Open access peer-reviewed chapter
Descriptive statistics of the studied parameters.
Abstract
The molecular explanation for the changes in pain perception in schizophrenia lies in nerve inflammation. The decrease in inositol, mainly localized in glial cells, can support these changes. There are also significant alterations in the viability and functioning of neurons, which are linked to a significant reduction of N-acetyl-aspartate (NAA). Our study demonstrates significantly increased myo-inositol levels in the anterior and posterior cingulate cortex. An increase in the myo-inositol/sum of the creatinine and phosphocreatinine (Cr + PCr) ratio and NAA levels additionally supports the notion of inositol’s beneficial impact on brain metabolism and neuronal integrity, which is particularly relevant to schizophrenia’s neurodegenerative changes. However, varying NAA/Cr + PCr ratios indicate a complex interaction between the brain’s inositol level and energy metabolism or neurochemical balance. These findings highlight inositol’s potential role in modulating neurochemical profiles in schizophrenia. Furthermore, high inositol levels are linked to significant reductions in trauma-related symptoms in schizophrenia, as indicated by the International Trauma Questionnaire and the Child Trauma Questionnaire. Inositol’s potential to mitigate trauma effects, and enhance social functioning and its multifaceted role in schizophrenia, offers a promising avenue for further research into its therapeutic applications.
Keywords
- pain perception
- myo-inositol
- negative symptoms
- schizophrenia
- precision psychiatry
1. Introduction
Globally, pain presents a significant challenge, affecting approximately 20% of adults, with 10% each year diagnosed with chronic pain. Pain manifests in various forms, including acute, chronic, and intermittent, or a mix of these. Chronic pain, in particular, is a profound source of distress, disrupting daily activities and often leading to significant suffering [1].
Pain is recognized as a multifaceted phenomenon, integrating the complex interplay of neuroanatomy and neurochemistry with cognitive and emotional mechanisms [2, 3].
The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [4]. Pain is a subjective experience shaped significantly by biological, psychological, and societal influences.
The experience of pain varies greatly in its intensity, nature, and duration. Pain transcends mere symptoms, and chronic pain is acknowledged as a distinct medical condition with its own unique developmental course and clinical features [5]. People’s pain perception thresholds vary significantly, making it challenging to accurately predict the level of injury that will cause pain [6].
Meta-analyses have elucidated that individuals with psychosis generally exhibit a lower pain sensitivity compared to those in the general population [7]. The recognition of reduced pain sensitivity in schizophrenia dates back to the foundational psychiatric studies by Bleuler and Kraepelin in the early twentieth century [8, 9]. Originally, Kraepelin described Dementia Praecox, noting that such patients could endure burns from cigarettes and tolerate needle punctures or wounds without typical adaptive responses. Bleuler, who coined the term “schizophrenia” for Kraepelin’s Dementia Praecox, made similar findings about reduced pain responses to harmful stimuli on the body or skin of these individuals.
A significant number of case reports and series have documented that individuals with schizophrenia exhibit a lower sensitivity to pain, a phenomenon that often confounds clinicians, especially when these patients fail to report pain despite having painful physical conditions [10, 11]. Studies have consistently shown that this demographic is prone to a higher incidence of physical health issues that are typically painful, such as fractures [12], diabetes [13], cancer [14], and cardiovascular diseases [15]. This paradoxical situation underscores the complex relationship between schizophrenia and pain perception. About 40% of individuals with schizophrenia experiencing clinical pain did not communicate their pain to a healthcare provider [16].
These meta-analyses reveal a general trend toward diminished pain sensitivity in schizophrenia, yet findings are not uniform [7, 10]. Some studies suggest that individuals with schizophrenia perceive pain similarly to the general population [17, 18], while others observe an increased sensitivity to acute pain but a decreased sensitivity to prolonged, chronic pain [19]. Additionally, it has been revealed that schizophrenia patients may actually be hypersensitive to pain induction compared to healthy controls, suggesting that their apparent hypoalgesia may stem more from a reduced tendency to report pain rather than a decreased perception of pain itself [17].
Research has shown that one in three individuals with psychosis indicates experiencing pain that is clinically significant. Furthermore, the existence of pain has been identified as an indicator of a reduced quality of life related to health in those with psychosis [20].
The explanation for the altered perception of pain in schizophrenia may be related to described neuro-metabolic changes involving significant differences in levels of neuron-glia activation. Reduced pain sensations in schizophrenia may be associated with decreased levels of anterior cingulate cortex (ACC) myo-inositol (compared to controls) [21] linked to astrocyte activation, among other factors such as the lack of response to conventional antipsychotic medications [22]. Conversely, decreased levels of N-acetylaspartate (NAA), most likely reflect a neuronal process supported by myo-inositol, which reflects a characteristic neurometabolic process characterizing the mutual interactions of neuron-glia in altered pain perception. Insensitivity to pain in schizophrenia is a complex phenomenon. Impairment of cognitive function and an excess of negative symptoms can strongly influence the expression of pain by patients with schizophrenia [23]. Chronic pain in the context of schizophrenia presents a complex issue, combining neurobiological dysfunction with manifesting psychotic symptoms. Understanding this phenomenon requires considering the role of N-methyl-D-aspartate (NMDA) receptors and the intricate interactions between Src kinase and neuregulin 1 (NRG1) signaling and its ErbB4 receptors [24]. The phenomenon of excessive NRG1-ErbB4 signaling, genetically associated with the positive symptoms of this disease, may lead to the suppression of physiological enhancement of NMDA receptor function by Src, resulting in NMDAR hypofunction [25, 26, 27, 28, 29]. Such a state may serve as the basis for many psychopathological symptoms characteristic of schizophrenia, including cognitive impairments and hallucinations, and may also contribute to the occurrence of chronic pain by disrupting the adequate processing of pain signals. Excessive NRG1-ErbB4 signaling, through the suppression of Src activity and NMDA receptor regulation, may lead to the persistence of pain states by disrupting adaptive pain mechanisms, thus contributing to the chronic nature of pain in schizophrenia [24].
The altered perception of pain underlies many theories regarding suicide [30]. In the case of individuals attempting suicide, “interoceptive numbness” has been demonstrated, characterized by increased tolerance for aversive experiences and decreased awareness of non-aversive sensations. Hence, blunted interoception may be associated with suicidal behaviors [31]. Researchers have always tried to understand the motivations of suicide victims, however, our current scientific knowledge about the factors contributing to suicidal behaviors and the increasing number of suicides each year are insufficient [32].
Based on the International Suicide Prevention Guidelines (InterSePT) in schizophrenia, factors that may contribute to reducing suicidal tendencies include improvement of positive and negative symptoms, reduction of extrapyramidal side effects (EPS), direct antidepressant effects, improvement of cognitive function, and strict adherence to recommendations [33].
It is hypothesized that the phenomenon of altered pain perception in schizophrenia may be intricately associated with neurochemical imbalances within the brain, specifically a diminution in myo-inositol levels in the anterior cingulate cortex and decreased levels of NAA. This reduction, alongside myo-inositol’s critical function in modulating glial cell volume amid neuroinflammatory events, might underpin the unique sensory processing aberrations observed in this condition. Consequently, it is further postulated that therapeutic strategies aimed at rectifying these neurobiological discrepancies, particularly through the administration of inositol, could not only ameliorate the aberrant pain perception but also confer wider benefits. These could potentially encompass the alleviation of associated affective disturbances and an enhancement in the overall functioning of individuals with schizophrenia, thereby suggesting a broader scope of inositol’s therapeutic efficacy.
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2. The aim of the study
The extent to which myo-inositol levels in the anterior cingulate cortex correlate with hematologic and neurochemical markers as well as with psychometric assessments, thus contributing to understanding of the neurobiological basis of psychiatric conditions primarily related to changes in pain perception in patients with schizophrenia.
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Y = g - 1 ( β 0 + β 1 · X 1 + β 2 · X 2 + … + β k · X k + ε ) , E = h - 1 ( α 0 + α 1 · Z 1 + α 2 · Z 2 + … + α m · Z m ) ,
3. Material and methods
This endeavor sought to determine the extent to which myo-inositol levels correlate with hematological and neurochemical markers, as well as with psychometric assessments, thereby contributing to a more integrated understanding of the neurobiological underpinnings of psychiatric conditions, mainly associated with changes in pain sensation.
3.1 Participants
Clinical assessment and recruitment of study participants were carried out at the Clinical Department of Adult, Child, and Adolescent Psychiatry at the University Hospital in Krakow, Poland. Diagnosis of schizophrenia (code F20 according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems, ICD-10), confirmed by two psychiatrists, was the inclusion criterion for participants in the research [34, 35]. The Positive and Negative Syndrome Scale (PANSS) was used for evaluation of symptomatology and severity of disease [36]. Study participants, in age ranging from 13 to 40 years, provided written consent for the research procedures. In the case of study participants under the age of 18, consent was signed by legal guardians. Study participants were inpatients. Duration of the disease ranged from 2 months to 2 years. The research was approved by Jagiellonian University Bioethics Committee: 1072.6120.252.2021 and 1072.6120.178.2022.
The study’s exclusion criteria include a lot of aspects. Excluded were participants with limited legal capacity, intellectual disabilities and under court-ordered treatment. Individuals with insulin resistance, diabetes, metabolic syndrome, severe cardiovascular diseases, or a history of central nervous system disorders were not included in the study. Additionally, taking specific medications, such as clozapine treatment within the last 3 months before the study, recent use (within 3 days before the study) of non-steroidal anti-inflammatory drugs, corticosteroids, vitamin supplements, antibiotics, probiotics, antioxidants, psychoactive, narcotic substances, and changes or modifications of antipsychotic treatment within 12 weeks before the study, were also exclusion criteria. Furthermore, ineligible were also individuals with substance dependence (diagnosed according to ICD-10) and participants with alcohol or substance abuse (excluding tobacco) within 3 months before the study. Hyperactivity, psychomotor agitation, intense affective symptoms, pregnancy, breastfeeding, inability to remain in a supine position (due to spinal deformity), severe claustrophobia, the presence of pacemakers, cochlear implants, neurostimulators, drug delivery pumps or other implanted electronic devices, vascular clips, artificial heart valves, metallic orthopedic implants such as screws, artificial joints, stabilizers, and wires, were encompassed as exclusion criteria. Grounds for exclusion were also metallic foreign bodies like iron filings or other metal instrumentation which are contraindicated in magnetic resonance techniques. The criterion for exclusion was age ≤ 13 and ≥ 40 years. Excluded were also participants without a diagnosis by a psychiatrist according to ICD-10.
The control group embraced 45 healthy volunteers, aged between 13 and 40 years, and with an equal gender distribution. These participants, based on the ICD-10 criteria, did not have a diagnosis of schizophrenia or other mental disorders.
The General Health Questionnaire-28 (GHQ-28) [37, 38], used for detecting possible mental disorders and emotional distress in general population, was completed by all participants [39]. The Global Assessment of Functioning (GAF) [40] (Axis V in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, DSM-IV-TR) was conducted for assessment of current social, occupational and mental functioning [41]. The Gastrointestinal Symptom Rating Scale (GSRS) was used to evaluate gastrointestinal symptoms [42, 43]. The Beck Depression Inventory (BDI-II) [44], the State and Trait Anxiety Inventory (STAI) [45], and the Experiences in Close Relationships-Revised Short (ECR-RS), were completed by all participants in order to assess attachment styles on the two dimensions of anxiety and avoidance in close relationships [46, 47]. The Traumatic Experiences Checklist (TEC) [48] was also conducted to self-assessment of potentially traumatic experiences in childhood and adulthood and to reflect the number of potentially adverse and traumatic events in life.
3.2 Treatment
Pharmacological treatment of schizophrenia patients was conducted in accordance with the guidelines of the American Psychiatric Association. Medications were received by patients in oral (p.o.) and intramuscular (i.m.) forms. Antipsychotic medications include perazine, levomepromazine, chlorpromazine, aripiprazole, risperidone, cariprazine, lurasidone, haloperidol, olanzapine, zuclopenthixol, amisulpride and quetiapine. One of the study participants was not prescribed any medications. Eight of the patients were on monotherapy, and the remainder 42 were undergoing polytherapy. Dose conversion of antipsychotics was based on the methods described by Davis and Chen (2004) [49], or Andreasen et al. (2010) [50], and conducted using chlorpromazine equivalent dose (CPZE). In the case of amisulpride the daily dose was determined using the WHOCC—ATC/DDD Index, 2023 [51]. Additionally, as recommended by Leucht et al. (2016), lurasidone was administered to seven study participants [52].
3.3 Blood collection for routine laboratory tests
From both patients and healthy volunteers, blood for comprehensive laboratory tests was collected in the morning, after overnight rest, an 8-h fasting period and in the case of chronic medications, before medication intake. These laboratory examinations included complete blood count, serum creatinine concentration, uric acid, ionogram (K+, Na+, Mg2+), lipid profile (low-density lipoprotein, high-density lipoprotein, LDL and HDL; total cholesterol, TC and triglycerides, TG), alanine aminotransferase (ALT) activity, glucose, insulin, HOMA-IR index, inflammatory markers (high-sensitivity C-reactive protein, hsCRP), complement components C3 and C4, thyroid function tests (free triiodothyronine, FT3, free thyroxine, FT4, and thyroid-stimulating hormone, TSH), as well as antibodies against thyroid peroxidase (anti-TPO), serum ferritin level and adrenal parameter assessment (dehydroepiandrosterone sulfate, DHEA-S).
Analyses were performed with using automated analyzers, in the laboratory of the University Hospital in Krakow. The University Hospital laboratory in Krakow, in accordance with standards for medical diagnostic laboratories, undergoes daily internal and systematic external quality control.
3.4 Magnetic resonance techniques
Magnetic resonance examinations were performed in the Diagnostic Imaging Department at the University Hospital in Krakow, Poland.
The determined metabolites were: Creatine (Cr 3.02 and 3.9 ppm), Phosphocreatine (PCr 3.02 ppm and 3.93 ppm), L-Alanine (Ala 1.48 ppm), Aspartate (Asp 3.8 ppm), Glutamine (Gln 2.45 and 3.7 ppm), Glutamate (Glu 2.1 and 3.7 ppm), Glucose (Glc 3.43 and 3.8 ppm), γ-aminobutyric acid (GABA 2.3 ppm), Phosphocholine (PCh 4.2 ppm), Glycerophosphocholine (GPC 3.6 ppm), Glutathione (GSH 3.7 ppm), N-Acetylaspartate (NAA 2.02 ppm), N-Acetylaspartylglutamate (NAAG 4.1 ppm), L-Lactate (Lac 1.33 ppm), myo-Inositol (Ins 3.6 ppm), scyllo-Inositol (Scyllo 3.35 ppm), Taurine (Tau 3.42 ppm), macromolecule (MM09 0.9 ppm, MM12 1.2 ppm, MM14 1.4 ppm, MM17 1.7 ppm, MM20 2.0 ppm) and Lipids (Lip09 0.9 ppm, Lip13a and Lip13b 1.3 ppm, Lip20 2.0 ppm). Calculated were concentrations of the sums of individual metabolites: Cr + PCr, Glu + Gln, NAA + NAAG, GPC + PCh, Lip13a + Lip13b, MM20 + Lip20, MM09 + Lip09, MM14 + Lip13a + Lip13b + MM12. The ratios of every metabolite to the sum of creatine and phosphocreatine were also calculated, e. g. NAA/(Cr + PCr). The MRS results were subjected to both qualitative and quantitative analysis.
Quality control was carried out in relation to the signal-to-noise ratio and to width of the spectral lines.
3.5 Statistical analysis
For the analysis presented, the threshold for statistical significance was set at an alpha level of 0.05. This means that results with p-values less than or equal to 0.05 were considered statistically significant, indicating a less than 5% probability that the observed effects were due to chance.
Descriptive statistics such as central tendency (mean, median), variability (standard deviation), positioning (the first and third quartiles), and extreme values (minimum and maximum), were employed to characterize the distributions of the parameters under study. These statistical measures provide a comprehensive summary of the dataset, aiding in the interpretation of the results and offering valuable insights into the underlying distribution and characteristics of the studied clinical parameters. This statistical approach ensures that the results are not only assessed for significance but also thoroughly described in terms of their distributional properties, which is essential for understanding the full context of the findings within the clinical research framework.
The investigation into the effects of inositol exposure on clinical outcomes was conducted using regression analyses that accounted for a set of critical covariates to ensure that the findings were adjusted for potential confounding variables. These covariates encompass demographic characteristics, specifically sex and age, which are fundamental factors known to influence clinical outcomes. Additionally, the analysis controlled for the variability in psychotropic medication dosages by standardizing them to chlorpromazine equivalents (further – CPZ equivalent), a common metric used to facilitate the comparison of antipsychotic drug potencies.
By including these covariates in the regression models, the analysis aimed to isolate the association between inositol exposure and the clinical outcomes from the effects of these other influential variables. This approach enhances the validity of the findings by reducing the likelihood that the observed associations are confounded by demographic differences or variations in psychotropic medication dosages. By doing so, it strengthens the inference that any significant associations uncovered between inositol exposure and the clinical outcomes are likely attributable to the effects of inositol itself, rather than extraneous factors.
3.5.1 Doubly robust generalized estimating equations (DGREE)
To mitigate the potential errors that might stem from incorrect model specifications, a doubly robust estimation approach was employed [53, 54, 55, 56]. This method relies on two separate models: one that predicts the outcome and another that estimates the exposure. The strength of this technique lies in its ability to provide unbiased estimates of the relationship between the exposure and the outcome, provided at least one of the two models is accurately specified — it is not required for both to be perfectly correct.
The generic equations for a doubly robust estimation are (1), (2):
Outcome model (structural model):
where
Exposure model:
where
The doubly robust estimation combines these two models, and it will yield unbiased estimates if either the outcome model or the exposure model is correctly specified. It does this by incorporating the predicted exposure (from the exposure model) and the observed exposure into the analysis of the outcome, thus adjusting for confounding factors and potential errors in model specification.
3.6 Characteristics of the studied cohort
In this study, we conducted a comprehensive analysis of a cohort consisting of 51 patients diagnosed with schizophrenia. The demographic breakdown of the cohort included 21 women, representing 41.2% of the sample, and 30 men, accounting for the remaining 58.8%.
The primary data metrics encompassed demographic profiles, hematological indices, neurochemical markers, and outcomes of standardized questionnaires. These variables were meticulously collated to furnish a descriptive summary. The aggregated data are methodically delineated in Table 1.
| Age, years | 51 | 27,71 | 9,36 | 30,00 | 18,00 | 35,50 | 14,00 | 46,00 |
| Chlorpromazine equivalent dose (100 mg CPZ equivalent) | 51 | 390.61 | 250.15 | 370.00 | 200.00 | 565.00 | 0.00 | 970.00 |
| WBC [×103/μL] | 51 | 7.42 | 2.30 | 6.93 | 5.74 | 8.45 | 3.55 | 14.03 |
| Neut, % | 51 | 60.31 | 16.17 | 58.50 | 52.05 | 65.40 | 37.70 | 79.7 |
| Lymphocyte count [×103/μL] | 51 | 2.15 | 0.66 | 2.24 | 1.60 | 2.60 | 0.71 | 3.52 |
| Myo-inositol [×10−6/μL], ACC ET 30,1 | 50 | 152.66 | 18.83 | 154.00 | 145.00 | 166.00 | 94.20 | 188.00 |
| Myo-inositol /cr + pcr, ACC TE 302 | 50 | 0.91 | 0.10 | 0.92 | 0.85 | 0.98 | 0.65 | 1.07 |
| NAA conc. [×10−6], ACC 30,3 | 50 | 200.14 | 21.47 | 199.00 | 185.00 | 213.25 | 138.00 | 244.00 |
| NAA /Cr + PCr, ACC 304 | 50 | 1.19 | 0.12 | 1.18 | 1.12 | 1.24 | 0.88 | 1.69 |
| Mio-inositol, ACC 1445 | 50 | 967.88 | 283.08 | 978.87 | 793.73 | 1107.50 | 437.34 | 2280.00 |
| Mio-inositol /Cr + PCr, AC 1446 | 50 | 0.98 | 0.26 | 0.94 | 0.86 | 1.11 | 0.45 | 2.24 |
| NAA, ACC 1447 | 50 | 1443.69 | 219.91 | 1440.00 | 1322.50 | 1557.50 | 888.31 | 2050.00 |
| NAA/Cr + PCr, ACC 1448 | 50 | 1.46 | 0.20 | 1.44 | 1.36 | 1.56 | 0.86 | 2.40 |
| Myo-inositol [×10−6], PCC 309 | 50 | 118.23 | 14.71 | 118.00 | 107.25 | 128.75 | 87.30 | 145.00 |
| Myo -inositol /Cr + Pcr, PCC 3010 | 50 | 0.85 | 0.09 | 0.85 | 0.80 | 0.90 | 0.65 | 1.09 |
| NAA conc. [×10−6], PCC 30 | 50 | 188.78 | 14.56 | 188.00 | 180.00 | 198.25 | 151.00 | 217.00 |
| NAA /Cr + PCr, PCC 30 | 50 | 1.36 | 0.13 | 1.34 | 1.27 | 1.46 | 1.06 | 1.64 |
| Myo-inositol, PCC 14411 | 50 | 680.54 | 170.02 | 663.08 | 564.07 | 775.42 | 372.01 | 1130.00 |
| Myo-inositol/Cr + PCr, PCC 14412 | 50 | 0.88 | 0.17 | 0.86 | 0.76 | 0.99 | 0.58 | 1.26 |
| NAA, PCC 144 | 50 | 1323.40 | 129.58 | 1325.00 | 1235.00 | 1415.00 | 1030.00 | 1580.00 |
| NAA/cr + pcr, PCC 144 | 50 | 1.73 | 0.17 | 1.73 | 1.61 | 1.87 | 1.35 | 2.03 |
| Positive symptoms score | 50 | 21.24 | 7.66 | 22.00 | 17.25 | 25.75 | 0.00 | 42.00 |
| Negative symptoms score | 50 | 20.72 | 7.32 | 23.00 | 16.25 | 25.75 | 0.00 | 33.00 |
| Disorganized speech score | 50 | 16.88 | 5.95 | 17.00 | 13.00 | 21.00 | 0.00 | 31.00 |
| Uncontrolled hostility/excitement score | 50 | 7.26 | 2.67 | 8.00 | 5.00 | 9.00 | 0.00 | 13.00 |
| Anxiety/depression score | 50 | 11.70 | 4.17 | 12.00 | 9.00 | 14.00 | 0.00 | 22.00 |
| Positive scale score | 50 | 17.84 | 6.32 | 19.00 | 14.00 | 22.00 | 0.00 | 33.00 |
| Negative scale score | 50 | 20.98 | 7.29 | 22.00 | 15.00 | 26.00 | 0.00 | 34.00 |
| General psychopathology scale score | 50 | 39.38 | 12.00 | 39.50 | 35.00 | 47.00 | 0.00 | 63.00 |
| Total score | 50 | 78.20 | 23.93 | 80.00 | 70.00 | 93.00 | 0.00 | 126.00 |
| Total score | 46 | 18.83 | 16.49 | 17.50 | 7.25 | 27.75 | 0.00 | 83.00 |
| Total score | 50 | 51.28 | 24.53 | 54.00 | 31.00 | 69.50 | 6.00 | 93.00 |
| Total score | 50 | 8.58 | 6.26 | 6.50 | 4.00 | 11.00 | 0.00 | 22.00 |
| Total score | 46 | 18.76 | 14.28 | 18.50 | 5.25 | 29.00 | 0.00 | 51.00 |
| Task-oriented coping scale score | 39 | 49.77 | 10.51 | 48.00 | 43.00 | 56.00 | 27.00 | 73.00 |
| Emotion-oriented coping scale score | 39 | 47.87 | 12.18 | 45.00 | 37.50 | 57.50 | 26.00 | 75.00 |
| Avoidance-oriented coping scale score | 39 | 44.23 | 8.51 | 44.00 | 39.00 | 50.00 | 23.00 | 61.00 |
| Distraction scale score | 39 | 20.46 | 5.64 | 21.00 | 18.00 | 24.00 | 2.00 | 30.00 |
| Social diversion scale score | 39 | 14.97 | 4.36 | 15.00 | 12.00 | 17.50 | 6.00 | 25.00 |
| Total score | 39 | 141.87 | 19.87 | 143.00 | 128.00 | 155.00 | 100.00 | 181.00 |
| Reexperiencing trauma score | 42 | 2.88 | 2.20 | 3.00 | 1.00 | 5.00 | 0.00 | 8.00 |
| Avoidance score | 42 | 3.74 | 2.52 | 4.00 | 2.00 | 6.00 | 0.00 | 8.00 |
| Threat score | 42 | 3.98 | 2.41 | 4.00 | 2.00 | 6.00 | 0.00 | 8.00 |
| Affective dysregulation score | 42 | 4.00 | 2.13 | 4.00 | 2.00 | 5.00 | 0.00 | 8.00 |
| Negative self-concept score | 42 | 3.93 | 2.82 | 4.00 | 2.00 | 6.00 | 0.00 | 8.00 |
| Disturbance relationships score | 42 | 3.98 | 2.57 | 4.00 | 2.00 | 6.00 | 0.00 | 8.00 |
| PTSDFI score | 42 | 5.93 | 3.90 | 6.00 | 3.00 | 9.00 | 0.00 | 12.00 |
| DSOFI score | 42 | 5.60 | 3.77 | 5.00 | 2.25 | 9.00 | 0.00 | 12.00 |
| PTSD score | 42 | 10.60 | 6.34 | 11.00 | 6.00 | 15.00 | 0.00 | 24.00 |
| DSO score | 42 | 11.71 | 7.05 | 10.50 | 6.50 | 18.75 | 0.00 | 24.00 |
| Total score | 42 | 33.83 | 18.06 | 31.50 | 21.50 | 48.75 | 0.00 | 71.00 |
| Emotional abuse score | 42 | 11.38 | 5.01 | 10.00 | 8.00 | 14.00 | 5.00 | 24.00 |
| Physical abuse score | 42 | 6.50 | 2.50 | 5.00 | 5.00 | 7.00 | 5.00 | 16.00 |
| Sexual abuse score | 42 | 6.64 | 2.68 | 6.00 | 5.00 | 6.00 | 5.00 | 15.00 |
| Emotional neglect score | 42 | 11.67 | 5.05 | 11.00 | 7.25 | 14.00 | 5.00 | 23.00 |
| Physical neglect score | 42 | 8.26 | 2.88 | 8.00 | 6.00 | 9.00 | 5.00 | 16.00 |
| Denial (minimization/denial) score | 42 | 9.12 | 2.47 | 9.00 | 7.00 | 11.00 | 3.00 | 13.00 |
| Total score | 42 | 66.45 | 16.67 | 64.00 | 53.25 | 76.00 | 43.00 | 105.00 |
Table 1.
The myo-inositol concentration in anterior cingulate cortex (ACC) at echo time (ET) 30 ms [×10−6/μL]).
The myo-inositol to Creatine and Phosphocreatine Ratio in ACC at TE 30 ms.
The concentration of N-acetylaspartate in the ACC at an ET of 30 ms.
The ratio of N-acetylaspartate to the sum of creatine and phosphocreatine in the ACC at an ET of 30 ms.
The concentration of myo-inositol in the ACC, potentially modulated by insulin, measured at an ET of 144 ms.
The ratio of insulin levels to creatine and phosphocreatine in the ACC at an ET of 144 ms.
The concentration of N-acetylaspartate in the ACC measured at an ET of 144 ms.
The ratio of N-acetylaspartate to the sum of creatine and phosphocreatine in the ACC at an ET of 144 ms.
The concentration of myo-inositol adjusted for insulin levels in the posterior cingulate cortex (PCC) at an echo time of 30 ms.
The ratio of myo-inositol to creatine and phosphocreatine adjusted for insulin levels in the PCC at an ET of 30 ms.
The concentration of myo-inositol in the PCC that adjusted by insulin, measured at an ET of 144 ms.
The ratios of myo-inositol to the sum of creatine and phosphocreatine in the PCC, measured at an ET of 144 ms.
3.6.1 Demographic
The data reflect a mean age within the late twenties, indicative of a patient cohort in which schizophrenia typically manifests, considering the peak onset of the disorder often occurs in early adulthood. Variability in age is moderate and encompasses both the prodromal phase of late adolescence and the established phase in middle adulthood.
3.6.2 Hematological measurements and drugs intake
Dosing of antipsychotics, expressed in chlorpromazine equivalents, reveals a wide distribution, suggesting a heterogeneity in the clinical presentation and severity of the disorder within the cohort, necessitating a broad range of pharmacotherapeutic interventions. This variance also implies potential differences in treatment response or tolerability, given the considerable spread in dosages required to achieve therapeutic effects or manage side effects.
The white blood cell count is within the normal reference range for the majority, which is reassuring as it indicates no widespread hematological impact that could be attributed to the chronic use of antipsychotic medications, which are known to sometimes cause agranulocytosis. However, the range does indicate that a few patients may be experiencing leukopenia or leukocytosis.
Neutrophil percentages sit within expected values for a non-acute cohort but do exhibit variability, potentially reflective of individual responses to stress, infection, or pharmacological effects. The absence of extremely high values mitigates concern for neutrophilia which could indicate acute infection or a severe stress response.
Lymphocyte counts are consistent and fall within normal limits, suggesting stable immunological profiles within the group. The lack of significant outliers in lymphocyte counts may indicate that the cohort, on the whole, is not experiencing acute immunological challenges or significant adverse effects from medication that would manifest in lymphocyte levels.
3.6.3 Neurochemical measurements
The neurochemical profile of the cohort provides data on the metabolic environment of the ACC and PCC, two regions implicated in the pathophysiology of schizophrenia. Myo-inositol levels and NAA concentrations, alongside their ratios to creatine and phosphocreatine (Cr + PCr), offer a window into neuronal health and glial activity, both of which are pertinent to the neuropsychiatric context.
Elevated myo-inositol levels, a putative glial marker, might suggest glial proliferation or altered glial function, which is consistent with neuroinflammatory hypotheses of schizophrenia. The mean myo-inositol levels in the ACC and PCC fall within a range that does not immediately indicate pronounced glial pathology, yet variability in these levels may correlate with individual differences in disease manifestation or progression.
The NAA concentration serves as an indirect marker of neuronal integrity and function, with aberrations often reflecting neuronal loss or dysfunction. The mean NAA levels in both ACC and PCC are within normal ranges but again reveal individual variability. The standard deviations and range of values intimate that subgroups within the cohort may exhibit neurochemical signatures of neuronal compromise.
Ratios of myo-inositol and NAA to Cr + PCr are critical in standardizing these metabolite concentrations against a relatively stable reference, which mitigates inter-individual and instrumental variability. The reported mean ratios are suggestive of preserved metabolic homeostasis in the context of schizophrenia, though the breadth of the data indicates a spectrum of neurochemical states within the cohort.
The extended echo time (TE) of 144 ms compared to the standard TE of 30 ms provides an enhanced specificity in the metabolite resonance and suggests a more robust signal for myo-inositol and NAA. The discrepancies in metabolite concentrations and ratios at different echo times may reflect the complex interplay of relaxation times and signal-to-noise ratios inherent to magnetic resonance spectroscopy.
3.6.4 PANSS questionnaire
Positive symptoms, characterized by the presence of psychopathology such as hallucinations, delusions, and disorganized thought processes, exhibited a mean score that suggests a moderate level of severity across the cohort. The range and standard deviation indicate substantial heterogeneity in the presentation of positive symptoms, with some individuals experiencing minimal symptomatology while others may be grappling with severe manifestations.
Negative symptoms, which reflect deficits such as blunted affect, social withdrawal, and anhedonia, also show a moderate mean score with variability comparable to that of positive symptoms. The breadth of negative symptom scores underscores the diverse impact of schizophrenia on emotional responsiveness and social functioning, which are crucial determinants of long-term outcomes and functional capacity.
Disorganized speech is a cardinal feature of schizophrenia, indicative of formal thought disorder. The scores here suggest a modest mean level of disorganization, which could impact communication and cognitive coherence. The range of scores points to the presence of subgroups within the cohort with varying degrees of communicative and cognitive disruption.
Uncontrolled hostility and excitement are less prevalent than other symptom domains, as reflected by the lower mean score.
Anxiety and depression, which can be secondary to the core symptomatology or intrinsic to the schizophrenia spectrum, present with a lower mean score relative to other symptom domains but are non-negligible.
The positive and negative scale scores, which are composite measures, corroborate the individual symptom domain scores, with the negative scale scores slightly exceeding the positive scale scores on average. This suggests that the negative symptoms may be more prominent or persistent in the cohort studied, which aligns with clinical understanding that negative symptoms are often more resistant to current pharmacotherapies and predictive of poorer functional outcomes.
General psychopathology scores, which encompass a wider range of symptoms such as guilt feelings, tension, and active social avoidance, are the highest among the domains. This reflects the broad impact of schizophrenia beyond the core symptom clusters of positive and negative symptoms, highlighting the complex interplay of affective, cognitive, and behavioral components in this disorder.
The total PANSS score, encompassing the spectrum of symptomatology, demonstrates considerable variability, indicative of the heterogeneity inherent in schizophrenia. The mean total score suggests a moderate to severe overall symptom burden, with implications for global functioning and prognosis.
3.6.5 Gastrointestinal symptoms
The gastrointestinal (GI) symptomatology in the cohort, as reflected by the descriptive statistics, suggests a varied presentation with a mean score that may be indicative of mild to moderate distress. The wide range in scores, extending to a maximum of 83, denotes that while some patients experience minimal GI complaints, others may suffer from severe symptoms.
3.6.6 SANS questionnaire
Turning to the Scale for the Assessment of Negative Symptoms (SANS), the mean total score suggests a moderate level of negative symptom burden. This scale measures affective flattening, alogia, avolition, anhedonia, and attentional impairment, which are core features of schizophrenia and have substantial implications for social and occupational functioning. The relatively high standard deviation indicates a diverse expression of negative symptoms within the cohort.
3.6.7 Calgary questionnaire
The Calgary Depression Scale for Schizophrenia (CDSS) is specifically designed to assess depressive symptoms in the context of schizophrenia, distinguishing them from negative and extrapyramidal symptoms. The mean score here is indicative of mild depressive symptoms, although the range of scores suggests that some patients may experience more pronounced depressive features.
3.6.8 BDI-II questionnaire
The Beck Depression Inventory-II (BDI-II) is a self-report inventory that measures the severity of depression. The mean score in the cohort suggests mild to moderate depression, while the range of scores implies that the severity of depressive symptoms is highly variable among patients.
3.6.9 CISS questionnaire
The cohort’s responses to the Coping Inventory for Stressful Situations (CISS) questionnaire offer a comprehensive overview of coping strategies employed in the face of stress. The data elucidate the predilection toward task-oriented, emotion-oriented, and avoidance-oriented coping mechanisms, including subcategories such as distraction and social diversion.
Task-oriented coping emerges as a moderately utilized strategy with the mean score leaning toward the upper half of the available range. This suggests a general tendency within the cohort to adopt an active and problem-focused approach when managing stress. Given the relatively moderate standard deviation, the cohort exhibits a semblance of uniformity in this coping style, though individual variations are present.
Emotion-oriented coping, with a mean score closely aligned with that of task-oriented coping, indicates a comparable reliance on internal processes characterized by emotional expression, rumination, and self-blame in response to stress. The broader range and higher standard deviation suggest a greater diversity in the use of emotion-oriented strategies, which may reflect variance in emotional self-awareness and regulation skills.
Avoidance-oriented coping, which includes distraction and social diversion, is engaged to a lesser extent than task-oriented and emotion-oriented strategies. The mean scores for these scales indicate a tendency within the cohort to sometimes defer confrontation with stressors, either by engaging in alternative activities (distraction) or seeking solace in social interactions (social diversion). The standard deviations in these scales are lower, implying a more homogenous use of avoidance strategies among the individuals.
The total score, representing the cumulative coping effort across all domains, falls within the upper mid-range of the scale. This cumulative score suggests that the cohort actively engages with stress, utilizing a repertoire of coping strategies. The range of total scores, however, indicates that while some individuals exhibit a robust and versatile coping profile, others may have a less adaptive approach, possibly indicating vulnerability to stress-related psychopathology or the need for interventions to enhance coping efficacy.
3.6.10 ITQ questionnaire
The clinical data derived from the International Trauma Questionnaire (ITQ) reflect a cohort’s trauma-related psychopathology with a particular emphasis on Post-Traumatic Stress Disorder (PTSD) and complex PTSD (C-PTSD), as operationalized by scores on reexperiencing, avoidance, threat, affective dysregulation, negative self-concept, and disturbance in relationships.
Reexperiencing trauma scores indicate a lower mean relative to other ITQ subscales, suggesting that while the involuntary and distressing reliving of traumatic events is present, it is not the most dominant symptom across the cohort.
The avoidance scores are slightly higher, implying that the behavioral or cognitive efforts to evade trauma-related stimuli are a more pronounced response among the individuals assessed.
Threat perception, a cardinal symptom of PTSD reflecting heightened arousal and reactivity, is slightly more severe on average than reexperiencing or avoidance symptoms.
Affective dysregulation, emblematic of C-PTSD, presents with the highest mean score among the ITQ subscales, which are at the upper limit of the lower half of the scale, indicating emotional responses that are not adequately modulated.
Negative self-concept encapsulates feelings of worthlessness and a persistent negative belief about oneself, which is marked by a mean score that is indicative of a moderate level of severity.
Disturbances in relationships, quantified by similar mean scores to negative self-concept, reflect the impairment in forming and maintaining close relationships, often due to pervasive distrust and a preoccupation with the possibility of betrayal.
The PTSDFI and DSOFI scores highlight the differentiation between PTSD and its dissociative subtype, a form of the disorder where symptoms of depersonalization and derealization are prominent. The means of these scores suggest a moderate expression of these symptoms within the cohort, with a range indicating variability in the severity of dissociative experiences and the functional impairment they entail.
The PTSD score, which may encompass both DSM-5 PTSD symptom clusters and C-PTSD features, shows that on average, individuals experience moderate levels of PTSD symptoms. The range, however, suggests that some individuals may exhibit minimal symptoms while others have severe PTSD symptomatology.
The DSO score, representing the dissociative subtype of PTSD, has a slightly higher mean than the PTSD score, suggesting that dissociative symptoms may be particularly salient in studied cohort. This is clinically significant as the dissociative subtype often requires specialized treatment approaches.
The total score, which amalgamates the symptomatology across the PTSD and C-PTSD spectrum, indicates a moderate to severe level of trauma-related psychopathology in the cohort. The wide range of total scores reflects the heterogeneity in the severity of trauma-related symptoms among individuals.
3.6.11 CTQ questionnaire
The Child Trauma Questionnaire (CTQ) scores from the presented data offer a quantifiable measure of childhood maltreatment across different domains, including emotional abuse, physical abuse, sexual abuse, emotional neglect, physical neglect, and a minimization/denial dimension.
Emotional abuse scores indicate a mean slightly above the median, with a non-negligible standard deviation, suggesting variability in the cohort’s experiences of emotional abuse during childhood. The range of scores indicates that while some individuals report low levels of emotional abuse, others have experienced higher levels, which could correlate with a greater risk for emotional dysregulation and disorders such as depression and anxiety.
Physical abuse scores are notably lower than emotional abuse scores, with a tighter range and lower standard deviation, indicating more homogeneity in experiences of physical abuse within the cohort.
Sexual abuse scores are similar to physical abuse, with a mean close to the median, suggesting that instances of sexual abuse within this cohort are relatively consistent, though the range indicates that experiences do vary among individuals.
Emotional neglect scores have a mean that is slightly above the median, with a range indicating a spread of experiences within the cohort.
Physical neglect scores, representing the failure to provide basic physical needs, show lower mean and median values relative to emotional neglect, yet with a range that reveals some individuals experienced higher levels of neglect.
The denial score, which reflects minimization or denial of maltreatment, exhibits a mean close to the median and a relatively low standard deviation, suggesting a commonality in the cohort’s tendency to minimize or deny the impact of childhood trauma.
The total CTQ score, which aggregates the different forms of maltreatment, reflects a moderate mean value with a broad range of scores.
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4. Results
SeeTable 2.
| WBC [×103/μL] | 50 | 1.21 × 10−3 | 2.45 × 10−3 | −0.50 | 0.620 |
| Neut % | 50 | 0.19 × 10−3 | 1.53 × 10−3 | 0.12 | 0.903 |
| Lymphocyte count [×103/μL] | 50 | −2.23 × 10−3 | 2.30 × 10−3 | −0.97 | 0.330 |
| Myo-inositol /Cr + PCr, ACC TE 30 | 50 | 3.94 × 10−3 | 0.57 × 10–3− | 6.87 | |
| NAA conc. ACC 30, [×10−6] | 50 | 1.26 × 10−3 | 0.48 × 10–3− | 2.62 | |
| NAA /Cr + PCr ACC 30 | 50 | −1.72 × 10−3 | 0.64 × 10–3− | −2.71 | |
| Myo-inositol, ACC 144 | 50 | 7.23 × 10−3 | 1.60 × 10−3 | 4.52 | |
| Mio-inositol /Cr + PCr, AC 144 | 50 | 4.23 × 10−3 | 1.85 × 10−3 | 2.29 | |
| NAA, ACC 144 | 50 | 1.43 × 10−3 | 0.83 × 10−3 | 1.72 | 0.085 |
| NAA/Cr + PCr, ACC 144 | 50 | −1.41 × 10−3 | 0.84 × 10−3 | −1.67 | 0.095 |
| Myo-inositol [×10−6], PCC 30 | 50 | 2.70 × 10−3 | 0.77 × 10−3 | 3.52 | |
| Myo-inositol /Cr + PCr, PCC 30 | 50 | 2.47 × 10−3 | 0.61 × 10−3 | 4.03 | |
| NAA conc. [×10−6], PCC 30 | 50 | 0.78 × 10−3 | 0.35 × 10−3 | 2.20 | |
| NAA /Cr + PCr, PCC 30 | 50 | 0.51 × 10−3 | 0.78 × 10−3 | 0.65 | 0.513 |
| Myo-inositol, PCC 144 | 50 | 0.46 × 10−3 | 2.08 × 10−3 | 0.22 | 0.824 |
| Myo-inositol/Cr + PCr, PCC 144 | 50 | 7.65 × 10−6 | 1.69 × 10−3 | 0.01 | 0.996 |
| NAA, PCC 144 | 50 | 1.23 × 10−3 | 0.40 × 10−3 | 3.09 | 0.002 |
| NAA/Cr + PCr, PCC 144 | 50 | 0.63 × 10−3 | 0.69 × 10−3 | 0.92 | 0.356 |
| Total score | 45 | −5.80 × 10−3 | 5.02 × 10−3 | −1.16 | 0.248 |
| positive symptoms score | 49 | 0.79 × 10−3 | 3.12 × 10−3 | 0.25 | 0.801 |
| negative symptoms score | 49 | −0.94 × 10−3 | 2.43 × 10−3 | −0.39 | 0.700 |
| disorganized speech score | 49 | −0.75 × 10−3 | 3.47 × 10−3 | 0.22 | 0.830 |
| uncontrolled hostility/excitement score | 49 | 0.71 × 10−3 | 3.56 × 10−3 | 0.20 | 0.842 |
| anxiety/depression score | 49 | −1.36 × 10−3 | 3.22 × 10−3 | −0.42 | 0.672 |
| positive scale score | 49 | 1.76 × 10−3 | 2.93 × 10−3 | 0.60 | 0.547 |
| negative scale score | 49 | −1.28 × 10−3 | 2.62 × 10−3 | −0.49 | 0.625 |
| general psychopathology scale score | 49 | −0.24 × 10−3 | 3.10 × 10−3 | −0.08 | 0.938 |
| total score | 49 | −0.67 × 10−6 | 2.77 × 10−3 | −0.02 | 0.981 |
| Total score | 49 | −1.87 × 10−3 | 4.08 × 10−3 | −0.46 | 0.646 |
| Total score | 49 | −2.94 × 10−3 | 7.31 × 10−3 | −0.40 | 0.687 |
| Total score | 45 | −11.37 × 10−3 | 6.05 × 10−3 | −1.88 | 0.060 |
| Task-oriented coping scale score | 39 | 2.47 × 10−3 | 1.96 × 10−3 | 1.26 | 0.208 |
| Emotion-oriented coping scale score | 39 | −2.52 × 10−3 | 1.87 × 10−3 | −1.35 | 0.179 |
| Avoidance-oriented coping scale score | 39 | 0.51 × 10−3 | 1.22 × 10−3 | 0.42 | 0.677 |
| Distraction scale score | 39 | −2.82 × 10−3 | 2.15 × 10−3 | −1.31 | 0.191 |
| Social diversion scale score | 39 | 3.05 × 10−3 | 1.89 × 10−3 | 1.61 | 0.108 |
| Total score | 39 | 0.24 × 10−3 | 0.96 × 10−3 | 0.25 | 0.805 |
| Reexperiencing trauma score | 41 | −12.66 × 10−3 | 7.62 × 10−3 | −1.66 | 0.097 |
| Avoidance score | 41 | −11.16 × 10−3 | 4.93 × 10−3 | −2.26 | |
| Threat score | 41 | −3.01 × 10−3 | 4.63 × 10−3 | −0.65 | 0.516 |
| Affective dysregulation score | 41 | −6.24 × 10−3 | 4.11 × 10−3 | −1.52 | 0.129 |
| Negative self-concept score | 41 | −12.25 × 10−3 | 6.55 × 10−3 | −1.87 | 0.061 |
| Disturbance relationships score | 41 | −9.67 × 10−3 | 4.59 × 10−3 | −2.11 | |
| PTSDFI score | 41 | −6.29 × 10−3 | 4.72 × 10−3 | −1.33 | 0.182 |
| DSOFI score | 41 | −7.23 × 10−3 | 4.52 × 10−3 | −1.60 | 0.109 |
| PTSD score | 41 | −8.33 × 10−3 | 4.28 × 10−3 | −1.95 | 0.051 |
| DSO score | 41 | −11.17 × 10−3 | 4.53 × 10−3 | −2.46 | |
| Total score | 41 | −8.62 × 10−3 | 3.40 × 10−3 | −2.54 | |
| Emotional abuse score | 41 | −6.79 × 10−3 | 2.77 × 10−3 | −2.45 | |
| Physical abuse score | 41 | −3.57 × 10−3 | 2.90 × 10−3 | −1.23 | 0.219 |
| Sexual abuse score | 41 | −4.59 × 10−3 | 3.37 × 10−3 | −1.36 | 0.173 |
| Emotional neglect score | 41 | −4.25 × 10−3 | 2.93 × 10−3 | −1.45 | 0.147 |
| Physical neglect score | 41 | −2.06 × 10−3 | 2.00 × 10−3 | −1.03 | 0.305 |
| Denial (minimization/denial) score | 41 | 1.56 × 10−3 | 1.89 × 10−3 | 0.83 | 0.409 |
| Total score | 41 | −2.43 × 10−3 | 1.79 × 10−3 | −1.36 | 0.174 |
Table 2.
Modulatory impact of brain inositol [Myo-inositol [×10−6/μL], ACC ET 30] on studied clinical outcome measures among a cohort of schizophrenic patients, adjusted for sex, age, and psychotropic medication dosage standardized to 100 mg chlorpromazine equivalents.
4.1 Hematological measurements
In the examination of inositol’s modulation within the ACC at a 30 ms ET on hematological parameters in schizophrenic patients, the statistical analysis reveals that none of the observed changes in white blood cell (WBC) count, neutrophil percentage (Neut %), or lymphocyte count reach statistical significance.
This could indicate that inositol’s therapeutic reach, if present, might be confined to the central nervous system without pronounced peripheral hematological effects, or there may be a lack of sensitivity in the current measurements to detect subtle changes.
4.2 Neurochemical measurements
The robust and statistically significant positive association between inositol exposure and myo-inositol levels in both the ACC and PCC at ET 30 ms, as evidenced by z-scores exceeding the critical threshold and
The myo-inositol/creatinine plus phosphocreatinine (Cr + PCr) ratio also demonstrates a significant increase in the PCC at ET 30 ms and in the ACC at both ET 30 ms and ET 144 ms. These findings further reinforce the notion that inositol exposure has a consistent impact on its relative concentration, perhaps indicating a compensatory or regulatory mechanism in cerebral metabolic processes that could be dysregulated in schizophrenia.
NAA, a surrogate marker for neuronal integrity and function, shows a significant increase in concentration in the PCC at ET 30 and 144 ms, as well as in the ACC at ET 30 ms, with corresponding p-values of 0.028, 0.002, and 0.009, respectively. These data suggest that inositol may have a beneficial effect on neuronal health or may indicate an upregulation of mitochondrial activity, which could be of substantial interest in the context of the neurodegenerative aspects of schizophrenia.
However, when assessing the ratios of NAA/Cr + PCr, results yield a more complex interpretation. In the ACC at ET 30 ms, there is a significant decrease in this ratio, as evidenced by
At ET 144 ms, both the NAA concentrations and ratios in the ACC, while showing positive beta coefficients, do not achieve statistical significance, suggesting that the effect of inositol may be time-dependent, or that the homeostatic mechanisms may equilibrate beyond the initial response period.
Clinically, these findings suggest that inositol has the potential to modulate neurochemical profiles in schizophrenia, particularly by increasing the availability of myo-inositol and possibly supporting neuronal integrity as indicated by changes in NAA levels. These neurochemical shifts could hypothetically translate into clinical improvements, given the association of myo-inositol with signaling pathways and NAA with neuronal health. However, the translation of these biochemical changes to clinical practice requires cautious interpretation and further validation through clinical trials assessing symptomatology and cognitive functions.
Additionally, these findings must be contextualized within the broader scope of schizophrenic pathophysiology, noting that the etiology of schizophrenia is multifactorial and the modulation of a single neurochemical parameter may not yield substantial therapeutic benefits in isolation. Further research should elucidate the implications of these neurochemical changes for the neurocognitive deficits and psychopathology inherent in schizophrenia.
4.3 Gastrointestinal symptoms, SANS, Calgary, and BDI-II questionnaires
While inositol appears to have a minimal impact on gastrointestinal, negative, and depressive symptoms in the studied schizophrenia cohort, it is essential to recognize the limitations of the current analysis. These include the relatively small sample size and the potential for idiosyncratic responses to inositol within the heterogeneous cohort of individuals with schizophrenia. Furthermore, the assessment tools used, although validated, may not capture subtle changes in symptomatology that could be clinically meaningful for patients.
4.4 PANSS questionnaire
The analysis suggests that inositol exposure does not lead to a notable amelioration in the positive symptoms of schizophrenia, which includes hallucinations and delusions, as evidenced by a positive beta coefficient that failed to reach statistical significance (
The subcomponent of uncontrolled hostility/excitement, indicative of the potential for agitation and aggression, also displayed insubstantial change post-inositol exposure (
When dissected into the positive and negative scale scores, again, no significant effects were observed. The positive scale score reflects the cumulative severity of the positive symptoms, and the data indicate no substantial response to inositol (
The general psychopathology scale score, which encompasses a broader range of symptoms including somatic concern, anxiety, guilt feelings, and active social avoidance, showed negligible change (
Lastly, the total PANSS score, which is a holistic measure of the overall symptom severity in schizophrenia, indicated no significant modulation by inositol exposure, as the negligible beta coefficient and very high p-value (
In drawing conclusions from this data, it is important to consider that while inositol’s neuromodulatory roles have been explored in various psychiatric conditions, this particular set of results does not support its efficacy in modifying the symptomatology of schizophrenia when assessed at a specific time point post-exposure. These findings should not negate the possible neurochemical benefits of inositol observed in other studies, but rather highlight the complexity of schizophrenia’s pathophysiology, where multiple interacting neurobiological pathways contribute to the manifestation of symptoms, and the therapeutic response can be highly individualized.
Furthermore, in considering the translation of these findings to clinical practice, one must weigh the absence of significant outcomes against the backdrop of extant treatment modalities for schizophrenia, which often involve antipsychotic medications with considerable side effect profiles.
4.5 CISS questionnaire
The numerical trends in the data suggest a nuanced modulation of coping strategies, albeit without reaching statistical significance across the different scales of coping measured. The task-oriented coping scale score shows a positive beta coefficient, suggesting a potential increase in task-focused coping strategies with inositol exposure, but the p = 0.208 indicates that this increase is not statistically significant.
Conversely, the emotion-oriented coping scale score indicates a negative beta coefficient, implying a possible decrease in emotion-focused coping strategies with inositol intervention. However, the statistical analysis yields a
The avoidance-oriented coping scale score, which encompasses strategies to divert attention from stressors, presents a very slight positive beta coefficient, yet this effect is statistically unsubstantial with a
The social diversion scale score, indicative of seeking social contact as a means of coping, shows a positive beta coefficient and the lowest p-value among the scales at 0.108. While this could suggest a tendency toward increased utilization of social diversion coping strategies with inositol exposure, the lack of statistical significance precludes definitive conclusions.
The total score for the CISS, which amalgamates the coping strategies into an overall assessment of coping effectiveness, shows an insignificant beta coefficient and a high p-value of 0.805. This further corroborates the lack of significant impact of inositol on coping mechanisms in studied cohort.
From a clinical and analytical standpoint, these findings suggest that inositol, within the parameters of this study, does not exert a significant modulatory effect on coping strategies as measured by the CISS in individuals with schizophrenia. The implications for clinical practice remain limited given the lack of statistical significance, yet the trends observed may inform future hypotheses and research directions.
4.6 ITQ questionnaire
The avoidance score, reflecting efforts to circumvent trauma-related thoughts or reminders, shows a statistically significant reduction in the case of highest inositol concentrations (
The disturbance in relationships score, indicative of impairments in forming and maintaining close relationships as a result of trauma, also presents a statistically significant decrease (p = 0.035), suggesting that inositol may confer benefits in enhancing social functioning and interpersonal relations among those afflicted with schizophrenia.
The DSO score, a cumulative measure of pervasive changes in affect regulation, self-concept, and relational difficulties, demonstrates a statistically significant decrement (
The total score, encapsulating the overall impact of trauma-related sequelae, shows a statistically significant reduction (
While the reexperiencing trauma score, affective dysregulation score, negative self-concept score, and PTSD score all exhibit negative β coefficients, suggesting a downward trend in symptomatology with inositol exposure, the lack of statistical significance precludes definitive assertions regarding their clinical relevance.
Notably, the threat score, which addresses hypervigilance and exaggerated startle response, and the PTSDFI and DSOFI scores, representing indices of PTSD and DSO respectively, do not indicate significant changes with inositol treatment. This underscores the multifaceted and heterogeneous nature of trauma-related disorders and the possibility that inositol’s efficacy may vary across different symptom clusters.
From a psychiatric perspective, these findings highlight a potential therapeutic niche for inositol in addressing specific facets of trauma-related psychopathology in schizophrenia, particularly avoidance behaviors and disturbances in relationships, which can profoundly affect the quality of life and functional outcomes. The data also suggest that inositol might contribute to improvements in the broader constellation of difficulties subsumed under DSO, warranting further research into its neuromodulatory effects within this domain.
4.7 CTQ questionnaire
Analyzing the data, the emotional abuse score exhibits a significant decrement with inositol exposure, as evidenced by a
While the other categories of abuse and neglect—physical abuse, sexual abuse, emotional neglect, and physical neglect—also demonstrate negative β coefficients, suggesting a trend toward symptom reduction with inositol, these results do not meet the threshold for statistical significance. Hence, while there is an indication of a potentially beneficial effect, these data do not provide robust support for the clinical efficacy of inositol in these domains of historical trauma within the schizophrenia cohort.
The denial score interestingly shows a positive β coefficient, although without statistical significance, indicating no substantial evidence for inositol’s impact on patients’ tendency to minimize or deny their traumatic experiences. This could imply that inositol does not influence the cognitive or psychological processes underpinning the acknowledgment or reporting of historical trauma as measured by the CTQ.
The total score, which aggregates the sum of the subscales, similarly does not reach statistical significance, suggesting that the overall effect of inositol on the combined dimensions of childhood trauma is not compelling within the confines of this dataset.
From a clinical psychiatry perspective, these findings suggest that inositol may possess specific modulatory properties on emotional abuse-related sequelae in schizophrenia, which can be significant considering the pervasive effects of emotional maltreatment on mental health. However, the absence of significant findings in other trauma-related domains signals the need for cautious interpretation and the necessity for further inquiry.
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5. Discussion
5.1 Part I
The heterogeneity of the clinical picture and severity of the disorder within the examined group of individuals with schizophrenia, and consequently insensitivity to pain, can be explained by the wide variability in the doses of antipsychotic drugs used, expressed in chlorpromazine equivalents. This, on the one hand, suggests a wide range of pharmacotherapeutic interventions in the studied cohort, and on the other hand, confirms the theory that the lesser experience of pain in schizophrenia may be due to the use of chronic neuroleptic pharmacotherapy [62]. The obtained range of results also implies potential differences in response to treatment or increased tolerance, considering the significant variability in doses required to achieve therapeutic effects or manage side effects. A systematic review conducted in 2004 indicated that up to 90% of atypical neuroleptics exhibited analgesic effects [63]. Our findings provide evidence suggesting that analgesia depends on both the dose and type of antipsychotic drug, although the use of neuroleptics remains problematic in improving depressive symptoms or cognitive functions and reducing suicide attempts associated with them in schizophrenia [64, 65, 66].
Positive symptoms, characterized by the presence of psychopathology such as hallucinations, delusions, and disorganized thought processes, among the examined individuals, showed a mean score suggesting a moderate level of severity in the entire cohort. However, the range and standard deviation indicate significant heterogeneity in the presentation of positive symptoms. The wide range of scores for negative symptoms emphasizes the diverse impact of schizophrenia on emotional response and social functioning, which are key determinants of long-term outcomes and functional abilities.
The results on the negative scale among the examined cohort slightly exceeded those on the positive scale, suggesting that negative symptoms may be more prominent or enduring in the studied cohort. This is consistent with the clinical understanding of the association of negative symptoms with altered pain perception, resistance to current pharmacotherapies, and poorer functional outcomes. Additionally, we cannot exclude the influence of a broader range of symptoms, such as guilt feelings, tension, and active avoidance of social contacts, which were highest among these domains in the studied group. This reflects the broad impact of the complex interaction of affective, cognitive, and behavioral elements in pain perception in schizophrenia.
5.2 Part II
Through conducting proton magnetic resonance spectroscopy (1H-MRS) in a group of individuals with schizophrenia, we evaluated the metabolic activity of the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) involving myo-inositol. Myo-inositol is an inert osmolyte abundantly present in glial cells. One of its important functions is the regulation of cell volume during morphological changes, such as those occurring during glial activation in neuroinflammatory processes and neuropathic pain [67]. Evaluating the correlation of this indicator with other measured parameters of clinical and neurometabolic assessment and based on available literature, elevated levels of myo-inositol may suggest glial proliferation or altered glial function, consistent with neuroinflammatory hypotheses of schizophrenia. Elevated levels of myo-inositol have been observed in viral infections such as HIV infection [68, 69], progressive multiple sclerosis [70], or in diffusion imaging models confirming glial activation [71, 72]. Higher levels of myo-inositol have been observed with aging [73, 74, 75]. Transcriptomic data indicate that aging is associated with increased markers of astrocytes and microglia [76], particularly with increased markers of reactive astrocytes in the prefrontal cortex [77]. Presumably, these glial changes may constitute a common mechanism responsible for similar neurometabolic profiles observed in aging and in the process of altered pain perception in schizophrenia. In our study, the average levels of myo-inositol in the ACC and PCC fall within a range that does not immediately indicate clear glial pathology; however, the variability of these levels may correlate with individual differences in symptoms or disease progression. The prolonged echo time (TE) of 144 ms compared to the standard TE of 30 ms provides increased specificity of metabolite resonance and suggests a stronger signal for myo-inositol and N-acetylaspartate (NAA).
There are individual studies indicating that changes in the concentration of myo-inositol in the orbitofrontal cortex may be associated with specific mood/affective states such as extreme pain perception. Additional support for altered pain perception may come from the reduced level of N-acetylaspartate in the dorsolateral prefrontal cortex, confirming the hypothesis that N-acetylaspartate depletion in the prefrontal cortex is a chemical marker of chronic pain, indicating neuronal degeneration which may be related to possible glutamate’s excitotoxicity [78, 79, 80, 81]. Inositol has neuromodulatory potential, particularly by increasing its availability and supporting neuronal integrity [82], as indicated by a wide range of changes in N-acetylaspartate levels. The observed neurochemical changes may hypothetically translate into clinical improvement and reduced pain perception in schizophrenia, considering the association of myo-inositol with signaling pathways and NAA with neuronal health. Translating these brain biochemistry changes into clinical practice requires careful interpretation and further validation through clinical studies assessing symptomatology and evaluating neuronal-glial mechanisms underlying pain modulation by cognitive and emotional states as pillars of cognitive-behavioral therapy. Key metabolites considered useful in assessing altered pain perception in schizophrenia are myo-inositol and NAA, which have previously been linked to increased pain symptoms in complex regional pain syndrome. Interestingly, there is also evidence that chronic pain itself alters brain circuits, including those related to endogenous pain control, suggesting that pain control becomes increasingly difficult as pain becomes chronic. In this case, the hypothesis of the existence of a negative feedback loop between impaired pain-modulating circuits and pain processing is justified, leading not only to exacerbation of chronic pain among individuals with schizophrenia but also to accompanying cognitive and emotional deficits associated with pain, which in the studied group indicated an average slightly above the median, with insignificant standard deviation, suggesting variability in cohort experiences related to emotional violence. Affective dysregulation, characteristic of C-PTSD, was characterized by the highest average score among the ITQ subscales, confirming the significant influence of emotional reactions that are not adequately modulated in the studied group of patients. The justification for the obtained results is that both the ACC region and the insula have long been considered components of the emotional brain [83, 84] responsible for encoding the emotional and motivational aspects of pain. Patients with alterations in these areas exhibit altered emotional responses to pain [85, 86, 87, 88] and imaging and stimulation studies demonstrate a relationship between emotional and motivational aspects of pain perception and neuronal activation in the ACC and insula [89, 90, 91, 92]. Another explanation for altered pain perception in schizophrenia may be reduced gray matter content in patients with chronic pain associated with possible glutamate excitotoxicity [93]. In schizophrenia at a very early stage of the disease, even before antipsychotic treatment, increased presynaptic dopamine release with a characteristic small increase in glutamate concentration was observed in PET studies [94]. Conversely, in healthy individuals, positron emission tomography studies have shown that reduced density of D2 receptors in the striatum was associated with an increased pain threshold [95]. These studies suggest that changes in neurotransmitter systems may mean that patients with chronic pain have reduced receptor availability or increased endogenous release of these neurotransmitters [96].
Understanding the pathophysiology of altered pain perception in schizophrenia and developing effective therapeutic interventions seems crucial for curbing the wave of adverse consequences of schizophrenia, including suicide attempts. Changes in the neurometabolic integrity of brain areas involved in both pain control and cognitive and/or emotional functioning may explain why patients suffering from schizophrenia with chronic pain develop cognitive deficits, as well as anxiety disorders or depression. Ongoing research suggests that emotional and cognitive changes may begin long after the onset of pain. For example, patients with psychotic symptoms may exhibit anxiety-like behaviors and attention deficits for several years after injury and onset of hypersensitivity, temporally coinciding with anatomical changes in the frontal cortex [97, 98]. The concept of pain control dependent on the level of myo-inositol in the prefrontal cortex in individuals with schizophrenia is confirmed in this study, where the result of emotional violence shows a significant decrease with exposure to inositol. This finding has significant clinical potential, as childhood emotional violence is strongly associated with exacerbation of psychotic symptoms and may contribute to worse prognostic outcomes in schizophrenia. Adversities in early life and mechanisms of altered pain perception may further explain the relationship between suicide risk and abnormalities in brain circuits and neurochemistry in schizophrenia [99].
A significant reduction in the index of emotional violence after treatment with inositol may indicate therapeutic potential in alleviating the long-term consequences of childhood trauma, potentially leading to a reduction in trauma-related symptomatology in the studied cohort. The presented study provides evidence that pain can be harmful to the brain and that chronic pain itself may decrease an individual’s ability to control pain endogenously and lead to numerous comorbidities that accompany schizophrenia.
5.3 Part III
Analyzing the results regarding emotional violence, it is evident that they show an average slightly above the median, with an insignificant standard deviation, suggesting variability in the experiences of the studied cohort related to childhood emotional violence. The range of results indicates that while some individuals reported low levels of emotional violence, others experienced higher levels, which may correlate with a greater risk of emotional dysregulation and future disorders such as depression and anxiety states. Results for physical neglect, representing unmet basic physical needs, showed lower mean and median values compared to emotional neglect. The literature on the subject suggests that while physical and sexual abuse in childhood are known risk factors for chronic pain in adulthood, the relationship between childhood emotional violence and chronic pain remains insufficiently explored [100].
In most studies describing hypoalgesia in schizophrenia, the subjective response of the patient to painful stimuli had strong emotional underpinnings. Insensitivity to pain in this case may reflect deficits in the patient’s expression of emotions. In other words, indifference to pain in patients with schizophrenia may not signify actual hypoalgesia. The aforementioned interoception is essentially supported by the insular cortex, with primary visceral sensation being associated with the mid and posterior insula regions, and integration of interoceptive information with cognitive functions, emotions, and other higher-order processes occurring in more anterior areas of the cerebral cortex [101, 102]. The medial prefrontal cortex, including the anterior cingulate cortex, prefrontal cortex, and infralimbic cortex, which are associated with shaping pain sensations in the central nervous system, is involved in these mechanisms [103]. The coexistence of psychological pain has been found to be an important moderator of the lasting benefits of treating patients with schizophrenia prone to suicide [104]. The analgesic action of schizophrenia treatment may explain the anti-suicidal effects of ketamine [104]. Research has revealed new possibilities for the use of this drug. It has been used in the treatment of acute, chronic, and cancer pain. The most interesting reports come from studies on the antidepressant and anti-suicidal properties of ketamine, offering hope for the development of an effective drug for major depressive disorders [105], although retrospective studies suggest that these effects may be short-lived [106].
In studies assessing the impact of childhood emotional violence on pain perception disturbances in populations with diagnosed mental health disorders, attention was drawn to the fact that among individuals receiving injectable drugs for chronic pain, experiences of childhood emotional violence were common, partly influenced by a history of diagnosed mental health disorders [107]. Similarly, it is known that individuals with mental health disorders have a high incidence of childhood trauma; however, little is known about how childhood emotional violence may be associated with chronic pain in this population [108]. Available data suggest that physicians should consider childhood trauma when treating psychiatric disorders in individuals experiencing chronic pain. Awareness of trauma-informed care may lead to more effective treatment in cases perceived as treatment-resistant [109], including suicide attempts. Childhood emotions, as demonstrated by this study, can be significant predictors of poor health outcomes in psychiatric patients, remaining unnoticed even with normal psychiatric assessment results. Considering the detrimental impact of high levels of pain disturbances, examining the potential influence of childhood emotions on altered pain perception in patients with schizophrenia appears crucial in designing interventions to improve the quality of life for this patient group. This approach may also facilitate identifying potential factors affecting the final clinical assessment outcomes for patients with schizophrenia and provide a better understanding of possible early interventions before pain interferes with daily activities. To the best of our knowledge, this is the first study to address the impact of childhood emotional exposure on the occurrence of chronic pain among individuals with schizophrenia. Further efforts are needed to determine pain perception intervention indicators to develop standards for therapeutic interventions among individuals with schizophrenia.
Emotional violence in childhood shapes interpersonal relationships, leading to weakened abilities to initiate and maintain connections. This factor has been identified as an important component of the experience of altered pain perception [110]. Addressing the issue of disruptions related to altered pain perception through effective psychosocial treatment and improving emotional awareness may result in a measurable indicator of pain control and the reduction of adverse effects on the quality of life and functioning of individuals with the condition [111, 112]. Increased access to effective prevention programs is therefore an urgent need, especially among marginalized populations, including schizophrenia, about which little is yet known regarding the assessment of pain expression by the patient. Interestingly, affective dysregulation, characteristic of C-PTSD, showed the highest mean score among the ITQ subscales, which fell within the upper limit of the lower half of the scale, clearly indicating emotionally reactive responses that were not adequately controlled. Conversely, the DSO score, representing the dissociative subtype of PTSD, exhibited a higher mean score than PTSD, suggesting that dissociative symptoms were particularly prominent in the studied cohort. This has clinical significance as the dissociative subtype often requires specialized treatment methods.
In investigating the relationship between inositol and its impact on emotional reactions in the studied cohort, attention is drawn to the significant decrease in emotional violence scores with exposure to inositol. This discovery has significant clinical implications, as childhood emotional violence has been strongly linked to exacerbating psychotic symptoms and may contribute to poorer prognostic outcomes in schizophrenia. The substantial reduction in the emotional violence index following inositol treatment may indicate its therapeutic potential in alleviating the long-term effects of such trauma, potentially leading to a reduction in trauma-related symptomatology in the studied cohort.
From a psychiatric perspective, these findings illuminate the potential role of inositol as a therapeutic agent in addressing specific aspects of psychopathology associated with a history of trauma in schizophrenia. This appears particularly pertinent in the context of avoidance behaviors and disturbances in relationships, which directly affect patients’ quality of life and functionality. Furthermore, these findings indicate that inositol may provide benefits in tackling the broadly defined challenges often linked to continuous, repeated, and diverse traumatic exposures, such as affective dysregulation, negative self-concept, and disturbances in relationships, underscoring the necessity for further investigation into its neuromodulatory effects.
Inositol, an endogenous biologically active compound in the human body, plays a pivotal role in neurocommunication, serving as a crucial component in the signal transduction processes within neuronal cells. It possesses the capacity to modulate various neurochemical pathways, which could be exceptionally advantageous in the context of schizophrenia and related trauma-induced disorders. It has been demonstrated that inositol exerts its therapeutic effect in depression and associated anxiety disorders, partly by reducing the function of the serotonin-2A receptor (5HT2A-R) and specifically by diminishing the receptor’s signaling capacity through Gq proteins. Additionally, inositol inhibits the function of the muscarinic acetylcholine receptor (mAChR), which may also contribute to its therapeutic effect in depression [113]. Through its influence on the neurotransmitter system, such as serotonin, inositol may aid in mitigating certain psychopathological symptoms, including anxiety, depression, and social-emotional processing issues related to trauma.
Moreover, owing to its potential neuroprotective [114] and anti-inflammatory actions [115], inositol may support the protection and regeneration of neural tissue, crucial in the face of chronic stress and trauma exposure, frequently observed in individuals with schizophrenia. This could, in turn, lead to enhancements in socio-emotional functioning, as well as patients’ quality of life. The role of inositol in promoting neuroplasticity and its anti-inflammatory properties could be a critical mechanism in mitigating the neurological impacts of trauma. Neuroplastic changes are crucial for recovery from traumatic experiences, and inositol’s contribution to synaptic formation and repair could facilitate the re-establishment of healthy neural networks disrupted by trauma. Trauma and stress induce inflammatory states within the brain, contributing to neuronal damage and deterioration of brain function [116]. Inositol, owing to its anti-inflammatory properties, may aid in reducing neuroinflammation, thereby protecting neural cells from damage and supporting their regeneration. Future research might explore how inositol influences neuroplastic pathways in the traumatized brain, potentially offering insights into its therapeutic effects in schizophrenia.
In summary, these insights herald new avenues for research and therapy focused on neuromodulation with inositol as a potential strategy to address specific trauma-related challenges in schizophrenia. Nonetheless, additional research is necessary to validate these initial findings and to elucidate the mechanisms of action of inositol, alongside establishing the best practices for its application in psychiatric therapy.
5.4 Limitations of the study
We failed to consider other important variables related to pain expression by patients, such as pain intensity, catastrophizing, and pain quality, as data that could provide significant measurable information allowing for the assessment of pain threshold cutoffs for which further diagnostic and therapeutic guidelines can be defined in the group of individuals with schizophrenia showing clear emotional neglect.
Emotional abuse in childhood may imply changes in pain perception among individuals diagnosed with schizophrenia. Childhood emotional abuse remained independently associated with neuroglial disturbances related to myo-inositol levels in the anterior cingulate cortex in adults with schizophrenia. Individuals with chronic pain should be assessed for childhood psychological trauma and the presence of mental disorders, and appropriate therapeutic measures should be provided to reduce distorted pain perception. Lastly, these findings underscore the importance of socio-behavioral interventions, including coping skills training and interpersonal skills enhancement, to mitigate disruptions in pain perception and improve the quality of life for patients with schizophrenia experiencing concurrent chronic pain and reporting a history of emotional abuse.
A limitation of this study was its reliance on retrospective self-reports of childhood trauma history, rather than employing a prospective approach, which could have provided greater accuracy. This retrospective methodology may introduce recall bias and affect the validity of the trauma histories reported, potentially influencing the study’s findings and interpretations.
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6. Conclusion
The complex nature of pain and its impact on the daily lives of millions of people entails the need for a thorough analysis of the processes and chemical compounds contributing to its development. Disturbed pain perception in patients with schizophrenia poses an additional diagnostic challenge for this disease. Reduced levels of myo-inositol in the anterior cingulate cortex may be the cause of reduced pain perception in patients with schizophrenia. One of the most important functions of myo-inositol, an osmolyte present in glial cells, is the regulation of the volume of glial cells during morphological changes occurring in the course of neuroinflammatory processes and neuropathic pain. The glial changes associated with increased levels of myo-inositol may be the cause of altered pain perception in schizophrenia. However, it is important to remember that schizophrenia is a complex disorder with a wide range of affective, cognitive, and behavioral symptoms, all of which may affect pain perception in patients. Understanding the basis of impaired pain perception in patients with schizophrenia may enable the introduction of appropriate therapy. Proper therapeutic intervention should reduce the emotional violence index, thus reducing the number of future disorders such as depression and anxiety, hopefully reducing the number of suicides in patients with schizophrenia. The use of inositol in therapy may result in a significant reduction in emotional violence which could be a future approach in the treatment of pain in schizophrenia.
Future research should delve into the intricate relationship between myo-inositol levels and the modulation of pain perception in individuals diagnosed with schizophrenia. It is crucial to conduct prospective, longitudinal studies to map out the changes in myo-inositol concentrations within the brain over time and to understand how these fluctuations correlate with the development and alteration of pain perception in this population. Investigating the neuroinflammatory and neuropathic mechanisms underlying pain perception in schizophrenia is paramount, with an emphasis on exploring how glial cell activity and the regulatory role of myo-inositol contribute to these processes. Additionally, a thorough analysis of the diverse symptomatology of schizophrenia, encompassing affective, cognitive, and behavioral dimensions, and their cumulative effect on pain perception is imperative. Such comprehensive research efforts are essential for uncovering the neurobiological and psychosocial dynamics influencing pain perception in schizophrenia, paving the way for more effective treatments and interventions.
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Author’s contribution
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