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Article

A Pilot Study on Plasma N-Acetylaspartate Levels at Admission and Discharge in Hospitalized Psychiatric Patients: Impact of Lithium Treatment and Clinical Correlations

by
Simone Pardossi
1,*,
Claudia Del Grande
2,
Beatrice Campi
3,
Andrea Bertolini
4,
Barbara Capovani
2,
Andrea Fagiolini
1,
Riccardo Zucchi
4,
Alessandro Saba
4,5,
Alessandro Cuomo
1 and
Grazia Rutigliano
4
1
Department of Molecular Medicine, School of Medicine, University of Siena, 53100 Siena, Italy
2
Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, “Santa Chiara” Hospital, 56126 Pisa, Italy
3
Institute of Clinical Physiology, National Research Council (CNR), Via Giuseppe Moruzzi, 56124 Pisa, Italy
4
Department of Pathology, University of Pisa, 56126 Pisa, Italy
5
Center for Instrument Sharing (CISUP), University of Pisa, 56126 Pisa, Italy
*
Author to whom correspondence should be addressed.
Psychiatry Int. 2025, 6(4), 130; https://doi.org/10.3390/psychiatryint6040130
Submission received: 25 July 2025 / Revised: 30 August 2025 / Accepted: 14 October 2025 / Published: 21 October 2025
Browse Figure
Versions Notes

Abstract

N-Acetylaspartate (NAA) plays a critical role in neuronal function, metabolism, and neurotransmitter release. Evidence from magnetic resonance spectroscopy indicates diminished NAA levels in individuals diagnosed with schizophrenia and bipolar disorder; however, this process is time-consuming, expensive, and not viable in individuals with acute illness exacerbation. In order to address these limitations, we developed a novel method for the quantification of plasma NAA based on tandem mass spectrometry coupled to liquid chromatography (HPLC-MS). Our study aimed to assess whether plasma NAA levels change during hospitalization and whether these changes correlate with symptomatic improvement in patients experiencing acute psychiatric exacerbations. We recruited 31 inpatients with acute symptoms of psychotic (48.39%) and/or mood (51.61%) disorders. Symptom severity was assessed using the brief psychiatric rating scale, Positive and Negative Syndrome Scale, and Clinical Global Impression Scale. Plasma NAA was measured at admission and discharge. We observed a significant decrease in symptom scores and a significant increase in plasma NAA levels between admission and discharge. The initiation of therapy with lithium salts significantly influenced plasma NAA changes. Our study shows that our HPLC-MS method can detect clinically meaningful changes in plasma NAA levels. These results might lay the groundwork for future research exploring the relationship between plasma NAA levels and cerebral NAA levels measured by MRS.

1. Introduction

N-Acetylaspartate (NAA) is a derivative of aspartic acid that is highly concentrated in the mammalian brain. NAA is mainly found in neurons and oligodendrocytes [1,2] and is synthesized in mitochondria from acetyl-coenzyme A and L-aspartate [1]. Several hypotheses have been proposed regarding NAA functions. NAA is an organic osmolyte that can maintain the osmolarity balance in the central nervous system (CNS); it provides a source of acetate for myelin lipid synthesis, it is involved in mitochondrial energy metabolism, and it is the precursor of N-acetylaspartylglutamate (NAAG) which in turn modulates the release of other neurotransmitters [1,3].
NAA is one of the most studied molecules in magnetic resonance spectroscopy (MRS). Due to its high concentration (as high as 8.8 ± 2.8 mmol/kg in the CNS) and the strong signal in water-suppressed proton MRS spectrograms [4], NAA is relatively easy to measure [4]. In animal models and humans, NAA reduction is associated with neuronal loss or damage [5], or reduced neuronal metabolic function [1], probably linked to impaired mitochondrial function [6]. NAA reduction has been observed in neurological disorders such as cerebral stroke [7], Alzheimer’s disease [8], Huntington’s disease [9], and multiple sclerosis [10]. Meta-analyses of MRS studies have found reduced NAA levels in psychiatric disorders, including schizophrenia (SCZ) [11], major depressive disorder (MDD) [12], and bipolar disorder (BD) [13].
There is some evidence that treatment with lithium salts may increase NAA levels in patients with BD [14], supporting lithium’s neurotrophic role. A significant increase in total brain NAA concentration was documented after lithium administration in both bipolar patients and healthy volunteers [6,15,16]. Lithium neuroprotective and neurotrophic effects are thought to be mediated by inhibition of glycogen synthase kinase-3 (GSK-3) [17,18], whose signaling pathway leads to reduced expression of brain-derived neurotrophic factor (BDNF) [19]. BDNF supports essential neural functions—including maturation, differentiation, survival, synaptic plasticity, and memory consolidation—and is especially expressed in the cerebral cortex and hippocampus [20]. BDNF levels are decreased in patients with bipolar depression and mania and have been shown to correlate with symptom severity [18]. A relationship between NAA and BDNF levels in the anterior cingulate cortex (ACC) has been described in healthy individuals [20]. Lithium increases the activity of antioxidant molecules and decreases inflammatory molecules [21], thereby improving mitochondrial function [18] which may account for increased NAA levels induced by lithium treatment.
Most of the existing literature on NAA levels in psychiatric disorders focuses on brain levels measured with MRS. An assay of plasma NAA levels could offer several advantages. First, it would be less invasive, thus reducing patient discomfort. It would be less time-consuming and less expensive than MRS. Additionally, the plasma assay provides an opportunity to assess patients who may not be compliant with MRS procedures, such as individuals in an acute psychotic state or experiencing a manic/hypomanic phase. These patients are unlikely to undergo MRS, but their NAA levels could still be assessed using the plasma assay.
In our mass spectrometry facility, which is a joint venture between the University of Pisa and the University of Pisa Medical Center, we have developed a high-performance liquid chromatography mass spectrometry (HPLC-MS)-based method to measure plasma NAA levels [22]. This method has been used in several studies involving patients with type II diabetes, impaired glucose tolerance (IGT), and non-diabetic obese individuals [23,24].
Our primary objective was to assess whether our HPLC-MS method to measure plasma NAA levels could detect clinically meaningful changes in symptom severity in patients with an acute exacerbation of SCZ spectrum and mood disorders. We explored clinical predictors of NAA changes, with a focus on the initiation of lithium salts.

2. Materials and Methods

2.1. Participants

Patients were recruited at the “Psychiatric Service for Diagnosis and Care” (SPDC), the inpatient acute psychiatric ward of the Italian national health system, at the Santa Chiara Hospital in Pisa, Italy, between March 2021 and May 2022.
We enrolled patients hospitalized for evaluation and management of acute symptom worsening in schizophrenia spectrum and mood disorders, with a severity of 5 or higher (markedly ill) on the Clinical Global Impression (CGI) scale. We included patients with exacerbation of symptoms without focusing on a particular diagnosis, as reduced NAA levels have been described across various diagnostic categories [11,12,25]. Patients with concomitant alcohol/substance use disorders were excluded. Lifetime and current diagnosis were performed according to the DSM-5 [26]. We also excluded patients with intellectual disabilities and neurological comorbidities.
An anamnestic questionnaire was administered to the enrolled patients to collect socio-demographic (age, gender, psychophysical development, educational attainment, employment history, and marital status) and clinical characteristics, including family history of psychiatric diseases, illness onset, duration of the current episode, and pharmacological treatment history. Psychiatric symptoms were assessed using standardized clinical scales, including the brief psychiatric rating scale (BPRS) [27], Positive and Negative Syndrome Scale (PANSS) [28], Clinical Global Impression (CGI) [29], and Social and Occupational Functioning Assessment scale (SOFAS) [30]. Specifically, regarding PANSS, the factors of the Marder factor score analysis were used (negative symptoms, positive symptoms, disorganized thought/cognition, uncontrolled hostility/excitement, and anxiety/depression), which make up the 5-factor structure of the PANSS, rather than the traditional 3-factor structure (positive, negative, and general psychopathology) [28,31]. For all scales, we used the Italian validated versions. For more details, the characteristics of each scale are reported in the Supplementary Materials (Table S1).
Psychiatric assessments were administered by one researcher (C.D.G.) at baseline and at the time of discharge.
Written informed consent for the anonymous use of clinical records was collected routinely at patients’ first visit. Plasma was obtained by using the remaining part of samples obtained drawn for independent clinical indications. All subjects gave informed consent. However, the Ethics Committee of the Tuscany Region—Northwest Wide Area (CEAVNO), in the meeting held on 8 February 2024, granted approval for the use of waste plasma samples from anonymous psychiatric patients under pharmacological treatment for the quantification of N-acetylaspartate through mass spectrometry. All procedures performed were in accordance with the Helsinki Declaration of 1975 as revised in 1983.

2.2. Mass Spectrometry-Based Assay

Plasma NAA concentrations were determined both at admission and discharge. All reagents employed for the quantification—NAA, the internal standard NAA-1,2,3,4-13C4 (IS, 13C4-NAA), acetonitrile (LC-MS grade), water (LC-MS grade), formic acid (MS grade), and 3N hydrochloric acid in butan-1-ol—were purchased from Merck KGaA (Darmstadt, Germany). The measurements of NAA were performed with an instrumental layout that included an AB Sciex API 4000 triple quadrupole mass spectrometer (Concord, ON, Canada), equipped with an electrospray (ESI) Turbo-V ion source and coupled to an Agilent 1290 Infinity UHPLC system (Santa Clara, CA, USA). The method relied on selected reaction monitoring (SRM) in positive ion mode, with parameters optimized to ensure maximal sensitivity and selectivity. Sample preparation was performed as follows: plasma samples, stored at −20 °C, were thawed at room temperature, vortexed (15 min), and a 100 μL aliquot was added to 300 μL of acetonitrile, formic acid 1% (V%), and internal standard. The obtained suspensions were vortexed (15 min) and centrifuged (18,620× g, 15 min) [22]. In total, 300 µL of supernatant was collected and evaporated to dryness under a N2 stream at 40 °C. The samples were derivatized to butyl esters (Fischer esterification reaction) by adding 100 μL 3N 1-butanol/HCl, vortexing (15 min), and heating at 60 °C for 40 min. The reaction products were dried under a gentle stream of nitrogen and the dry residues were reconstituted with 100 μL can/H2O (20/80; v/v) and vortexed for 15 min, then 5 µL of the final solution was injected into the LC-MS/MS system for analysis.
The analytical method was validated in compliance with EMA guidelines [32].

2.3. Statistical Analysis

Data normality was assessed using the Shapiro-ilk test. We compared baseline plasma NAA levels between patients with mood disorders and SCZ spectrum disorders using the Wilcoxon test. Plasma NAA levels and clinical scores were compared between admission and discharge using the paired-sample t-test (or the Wilcoxon test for non-normally distributed data). We conducted correlation analyses to assess the relationship between baseline NAA concentration and the duration of illness and baseline clinical scales scores, using Pearson’s coefficient for normally distributed data and Spearman’s coefficient for data with a non-normal distribution. We studied the correlations between NAA percentage changes from baseline to discharge and percentage changes in CGI, BPRS, PANSS, and SOFAS scores from baseline to discharge, using Pearson’s coefficient for normally distributed data and Spearman’s coefficient for data with a non-normal distribution. The results were Bonferroni-corrected for multiple testing, by dividing the threshold for statistical significance of 0.05 by the overall number of tests performed. PANSS values were used for analyses after subtracting the minimum scores.
Finally, we conducted a stepwise backward linear regression to identify possible predictors of the outcome NAA variations out of the following candidate variables: lithium initiation, variations in PANSS Marder factor scores, variations in CGI scores, duration of illness. Predictors were selected a priori. The number of predictors was constrained by the small sample size. We selected lithium as a possible predictor of NAA changes due to the evidence of its neurotrophic role and modulation of NAA [6,14,15]. In the regression analyses, lithium initiation was modeled as a binary predictor (yes/no depending on whether lithium was introduced during the inpatient stay). BPRS was not included in the model given its correlation with the CGI and PANSS scales [33].
At each step, variables were excluded based on p-values, and a p-value threshold of 0.3 was used to set a limit on the total number of variables included in the final model.
All statistical analyses were performed using R (R version 4.2.1, 2022 The R Foundation for Statistical Computing Platform).

3. Results

3.1. Demographic and Clinical Characteristics at Admission

The current sample included 31 patients. Patients had an average age of 44.19 years (sd = 13.5), and 58% (n = 18) of them were female. Other socio-demographic characteristics are summarized in Table S2 (Supplementary Materials). Patients were aged 31.71 years (sd = 14.82) on average at illness onset. The disease duration followed a non-normal distribution, with a median of 72.00 months (first quartile 25%: 12.00; third quartile 75%: 276.00). The distribution of diagnosis of our sample is shown in Table S3 (Supplementary Materials). In total, 45.16% (n = 14) of patients had a lifetime diagnosis of SCZ spectrum disorder, 48.38% (n = 15) of mood disorder, and 6.45% (n = 2) of eating disorder. At admission for acute exacerbation, 48.39% of patients had a current diagnosis of SCZ spectrum disorders, while 51.61% had mood disorders. Most patients’ pharmacological treatment included antiepileptic drugs, lithium salts, antidepressants, and benzodiazepines, as shown in Table S4. Specifically, 25.81% (n = 8) had taken lithium salts at some point in their life and 12.90% (n = 4) were on lithium therapy at the time of admission. In total, 12.9% of patients were already on lithium at admission. Lithium was initiated during hospitalization in 58.06% (n = 18) of patients; therefore, by the end of hospitalization a total of 70.97% (n = 22) of patients were receiving lithium therapy [6,14,15].

3.2. Association Between Baseline Plasma NAA Levels and Clinical Variables

We found no statistically significant differences in plasma NAA values between patients with a lifetime diagnosis of mood disorder versus SCZ spectrum disorders (V = 59; mood disorder, mdn = 65.77; SCZ spectrum disorder, mdn = 58.86; p = 0.978).
There was no correlation between any of the PANSS Marder factors or BPRS scores and baseline plasma NAA levels (Table 1).

3.3. Change in Clinical Measures and Plasma NAA Levels from Admission to Discharge

We observed a significant improvement in symptoms from admission to discharge (Table 2). There was a significant reduction in PANSS positive symptoms (t = 4.33, p < 0.0001), PANSS uncontrolled hostility/excitement (t = 8.88, p < 0.0001), PANSS anxiety/depression (t = 8.49, p < 0.0001), PANSS negative symptoms (V = 225, p = 0.0001), and PANSS disorganized thought/cognition (V = 465, p < 0.0001). We also observed reductions in BPRS (t = 15.50, p < 0.0001) and CGI (V = 465, p < 0.0001) scores. Plasma NAA levels at discharge were significantly raised as compared to those at admission (mean diff. = 9.67, sd = 2.23, t = 4.36, p < 0.001) (Figure 1). However, there was no significant correlation between percentage increase in NAA levels and percentage decrease in scores on clinical scales. The results of the correlation between score changes and NAA increase are shown in Table 3.

3.4. Predictors of Changes in Plasma NAA Levels

The initiation of treatment with lithium salts was associated with increased NAA concentration at discharge (β = 0.245, Std β = 0.059, p < 0.0001). At discharge, 70.97% (n = 22) patients were on lithium salts. Of these, lithium therapy was initiated for 18 patients during the current admission. The symptomatic domains retained in the final regression model were not significantly associated with changes in NAA levels: PANSS negative symptoms (β = −0.111, Std β = 0.073, p = −0.253), PANSS disorganized thought/cognition (β = 0.283, Std β = 0.148, p = 0.068), PANSS uncontrolled hostility/excitement (β = −0.235, Std β = 0.122, p = 0.066) (Table 4). The model explained 46.1% (Adj. R2 = 0.375) of the variance in NAA changes.

4. Discussion

In our study, we measured NAA plasma levels in patients with acute exacerbation of psychiatric disorders, including both SCZ spectrum and mood disorders. NAA levels increased from admission to discharge, in parallel with reductions in all psychometric scales. NAA changes were influenced by initiating treatment with lithium salts.
We observed no significant differences in plasma NAA levels between patients with different diagnoses. Using MRS, lower NAA levels were found across psychiatric disorders, encompassing SCZ [11], BD [25], and MDD [12], as compared to healthy controls, with topographical differences. Both patients with chronic SCZ and a first episode of psychosis showed lower NAA levels in the frontal lobe and thalamus, while patients with chronic SCZ also had reduced NAA levels in the hippocampus, temporal lobe, and parietal lobe [11]. Individuals at risk of developing SCZ also showed lower hippocampal NAA levels relative to healthy controls [11]. Lower NAA levels were also reported in chronic MDD in the frontal lobe, occipital lobe, and frontal and parietal white matter [12]. Evidence of NAA reduction in first episodes of depression is still sparse, although individual studies have shown a reduction in the thalamus [34] and in the frontal white matter [35]. Patients with BD showed lower NAA levels in the dorsolateral prefrontal cortex compared with healthy controls [25]. Moreover, NAA levels in patients with BD were associated with disease phase [13], with lower levels in the left white matter of the prefrontal cortex during depressive and euthymic phases, and higher levels in the left dorsolateral prefrontal cortex during depressive phases.
We found significantly increased NAA levels at discharge, in parallel with significant improvement in all clinical scores. In our sample, the initiation of treatment with lithium salts was a significant moderator of NAA changes; lithium salt treatment has been associated with increased NAA levels in both BD patients and healthy volunteers, highlighting its neurotrophic effects [6,14,15,16]. However, a review conducted in 2018, focusing on the impact of lithium salts on brain metabolites in individuals with BD, produced inconclusive findings regarding its effect on NAA levels [36].
The moderating effect of lithium salts on NAA changes supports its neurotrophic and neuroprotective properties. Lithium has been reported to prevent apoptosis and increase the expression of neurotrophins and cell-survival molecules involved in neuronal survival and plasticity [18,37], particularly B-cell lymphoma 2 (Bcl-2) [38] and BDNF [19]. Furthermore, in vitro studies indicate lithium’s positive effects on neurogenesis and inflammation. Lithium treatment has been found to reduce proinflammatory activity and oxidative stress [39], modulate autophagy processes through the enhancement of mitochondrial function [18], provide protection against excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors [40], and inhibit GSK-3, a serine/threonine kinase implicated in regulating various cellular processes such as synaptic plasticity, cell apoptosis, cellular structure, resilience, and the circadian cycle [17,37,41]. As mentioned earlier, NAA is synthesized in the mitochondria of neurons and oligodendrocytes. The enzyme responsible for its production, aspartate N-acetyltransferase (ANAT), is located within the mitochondrial matrix. By promoting mitochondrial biogenesis, boosting energy production, and maintaining mitochondrial membrane potential, lithium may create conditions that support the optimal activity of mitochondrial enzymes like ANAT [42,43].
Our sample size did not allow us to include all pharmacological treatments in our model. However, based on previous reports, the moderating effect of other drugs on NAA changes cannot be excluded. Antidepressants [44] and lamotrigine [45] were associated with increased NAA levels in the frontal lobe, ACC, and hippocampus [46]. Haloperidol and clozapine increased NAA levels in SH-SY5Y human neuroblastoma cells cultures [47]. Haloperidol resulted in a significant increase in NAA levels in the striatum of rats [48]. In a study involving antipsychotic-naïve patients with SCZ who were treated with atypical antipsychotics, no significant increase in NAA levels was observed after 12 months, while a notable increase in NAA could be detected in patients who showed a good treatment response [49]. However, the limited number of participants in our study constrained our ability to include these variables in the regression model. As a result, we were unable to account for the potential impact of antidepressants and antipsychotics on NAA levels, which could have influenced our findings. Although a statistically significant mean increase in plasma NAA was observed, some patients did not show an individual rise. Indeed, the regression model demonstrated a significant effect of lithium initiation at the group level, but this effect does not necessarily extend to every patient.
We did not find a significant correlation between increased NAA levels and decreased clinical scores. A possible explanation for this could be the lack of correlation between plasma NAA levels and cerebral NAA levels. In patients with Type II diabetes and non-diabetic obese individuals, no correlation was found between peripheral NAA levels quantified using HPLC-MS and brain levels measured by MRS [24]. Of note, NAA brain levels, but not plasma levels, were significantly associated with cognitive functions. Several factors could contribute to this mismatch, including differences in the overflow of NAA from the brain into the bloodstream or variations in NAA clearance from the plasma among different individuals, or possibly a combination of these factors [24]. Another possible explanation could be that other clinical and/or pharmacological factors, including lithium salts, contribute to moderating the relationship between NAA levels and clinical scores. Finally, it is possible that our sample size might not be large enough to reveal a statistically significant correlation between increases in plasma NAA and clinical score reductions.

5. Limitations

We acknowledge several limitations to our study. First, the small sample size of this preliminary, observational study does not allow for generalization of the results. The findings should be interpreted with caution, and further research is required to validate these preliminary data. Specifically, larger longitudinal studies are needed to confirm or refute our initial observations and to better understand the potential implications of NAA level changes in the context of psychiatric treatment.
One pivotal limitation of our study is the absence of topographical resolution in the plasma NAA analysis. This is an important point considering that NAA variations in psychiatric disorders have been observed to be region-specific rather than uniform throughout the brain. Prior research has demonstrated that NAA alterations can differ significantly across various brain regions, reflecting the heterogeneous pathophysiology underlying SCZ spectrum and mood disorders [12,25]. Although there is evidence of a correlation between NAA levels in specific brain regions and psychiatric symptoms, no study has yet demonstrated a correlation between plasma NAA levels and cerebral NAA levels in specific regions.
Another limitation is the heterogeneity in the diagnosis and clinical characteristics of our sample. It would have been interesting to include the type of diagnosis in the regression model, but the small sample size did not allow for this [11,12,13]. On the other hand, many authors support the view that different psychiatric diagnoses exist on a continuum from a dimensional perspective [50,51]. Meta-analytical evidence further suggests that the reduction in NAA at the cerebral level may be transdiagnostic, which supports the approach of not differentiating between diagnoses in our analysis [11,13].
We also acknowledge the limitation of not utilizing specific scales for affective disorders, as psychotic symptoms were predominant, even within the context of affective disorders. However, we assessed the overall condition of the patients using the CGI scale. Furthermore, although the increase in plasma NAA levels occurred concurrently with symptomatic improvement, as evidenced by the reduction in the psychometric scores considered, no statistically significant correlation was observed between changes in plasma NAA levels and changes in the score values.

6. Conclusions

This study is the first to analyze plasma NAA levels in patients with an acute exacerbation of mental disorders. We showed that our HPLC-MS method can detect clinically meaningful changes in plasma NAA levels. In our sample, lithium was found to be a variable influencing NAA changes. This could be consistent with its neurotrophic, anti-inflammatory, and antioxidant effects, but certainly, larger longitudinal studies are needed to confirm or refute this finding. Moreover, when evaluating plasma NAA levels, it is important to consider that NAA, although primarily a brain metabolite, is also active in other tissues like adipose tissue and various cancers. In our clinical population, no significant physical health issues emerged during the hospitalization period, but future studies should also consider other potential factors that could impact plasma NAA levels. The preliminary observation of a variation in plasma NAA levels between admission and discharge in psychiatric patients provides an initial basis for exploring the potential relationship between plasma NAA and cerebral NAA levels measured through MRS. This finding highlights the relevance of investigating how changes in peripheral NAA might reflect alterations in brain networks involved in mental disorders. Moreover, with larger sample sizes, it would be possible to assess the influence of additional variables, such as specific diagnoses and treatments, on these dynamics.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/psychiatryint6040130/s1, Table S1: Characteristics of the clinical scales used in the study; Table S2: Demographic and clinical characteristics of the sample; Table S3: Psychiatric characteristics of the study population: current and lifetime diagnosis according to the DSM-5; Table S4: History of psychopharmacological treatments received by the study participants.

Author Contributions

S.P.: Writing—original draft, formal analysis, data curation, visualization. C.D.G.: Conceptualization, investigation, supervision, writing—review and editing. B.C. (Beatrice Campi): Formal analysis. A.B.: Formal analysis. B.C. (Barbara Capovani): Conceptualization, resources, supervision. A.F.: Supervision, writing—review and editing. R.Z.: Supervision. A.S.: Formal analysis, resources, supervision. A.C.: Supervision. G.R.: Conceptualization, formal analysis, data curation, supervision, writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Tuscany Region—Northwest Wide Area (CEAVNO), which granted approval for the use of waste plasma samples from anonymous psychiatric patients under pharmacological treatment for the quantification of N-acetylaspartate through mass spectrometry in the meeting held on 8 February 2024.

Informed Consent Statement

Informed consent was waived by the Ethics Committee of the Tuscany Region – Northwest Wide Area (CEAVNO), as the study utilized anonymized waste plasma samples, the recruitment was conducted three years ago (the quantification procedures and subsequent analyses required considerable time) and the research protocol had received full ethical approval.

Data Availability Statement

The data presented in this study are available on request from the corresponding author due to privacy reasons.

Acknowledgments

This work would not exist without the contribution of Barbara Capovani. Barbara was a humane, sympathetic, and talented psychiatrist. She was the head of the Psychiatric Service for Diagnosis and Care at Santa Chiara Hospital in Pisa (Italy). With her inexhaustible passion for science, she was the heart and soul of our research team. On 21 April 2023, Barbara was brutally assassinated in her workplace. It pains us unbearably that Barbara will not see the completion of her many projects, and we dedicate this paper to her memory.

Conflicts of Interest

G.R. has been a consultant for Sumitomo Pharma and is supported by the EU Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie grant agreement 101026235 and by Guarantors of Brain with a Post-Doctoral Clinical Fellowship. A.F. is/has been a consultant and/or speaker and/or has received research grants from Angelini, Aspen, Boheringer, Ingelheim, Glaxo Smith Kline, Italfarmaco, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, Viatris, and Vifor. A.C. is/has been a consultant and/or a speaker for Angelini, Glaxo Smith Kline, Lundbeck, Janssen, Otsuka, Pfizer, and Recordati.

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Psychiatryint 06 00130 g001
Figure 1. Changes in individual plasma N-acetylaspartate (NAA) concentration from admission to discharge in n = 31 in patients with acute exacerbation of symptoms of schizophrenia spectrum and mood disorders. ***: p-value < 0.001.
Figure 1. Changes in individual plasma N-acetylaspartate (NAA) concentration from admission to discharge in n = 31 in patients with acute exacerbation of symptoms of schizophrenia spectrum and mood disorders. ***: p-value < 0.001.
Psychiatryint 06 00130 g001
Table 1. Correlation between NAA levels and clinical variables.
Table 1. Correlation between NAA levels and clinical variables.
Clinical VariablesNAA
rp
Disease duration (months)0.140.47
PANSS negative symptoms−0.340.06
PANSS positive symptoms−0.110.56
PANSS disorganized thought/cognition−0.070.72
PANSS uncontrolled hostility/excitement−0.180.33
PANSS anxiety/depression0.160.41
CGI−0.220.24
BPRS−0.360.05
BPRS: Brief psychiatric rating scale; CGI: Clinical Global Impression Scale; NAA: N-Acetylaspartate; p: p-value; PANSS: Positive and Negative Syndrome Scale; r: correlation coefficient.
Table 2. Comparison of biochemical and clinical variables between admission and discharge.
Table 2. Comparison of biochemical and clinical variables between admission and discharge.
Clinical VariablesAdmissionDischargeTp
m (sd)m (sd)
NAA64.77 (16.30)74.44 (18.29)4.33<0.001
PANSS Positive symptoms25.30 (10.03)12.90 (5.49)8.48<0.0001
PANSS Negative symptoms *12.00
25% 7.00
75% 16.75		7.00
25% 7.00
75% 9.00		V = 225<0.001
PANSS Disorganized thought/cognition *20.00
25% 16.00
75% 22.75		9.00
25% 8.00
75% 11.00		V = 465<0.0001
PANSS Uncontrolled hostility/excitement13.30 (5.69)4.87 (1.28)8.88<0.0001
PANSS Anxiety/Depression14.60 (5.72)5.40 (1.33)8.49<0.0001
CGI *6.00
25% 6.00
75% 7.00		2.00
25% 2.00
75% 3.00		V = 465<0.0001
BPRS52.87 (12.78)23.87 (5.57)15.50<0.0001
BPRS: Brief psychiatric rating scale; CGI: Clinical Global Impression Scale; m: mean; NAA: N-Acetylaspartate; PANSS: Positive and Negative Syndrome Scale; sd: standard deviation; T: t-test value; V: Wilcoxon test value. * Variable with non-normal distribution, for which 1st and 3rd quartiles, median and V are reported (according to Wilcoxon’s test); p: p-value;
Table 3. Correlation between % change in NAA concentration and clinical variables between.
Table 3. Correlation between % change in NAA concentration and clinical variables between.
Clinical VariablesΔ% NAA
rp
Δ% PANSS Positive symptoms−0.040.85
Δ% PANSS Negative symptoms−0.130.50
Δ% PANSS Disorganized thought/cognition0.060.76
Δ% PANSS Uncontrolled hostility/excitement0.020.93
Δ% PANSS Anxiety/depression−0.100.62
Δ% CGI0.020.92
Δ% BPRS −0.140.46
BPRS: Brief psychiatric rating scale; CGI: Clinical Global Impression Scale; NAA: N-Acetylaspartate; p: p-value; PANSS: Positive and Negative Syndrome Scale; r: correlation coefficient.
Table 4. Stepwise backward linear regression model.
Table 4. Stepwise backward linear regression model.
Variableβ (Std Error)Std βp
Lithium initiation0.2450.059<0.0001
ΔPANSS Negative symptoms−0.1110.073−0.253
ΔPANSS Disorganized thought/cognition0.2830.1480.068
Δ PANSS Uncontrolled hostility/excitement−0.2350.1220.066
β: regression coefficient; PANSS: Positive and Negative Syndrome Scale; p: p-value; Std β: standardized regression coefficient.
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Pardossi, S.; Del Grande, C.; Campi, B.; Bertolini, A.; Capovani, B.; Fagiolini, A.; Zucchi, R.; Saba, A.; Cuomo, A.; Rutigliano, G. A Pilot Study on Plasma N-Acetylaspartate Levels at Admission and Discharge in Hospitalized Psychiatric Patients: Impact of Lithium Treatment and Clinical Correlations. Psychiatry Int. 2025, 6, 130. https://doi.org/10.3390/psychiatryint6040130

AMA Style

Pardossi S, Del Grande C, Campi B, Bertolini A, Capovani B, Fagiolini A, Zucchi R, Saba A, Cuomo A, Rutigliano G. A Pilot Study on Plasma N-Acetylaspartate Levels at Admission and Discharge in Hospitalized Psychiatric Patients: Impact of Lithium Treatment and Clinical Correlations. Psychiatry International. 2025; 6(4):130. https://doi.org/10.3390/psychiatryint6040130

Chicago/Turabian Style

Pardossi, Simone, Claudia Del Grande, Beatrice Campi, Andrea Bertolini, Barbara Capovani, Andrea Fagiolini, Riccardo Zucchi, Alessandro Saba, Alessandro Cuomo, and Grazia Rutigliano. 2025. "A Pilot Study on Plasma N-Acetylaspartate Levels at Admission and Discharge in Hospitalized Psychiatric Patients: Impact of Lithium Treatment and Clinical Correlations" Psychiatry International 6, no. 4: 130. https://doi.org/10.3390/psychiatryint6040130

APA Style

Pardossi, S., Del Grande, C., Campi, B., Bertolini, A., Capovani, B., Fagiolini, A., Zucchi, R., Saba, A., Cuomo, A., & Rutigliano, G. (2025). A Pilot Study on Plasma N-Acetylaspartate Levels at Admission and Discharge in Hospitalized Psychiatric Patients: Impact of Lithium Treatment and Clinical Correlations. Psychiatry International, 6(4), 130. https://doi.org/10.3390/psychiatryint6040130

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