzione. L’infiammazione ha un ruolo importante nell’eziologia e nella fisiopatologia dei sintomi della schizofrenia, attraverso gli effetti di citochine proinfiammatorie come l’IL-1β. I datteri Ajwa sono una delle modalità non farmacologiche con proprietà antinfiammatorie e antiossidanti. Tuttavia, gli studi clinici sono ancora limitati nell’esplorare il ruolo dei datteri Ajwa come adiuvanti nella gestione della schizofrenia. Obiettivo. Determinare l’effetto della terapia adiuvante con datteri Ajwa sul miglioramento dei sintomi clinici e dei livelli sierici di IL-1β nei pazienti schizofrenici, oltre a determinare la correlazione tra sintomi clinici e livelli sierici di IL-1β. Metodi. Studio quasi sperimentale con selezione casuale dei gruppi utilizzando un metodo in singolo cieco. Il numero di soggetti era 60, suddivisi in un gruppo di trattamento che ha ricevuto risperidone 4-6 mg/die più 7 datteri Ajwa/die per 8 settimane e un gruppo di controllo che ha ricevuto solo risperidone. Il miglioramento dei sintomi clinici è stato valutato utilizzando la scala PANSS, e i livelli sierici di IL-1β sono stati misurati nella prima settimana (basale) e nell’ottava settimana, con immunodosaggio enzimatico. Risultati. Il miglioramento dei sintomi clinici è stato osservato nel gruppo di trattamento. Una significativa diminuzione dei livelli sierici di IL-1β è stata osservata in entrambi i gruppi dopo 8 settimane di terapia, ma il gruppo di trattamento ha mostrato una diminuzione maggiore rispetto al gruppo di controllo. È stata riscontrata una correlazione significativa tra il miglioramento dei sintomi positivi e dei sintomi psicopatologici generali con una diminuzione dei livelli sierici di IL-1β nel gruppo di trattamento. Conclusioni. I datteri Ajwa hanno un effetto adiuvante nel migliorare i sintomi clinici e ridurre i livelli sierici di IL-1β grazie alle loro proprietà antinfiammatorie nei pazienti schizofrenici sottoposti a terapia con risperidone.

Parole chiave. Datteri Ajwa, IL-1β, PANSS, risperidone, schizofrenia.

Introduction

Schizophrenia is a debilitating psychiatric disease characterized by three symptom domains (positive, negative, and cognitive) and has important public health implications. Various sources claim it affects up to 1% of the population1. According to the WHO, approximately 24 million people globally have schizophrenia, which is equivalent to 1 out of every 300 individuals (0.32%) around the world2.

While genetic susceptibility and early environmental stressors are essential in the onset of schizophrenia, inflammation is rather regarded as a core causative/contributing/mediating factor in schizophrenia onset. Thus, disruptions within the immune system and its complex interplay with the nervous system may play a part in the pathogenesis and pathophysiology of schizophrenia3.

According to the available meta-analytical data, one of the proposed models of pathogenesis are the disturbances in the relative balance between pro-inflammatory cytokines, like interleukin-6 or interleukin-1β, and anti-inflammatory cytokines like interleukin-10. Interleukin-1β (IL-1β) is secreted primarily by monocytes, macrophages, microglia, and lymphocytes in response to lipopolysaccharide (LPS), other cytokines, and complement fragments and is considered one of the key pro-inflammatory cytokines. Peripheral IL-1β levels correlate with the severity of positive and negative symptoms as well as the overall psychopathological picture4.

Risperidone is a benzisoxazole-derived atypical antipsychotic. The mechanism of action of antipsychotics is blocking the dopamine D2 receptors and serotonin 5HT2A receptors, leading to the modulation of serotonin and dopamine levels on four dopamine pathways in the brain. It has been shown to be effective in reducing a variety of positive and negative symptoms in people with schizophrenia, and it also has fewer extrapyramidal side effects5.

Ajwa dates are a food ingredient that has spiritual value for Muslims. Their comprehensive nutritional profile contributes to the biological effects of Ajwa dates within the human body (both macronutrients and micronutrients appear in them), offering innumerable health benefits as a result6. Based on a phytochemical study, Ajwa dates are reported to contain phenolic compounds and flavonoids in the flesh and pits that exhibit potent antioxidant activity and have favorable preventive effects on human health. Ajwa dates have strong antioxidant, anti-inflammatory, anti-mutagenic, hepatoprotective, nephroprotective, and anti-cancer potentials that have been confirmed through preclinical studies7. Other studies emphasize the role of Ajwa dates as a natural antioxidant fruit that, by reducing oxidative stress, lipid peroxidation, apoptosis and the release of pro-inflammatory cytokines, may offer protection against many diseases. This may be due to the bioactive compounds found in Ajwa dates, which may include anti-inflammatory compounds8.

Various studies in Indonesia related to Ajwa dates as an adjuvant, to assess their health benefits, have been extensively conducted. Among them, in 2019, Royani et al.6 conducted a study on 40 pregnant women at risk of preeclampsia due to preeclampsia risk factors. The participants were divided into an intervention and control group. The intervention group consumed seven Ajwa dates every morning for eight consecutive weeks. Results showed significantly diminished preeclampsia progression, evidenced by reduction of MAP, ROT and sFlt-1/PlGF ratios. The separate quasi-experimental study of Azizah9 evaluated the effect of Ajwa dates’ consumption on prostaglandin levels during childbirth in pregnant females from gestational week 28 to delivery; the study also included an intervention and control group. This study shows that the consumption of Ajwa dates can stimulate prostaglandin levels during labor, affecting the duration of the latent and active phases. Mulyadi et al.10 indicated that administering an adjuvant therapy of seven Ajwa dates daily for a period of eight weeks in the intervention group resulted in a notable difference when compared to the control group. Specifically, in participants of the intervention group, the reduction in anti-Müllerian hormone they generated was less significantly than it was for participants in the control group. This study shows that the research subjects, perimenopausal women aged 42-48 who regularly consume Ajwa dates experience a slower decline in anti-Müllerian hormone compared to women who do not consume them6. However, to the best of this study’s knowledge, this is the initial research on the adjunctive use of Ajwa dates in schizophrenia patients.

Therefore, this study aims to explore the effect of risperidone therapy and Ajwa dates adjuvant therapy on improving clinical symptoms in schizophrenia patients, as well as to understand its impact on decreasing IL-1β levels as a marker of inflammation. Thus, this study is expected to provide new insights into the holistic management of schizophrenia and improve the well-being of patients affected by this disease.

Research methods

A quasi-experimental study using a pre- and post-test design of randomly selected groups with a single-blind method was performed. This research was conducted from June to August 2024 at the Dadi Makassar Regional Mental Hospital, South Sulawesi, Indonesia. Inclusion criteria were as follows: a diagnosis of schizophrenia based on the ICD-10 criteria, aged between 20 and 45 years, the onset of the illness less than five years prior, a PANSS-EC score of <15 (participants who had moved beyond the acute phase of their illness), and willingness to participate in the study. Subjects were hospitalized schizophrenia patients treated with risperidone (4-6 mg/day). Consecutive sampling is used to select patients who match the research requirements until the necessary sample size is reached, with a minimum sample size of 30 subjects per group. The exclusion criteria are having physical comorbidities, having a history of drug consumption before being hospitalized, and using anti-inflammatory, antioxidant and antibiotic drugs. Those classified as dropouts from the study were individuals who 1) did not consume Ajwa dates and/or risperidone regularly, or 2) withdrew from the study, or 3) pass away. Measurements on variables were carried out before and after the intervention. The PANSS score was used to evaluate clinical symptoms. Analyses of the IL-1β serum levels were based on blood tests using an enzyme-linked immunosorbent assay (ELISA) kit entitled “Human Interleukin 1β, IL-1β ELISA Kit Cat No E0143Hu” which was issued by Bioassay Technology Laboratory; the samples were subsequently dispatched to a laboratory for examination.

The medical history of all eligible participants was recorded. Subjects were divided into two groups; the treatment group received risperidone combined with seven Ajwa dates (60-65 grams) as adjuvant treatment, whereas the control group received only risperidone. Clinical symptoms were assessed using the PANSS score at baseline and during weeks 2, 4, 6, and 8; serum IL-1β levels were examined at both baseline and week 8. Statistical result was done by SPSS version 24.0 and Microsoft Excel software.

The Biomedical Research Ethics Committee in Humans of the Faculty of Medicine, Hasanuddin University, granted ethical approval for this research. We obtained informed consent from participants and their families and maintained confidentiality.

Results

A total of 73 subjects were found to meet the inclusion criteria in this investigation. These participants were divided into two groups, namely the treatment and control groups. However, during the observation process, 13 subjects experienced dropout; observation/subjects were sent home, underwent changes in antipsychotic therapy, or were irregular in taking medication, leading to their exclusion from the research subjects.

It was sought to make the observation with 60 subjects, which included those who were randomized into two groups: the treatment group consisting of 30 subject who were given risperidone therapy (4-6 mg/day) and Ajwa dates as adjunt treatment (7 pieces/day or 60-65 g/day) in the morning, and the control group consisting of the other 30 subject who received risperidone therapy (4-6 mg/day) only. The observation period was defined as 8 weeks. All of the partisipant were male and had been symptomatic with the disease for under five years. Table 1 outlines a comparison of participant characteristics between both groups.




No significant differences were found between the treatment group and control group regarding participant characteristics including age, education level, occupation, and marital status. All outcome from homogeneity test of all variables showed that character of participant in both groups are homogenous (p>0.05).

The PANSS scores were assessed at baseline and at weeks 2, 4, 6 and 8 for both groups. Serum IL-1β levels were also measured before (baseline) and after at week 8. Based on Table 2, there is no difference in the mean baseline total PANSS scores between the two groups (p>0.05). However, the two groups differed significantly in mean baseline positive symptom scores (p=0.001) and general psychopathology scores (p=0.011).




Patients in the treatment group showed a significant decrease in baseline serum IL-1β from 804.35 pg/ml to 572.62 pg/ml by week 8. The control group had baseline and week 8 values of 776.55 pg/ml and 616.08 pg/ml, respectively. Serum IL-1β levels did not differ significantly between groups at baseline or at week 8 (baseline p=0.591; week 8 p=0.341), but significant differences were observed within each group across the study period from baseline to week 8 (p=0.001). Moreover, total PANSS scores, positive symptoms, negative symptoms, and general psychopathology also showed significant differences from baseline to weeks 2, 4, 6, and 8 for each group as well (p=0.001).

Incremental analysis and comparison for PANSS total, positive, negative and general sub-scores as shown in table 3, significant differences were observed based on mean differences graphic estimates in PANSS total and its constituent sub-scales between the groups (p<0.05) between baseline, week 2, 4, 6 and 8.




On comparison of both groups using the Mann Whitney test, significant differences were found between mean decrease in total PANSS scores and positive and negative symptom scores at baseline, week 2, week 4, week 6, and week 8 (p<0.05). There were no differences on general psychopathology scores, although a trend for reduction was found, the treatment group had a significantly greater reduction in total PANSS or a reduction in their clinical symptoms compared to the control group, with the largest reduction occurred during week six of treatment.

The evaluation of clinical symptom improvement was calculated as percentage decreases in total PANSS scores: a decrease of 56.18% (corresponding to significant improvement) occurred in the treatment group while the corresponding figure for the control group was 46.01% (corresponding to much improvement). After eight weeks, there was a substantial difference in mean serum IL-1β levels reduction between both groups (271.73 pg/ml vs. 160. 47 pg/ml; p=0.010), showing that the treatment group’s mean decrease of serum IL-1β levels was superior to that of control group after week eight (table 3 and figure 2).







This study investigated the correlation between serum levels of IL-1β and clinical manifestations of schizophrenia in risperidone-treated patients with Ajwa date therapy.

Table 4 displays the results of the correlation tests performed with both Pearson and Spearman methods, which show:

– a strong positive correlation between total PANSS scores, positive symptoms, and general psychopathology, as well as a moderate correlation of negative symptoms with serum IL-1β levels at baseline in the significant treatment group;




– a moderate positive correlation between total PANSS scores, positive symptoms, and general psychopathology with serum IL-1β levels at baseline in the significant control group;

– a moderate positive correlation between total PANSS scores and positive symptoms with serum IL-1β levels at week 8 in the significant treatment group;

– a moderate positive correlation between the decrease in positive symptom scores from baseline week to week 8 and the decrease in serum IL-1β levels from baseline to week 8 in the significant treatment group;

– a weak positive correlation between the decrease in general psychopathology scores from baseline week to week 8 and the decrease in serum IL-1β levels from baseline to week 8 in the significant treatment group.

The correlations detected between the total PANSS score, positive symptoms, negative symptoms, and general psychopathology with serum IL-1β levels (baseline and week 8) indicate that improvement of these clinical scores is correlated with disminution of serum IL-1β levels in both groups.

Discussion

Characteristics of the research subjects

The mean age of subjects was 30.83±7.14 years in the treatment group and 33.53±7.53 years in the control group, with a predominance of males. As schizophrenia is commonly diagnosed from late teens through early thirties (with a later onset in females than males - late teens to early twenties for males and early twenties to early thirties age for females), this finding aligns with the known age of diagnosis. Cognitive and interpersonal relationship alterations may start earlier, resulting in a proper diagnosis being determined after some years11,12. A global meta-analysis of 192 epidemiological studies in 2021 estimated the mean age of onset of schizophrenia for the general population to be between 25-27 years13. This study only included male participants, as male cases are considerably higher than the number of female cases at the investigating hospital for temporary hospitalization.

The treatment and control groups were almost matched in education levels among schizophrenia patients in this study, as they were available. The high school completion rate was the most common highest educational attainment in both the treatment and control group (53.3% and 63.3%, respectively). This study is in line with previous research on the sociodemographic characteristics of schizophrenia patients in Cyprus, which also found the highest prevalence at the high school education level14.

This is different from studies that show individuals who do not complete elementary school, receive low education, and have low academic achievement associated with a higher risk of schizophrenia in the future15. Overall, people with schizophrenia are less likely to reach higher education than those who do not have the condition. Furthermore, academic failure before the age of 16 could represent cognitive risk, which contributes to the propensity for subsequent schizophrenia later in the educational trajectory16.

Employment status: 76.7% of participants in the treatment group were employed, versus 66.7% in the control. This is in contrast to a long tradition of findings indicating that people with schizophrenia have considerable impairments related to work capacity, i.e. high rates of unemployment or abandonment of jobs. In a study, the duration of work for individuals with schizophrenia before the onset was higher compared to after the onset of schizophrenia. Several factors that may play a role in the work function of patients with schizophrenia are poor neurocognitive function, problems with interpersonal or social functioning, symptoms such as paranoia or anhedonia, rejection of previous jobs, stigmatization, discrimination, and poor motivation17.

Looking at marital status shows that the two groups are pretty balanced: 80% of patients in the treatment group were married, versus 70% in the control group. This differs from previous studies, which indicated that unmarried or single schizophrenia subjects were more prevalent compared to those who were married or had partners.

Functional impairments of schizophrenia have extended to social roles, including marriage, even during clinical remission, and schizophrenia has been associated with higher divorce rates and greater marital discord. However, some studies indicate that marriage may act as a protective factor against schizophrenia18.

Comparison of PANSS scores and clinical symptom improvement between the treatment and control groups

All subjects in this study received risperidone at a dose of 4-6 mg, daily in both groups.

This was shown by decreased values of PANSS score [total PANSS, positive symptoms, negative symptoms, and general psychopathology] from baseline measurements to weeks 2, 4, 6, and 8. Risperidone therapy significantly improved the PANSS scores for both positive and negative schizophrenia symptoms, indicating clinical symptomatology improvement. The attenuation of positive symptoms induced by risperidone treatment is thought to occur largely due to the blockade of D2 receptors in the mesolimbic pathway. Additionally, the antipsychotic’s effectiveness at inhibiting D2 receptors in the prefrontal cortex and nucleus accumbens is also implicated in alleviating schizophrenia-related symptomatology19. Moreover, this antipsychotic has significant antagonist activity at serotonin 5-HT2 receptors that could be implicated in alleviating negative symptoms of schizophrenia20. In general, risperidone addresses well the positive and negative aspects of schizophrenia5.

Analysis of total PANSS scores recorded at 6 and 8 weeks revealed significantly lower average scores (indicating better clinical outcomes) from participants receiving adjuvant Ajwa date therapy. This was also seen in positive symptoms at week 6, negative symptoms at weeks 4, 6, and 8, and general psychopathology at week 2. In addition, the decline in total PANSS (excepting general psychopathology) and positive and negative symptoms scores from baseline to weeks 2, 4, 6, and 8 were much more evident; their total PANSS scores showed a similar decrease, implying an improvement in clinical symptom management. This study demonstrated that Ajwa dates adjuvant therapy for 8 weeks was effective in ameliorating clinical symptoms in schizophrenia patients, as suggested by the decreased total PANSS scores and improved positive, negative symptoms, and general psychopathology.

Zhang et al.21 investigated Ajwa dates for their antioxidant and anti-inflammatory activities via different extraction methods, including hexane, ethyl acetate, methanol, and water, using MTT antioxidant assays as well as lipid peroxidation inhibition (LPO) and cyclooxygenase enzyme inhibition (COX-1 and COX-2). It was thereby concluded that via flavonoid glycosides, Ajwa dates act as an antioxidant, inhibiting lipid peroxidation and stimulating nitric oxide production, and about COX-1 and COX-2, it was found that COX-1 inhibition obtained from Ajwa is comparable to aspirin and COX-1 inhibition obtained from Ajwa is similar to naproxen. The adjuvant therapy of Ajwa dates has a positive impact on the improvement of clinical symptoms in schizophrenia patients, presumably through anti-inflammatory effects, as neuroinflammation is known to be a major contributor to the occurrence of schizophrenia.

Comparison of serum IL-1β levels between treatment and control groups

The imbalance of the immune system observed in schizophrenia and related psychosis is highly diverse and overlapping, involving many immune components22. Neuroinflammation following activation of microglia has been proposed as a mechanism behind psychosis, while the increase of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, is aggravated by the reduced levels of anti-inflammatory cytokines like IL-10, creating a synergistic relationship. Neuroinflammation can cause high levels of kynurenic acid with an increase in the production of quinolinic acid, increased oxidative stress, elevated levels of cortisol, decreased levels of serotonin; all of these factors can affect synaptic plasticity. These alterations are associated with the emergence of positive symptoms, negative symptoms, cognitive deficits, neurodegeneration, and neurodevelopmental disorders22. A meta-analysis study showed that IL-1β levels increased in first-episode psychotic cases and relapse cases, making it a potential marker for schizophrenia conditions. Subsequent meta-analyses indicated that IL-1β levels increased in first-episode psychotic cases, relapse cases, and chronic schizophrenia cases23-25.

Dopamine expression release patterns could be altered by IL-1β to exert direct effects on dopaminergic neurons. Several pro-inflammatory cytokines have been known to cause oxidative stress and neuroinflammation, affecting dopamine synthesis, storage, and release mechanisms in dopaminergic neurons. IL-1β causes indentation of microglia to increase indoleamine-2,3-dioxygenase (IDO) by the NMDA receptor, ultimately inducing QUIN Quinolinic acid, which causes glutaminergic excitotoxicity. QUIN-induced over-stimulation is associated with NMDA receptor-mediated neurotoxic dysfunction of glutamate neurotransmission, which can lead to glutamatergic hyperactivity in pheno-typical regions of the frontal cortex, returning directly to typical gross hallmarks of alcoholism with schizophrenia disorders. Moreover, changes in glutamate-mediated transmission, particularly as they relate to subcortical GABAergic outputs, could lead to elevated dopamine release from mesolimbic output pathways, leading to the hallucinatory/delusional features observed during psychotic episodes. In addition, IL-1β may affect the hypothalamic-pituitary-adrenal (HPA) axis, controlling stress responses, which may cause cortisol secretion, compromising the generalized functions of dopaminergic systems26.

In our study, the average serum IL-1β levels in the treatment group at baseline week were 804.35 pg/ml and decreased to 572.62 pg/ml by week 8. In the control group, the average serum IL-1β levels at baseline week were 776.55 pg/ml and decreased to 616.08 pg/ml by week 8. It appears that the decrease in average serum IL-1β levels was greater in the treatment group compared to the control group (271.73 pg/ml vs 160.47 pg/ml, p=0.010). Supporting these findings Song et al.27 examined changes taking place in pro-inflammatories (IL-1β, IL-6 and TNF-α) over a period of six months of risperidone treatment: significant decrease was noted in second week (48.02±16.00pg/ml, p<0.01), fourth week (44.70±16.63 pg/ml, p<0.001), as latter recognised eighth week reflect gradual rise again approaching initial levels, once again indicating long term trends depicted previously where chronic treatment appears hitches rises which are apparently impacted as result the side-effects profil antipsychotic medications (most notably atypicals)27. The difference in the serum IL-1β levels measured in this study compared in the Song et al.27 study is due to the different ELISA cytokine IL-1β test kits used.

The decrease in serum IL-1β levels seen could be explained by the fact that both groups received antipsychotic medication. In both treatment and control groups, risperidone was given at the therapeutic set dose of 4-6 mg/day. For weeks 1-8 post-treatment of typical or atypical (risperidone) antipsychotics, there is an apparent decrease in IL-1β levels. But in the long run, those levels, compared with baseline measurements, might go up or plateau. The corresponding increase of IL-1β but not another proinflammatory cytokine that is a common denominator, namely TNF-α might also be consistent with established adverse side effects of antipsychotic medications especially atypical ones, which after several months, produce features of metabolic syndrome in these patients whereby IL-1β has also been known to be elevated in such metabolic syndrome affected patients28.

One study revealed that in microglia stimulated with IFN-ϒ, risperidone significantly and dose-dependently downregulated nitric oxide (NO), reduced the expression of inducible nitric oxide synthase (iNOS), and decreased the expression of other inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. The methodologies used were the Griess test, Western blotting, and ELISA. The results showed that risperidone significantly inhibits nitric oxide release and IL-1β, IL-6, and TNF-α production from IFN-ϒ-stimulated microglia29. The better reduction of serum IL-1β levels in the treatment group indicates the influence of Ajwa date adjuvant. Ajwa dates have advantages over other date varieties in chemical composition due to their high concentrations of essential minerals, vitamins, and fiber, making them highly nutritious for humans30. Research conducted demonstrates a significant presence of total phenolics, with Ajwa Al Madinah in its concentration merits registering up to 22.11 mg/100 g. Phenolic compounds in predominant derivatives were gallic acid, p-coumaric acid, and ferulic acid. Gallic acid, or as most often called 3,4,5-trihydroxybenzoic acid, is a phenolic compound. Such a substance is characterized by the ability to reduce free radicals, exhibit anti-inflammatory, anti-mutagenic, and histochemical movement. However, the flavonoid composition of the Ajwa date fruit is comprised of phytochemicals, including quercetin, luteolin, apigenin, isoquercitrin, and rutin. Ajwa Al Madinah, in particular, reflects a higher flavonoid amount (2.78 mg per 100 g), being the second highest31. As an anti-inflammatory agent, quercetin reduces the permeability of the capillaries by inhibiting hyaluronidase and inhibiting activities of cyclooxygenase and lipoxygenase32.

Ajwa dates contain a large amount of amino acids-lysine (7.3 mol/g), tyrosine (65 mol/g), and glycine (0.80 mol/g)31. L-lysine was found neuroprotective against intracranial hemorrhage in both in vitro and in vivo animal models. This effect might be related to its ability to inhibit the release of proinflammatory cytokines like TNF-α, IL-1β, and IL-633.

In neuroinflammation, NF-κB is known to be involved in the response of most cells to mediation by a wide array of external stimuli, including cytokines, stressors, ultraviolet light, antigen stimulation, and heavy metals. Previous research has suggested a role for the NF-κB signaling pathway in various physiological and pathological mechanisms. These mechanisms encompass immune responses, inflammation, cell survival and proliferation, metabolism, synaptic plasticity, and memory-related processes. In inflammatory conditions, the NF-κB pathway is profoundly activated, leading to the overexpression of inflammation-relevant genes. In addition to its roles mediating the development and activation of T and B cells, adaptive immunity is also impacted through NF-κB’s control over pro-inflammatory cytokine production. Once immune cells are infected or injured, NF-κB is activated and signals the production of multiple pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. These cytokines can trigger an inflammatory response and attract more immune cells to deal with pathogens or heal damaged tissue. In addition, NF-κB plays a pivotal role in mediating immune regulation in adaptive immunity34.

Lipid peroxidase and NF-kB are transcription factors that play an important role in the inflammatory process. Natural agents are good NF-kB inhibitors and anti-inflammatory agents. Plant-derived compounds like phenolics and flavonoids have been shown to reduce inflammation significantly in previous studies. Dates are known to have an important anti-inflammatory role. Recent studies on Ajwa dates indicate that their extracts, prepared with ethyl acetate, methanol, and water, are able to inhibit the lipid peroxidation of COX-1 and COX-2 cyclooxygenase enzymes35. The content of phenolic compounds, flavonoids, and amino acids in Ajwa dates, known to have anti-inflammatory activity, may contribute to the decrease in pro-inflammatory cytokine levels of IL-1β observed in this study.

Correlation of PANSS scores with serum IL-1β Levels between treatment and control groups

In our study, we found a positive correlation between serum IL-1β levels and total PANSS scores and positive as well as negative symptoms and general psychopathology, at both baseline and after 8 weeks in our investigation. Both treatment and control groups showed a decrease in total PANSS score with a significant reduction in positive (p=0.008), negative (p=0.019) symptoms, and general psychopathology scores (p=0.001). Serum IL-1β levels decreased in both treatment and control groups. In particular, in the treatment group, the change in positive symptoms and general psychopathology scores strongly correlated (p<0.05) with the baseline to week 8 change in IL-1β serum levels.

The concentration of cytokines in the body correlates with the course of the disease and the severity of symptoms. Meta-analysis data have shown increased serum inflammatory cytokines, such as IL-1β, in patients with schizophrenia. Our result is in line with the positive relationship that was found between IL-1β levels and positive symptoms and total PANSS score28. This is in line with what is shown in this study. Positive symptoms include delusions, disorganized thinking, hallucinations, agitated behavior, grandiosity, paranoia or persecution, and hostility. Negative symptoms include flat affect, emotional withdrawal, poverty of rapport, difficulty in abstract thinking, lack of spontaneity, and stereotyped thought and speech.

Our results are in agreement with those reported by Noto et al.36, who reported a strong association between the level of IL-1β and PANSS scores, with a correlation coefficient of 0.374 and a p-value of 0.023. This indicates that increased IL-1β levels may be associated with an increase in symptom severity in schizophrenia patients.

Unlike our previous reporting of the comparatively less prominent associations between serum IL-1β levels and levels of general psychopathology relative to total PANSS scores or levels of individual symptomatologies (general psychopathology contains syndromes involving somatic concerns, anxiety disorders, guilt feelings, tension states, mannerisms/posturing tendencies, depressive episodes, motor retardation problems, uncooperativeness traits accompanied by atypical thought contents or disorientation problems) have here an association with elevated serum IL-1β levels. The general psychopathology scale is considered an addition to the assessment of positive and negative syndromes because it provides a separate yet parallel measure of the severity of schizophrenia that can serve as a reference point for interpreting positive and negative scores. The general psychopathology scale is usually not assessed individually but measured in total scores37.

This is in contrast to previous studies that showed relationships between certain inflammatory cytokines and general psychopathological measures in patients with schizophrenia. For example, IL-3 levels appeared to correlate positively with the general psychopathology subscale in patients treated for a long time, but not in FEDN schizophrenia3. Moreover, general psychopathology scores were positively correlated with IL-23 and TGF-β1 levels28. Further studies have shown that levels of IL-10 in the periphery correlate positively with negative symptoms and attention impairment and negatively with cognitive impairment4.

Other studies imply a negative correlation, noting that increased serum IL-1β levels across schizophrenia patients may positively link to milder psychopathological syndromes (r=-0.353, p value=0.026)38. Unlike our study, which showed a significant positive correlation between the decrease in the general psychopathology score and the decrease in serum IL-1β levels in the treatment group (r=0.380, p value=0.039).

Such a decrease of interleukin 1 beta (IL-1β), however, might be one of the inflammatory markers linked to schizophrenia pathophysiology that could contribute to the modulation of the clinical signs of the schizophrenia patients who were involved in the study reported here. As IL-1β is a central point in initiating an inflammatory response, which may modulate cerebral function resulting in symptomatic manifestations, its reduction could reduce inflammation, possibly leading to better clinical outcomes39. The correlation between IL-1β and schizophrenia symptoms is very complex and can be influenced by various factors, including antipsychotic treatment, disease stage, and different sociodemographic characteristics of patients (gender, smoking, body mass index, and education or socioeconomic status), all of which have been shown to be associated with changes in inflammatory molecules. Therefore, further research is needed to fully understand the mechanisms underlying this relationship and how IL-1β can influence the course and treatment of schizophrenia23,28.

This study found a correlation between total PANSS score (positive, negative, and general psychopathology) and IL-1β levels during the baseline week (week before the start of therapy) in the treatment and control groups. Such an association remained but was less strong by week 8. This is in accordance with the study done by Song et al.27, which investigated fluctuations in the levels of pro-inflammatory cytokines (serum IL-1β, IL-6, and TNF-α) in patients suffering their first episode of schizophrenia receiving therapy with risperidone. Results showed a significant decrease in serum IL-1β from weeks 2 to 4, with levels returning to baseline by the end of the 6-month period. This occurs due to the anti-inflammatory properties of the antipsychotic medication risperidone. Prolonged use of this drug may lead to a range of side effects, including weight gain and obesity, which are significantly associated with heightened production of pro-inflammatory cytokines and ongoing inflammation27. Thus, although there was clinical improvement marked by a decrease in PANSS scores at week 8, it is suspected that serum IL-1β levels may increase again as a side effect of risperidone.

Research limitation

This study has several limitations. The brief study period and difficulties in recruiting patients with schizophrenia resulted in a small sample size. It used a single-blind design, which may have led to potential biases. There was no placebo-controlled group. Ajwa dates might have had a direct or indirect effect on schizophrenia, for example, by increasing the efficacy of risperidone. Since the patients were drawn from a single hospital, the conclusions of this study might not be relevant for individuals with various socioeconomic features or those treated at other Indonesian hospitals. The measurement of serum IL-1β levels was only conducted at baseline and week 8, the observation duration was short at only 8 weeks, and the biomarker examined was only the pro-inflammatory cytokine IL-1β without examining oxidative stress level biomarkers.

Conclusions

Ajwa dates can be adjuvantively given to schizophrenia patients receiving risperidone treatment to obtain improved clinical symptoms, such as positive symptoms, negative symptoms, and general psychopathology. Serum IL-1β levels show a negative correlation with PANSS scores in both groups. Moreover, serum IL-1β was reduced, associated with improved positive symptoms and general psychopathology in the Ajwa date adjuvant therapy group. Further studies should examine the capacity of Ajwa date adjuvants and perform serial serum IL-1β levels to compare the activity of these adjuvants in reducing pro-inflammatory cytokines over time. A larger sample size and a longer study duration (>8 weeks) are needed to visualize patterns regarding changes in serum IL-1β levels. Additionally, measuring oxidative stress levels will help measure the antioxidant power of Ajwa dates in alleviating clinical symptoms in patients with schizophrenia.

Acknowledgements: the study was supported by the Department of Psychiatry, Faculty of Medicine, Hasanuddin University, and we would also like to thank the Faculty of Medicine, Hasanuddin University, which has provided grant funding for this research. All errors and omissions are our own.

This study was funded by the Faculty of Medicine, Hasanuddin University, through a collaborative research grant, as stated in Decision Number: 3260/UN4.6/KEP/2024.

Conflict of interests: the authors have no conflict of interests to declare.

Ethics committee approval: this study was approved by the Biomedical Research on Humans Ethics Committee of the Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia. Based on recommendation letter Number: 476/UN4.6.4.5.31/PP36/2024 with protocol number: UH24050357.

Author contribution statements. Saidah Syamsuddin: conceptualization, formal analysis, investigation, methodology, data curation and writing the manuscript; Firdaus: administration, writing the manuscript; Erlyn Limoa: conceptualization, writing-original draft; Irfan Idris: conceptualization, investigation, formal analysis, writing the manuscript; Sonny Teddy Lisal: writing the manuscript and methodology. All authors read and approved the final version of the manuscript.

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