Abstract
This study was conducted to investigate the effects of long-term low-dose lithium adjunct to antipsychotic agent use on the cognitive performance, whole-brain gray-matter volume (GMV), and interleukin-6 (IL-6) level in drug-naive patients with first-episode schizophrenia, and to examine relationships among these factors. In this double-blind randomized controlled study, 50 drug-naive patients with first-episode schizophrenia each took low-dose (250 mg/day) lithium and placebo (of the same shape and taste) adjunct to antipsychotic agents (mean, 644.70 ± 105.58 and 677.00 ± 143.33 mg/day chlorpromazine equivalent, respectively) for 24 weeks. At baseline and after treatment completion, the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive performance, 3-T magnetic resonance imaging was performed to assess structural brain alterations, and serum IL-6 levels were quantified by immunoassay. Treatment effects were assessed within and between patient groups. Relationships among cognitive performance, whole-brain GMVs, and the IL-6 level were investigated by partial correlation analysis. Relative to baseline, patients in the lithium group showed improved working memory, verbal learning, processing speed, and reasoning/problem solving after 24 weeks of treatment; those in the placebo group showed only improved working memory and verbal learning. The composite MCCB score did not differ significantly between groups. The whole-brain GMV reduction was significantly lesser in the lithium group than in the placebo group (0.46% vs. 1.03%; P < 0.001). The GMV and IL-6 reduction ratios correlated with each other in both groups (r = −0.17, P = 0.025). In the lithium group, the whole-brain GMV reduction ratio correlated with the working memory improvement ratio (r = −0.15, P = 0.030) and processing speed (r = −0.14, P = 0.036); the IL-6 reduction ratio correlated with the working memory (r = −0.21, P = 0.043) and verbal learning (r = −0.30, P = 0.031) improvement ratios. In the placebo group, the whole-brain GMV reduction ratio correlated only with the working memory improvement ratio (r = −0.24, P = 0.019); the IL-6 reduction ratio correlated with the working memory (r = −0.17, P = 0.022) and verbal learning (r = −0.15, P = 0.011) improvement ratios. Both treatments implemented in this study nearly improved the cognitive performance of patients with schizophrenia; relative to placebo, low-dose lithium had slightly greater effects on several aspects of cognition. The patterns of correlation among GMV reduction, IL-6 reduction, and cognitive performance improvement differed between groups.
Similar content being viewed by others
Introduction
Schizophrenia is characterized by cognitive impairment, which has major impacts on functional outcomes, in about 98% of cases1,2,3,4,5,6. This impairment can be broad in scope, affecting individuals’ executive functions and related processes, thereby substantially compromising their ability to plan, reason, solve problems, and think abstractly7. Many strategies have been proposed to rescue cognitive impairment in patients with schizophrenia8,9,10,11. Cognitive impairment in patients with schizophrenia has been related to gray-matter volume (GMV) reduction in key brain regions12,13,14,15,16,17,18,19 and increased interleukin-6 (IL-6) levels20,21.
GMV reduction is a typical structural change in patients with various neuropsychiatric disorders, resulting from the alteration of synaptic pruning and microglial and astrocytic function, and usually associated with cognitive impairment15,22. For example, Zierhut et al. 12 reported that GMV reductions in the temporal lobe and mediofrontal cortex were associated with the impairment of working memory and other cognitive dimensions.
High levels of the inflammatory factor IL-6 have been associated with cognitive impairment in first-episode and high-risk schizophrenia cases21,23,24,25,26,27,28,29,30,31,32,33,34. IL-6 affects neuronal transmission and survival in the prefrontal cortex and hippocampus and causes the reduction of gray-matter thickness, and thus cognitive impairment, in patients with schizophrenia and other mental disorders26,27,34,35,36,37,38,39,40,41 Several therapeutic agents, including antipsychotics, reduce the IL-6 level and thus alleviate this effect25,42,43,44,45,46,47. However, the ability of IL-6 and its receptor to cross and increase the permeability of the blood–brain barrier, enabling the entry of other inflammatory agents, may contribute to poor functional outcomes and treatment resistance in patients with schizophrenia31,48,49. Several mechanisms underlying these effects have been proposed50,51,52,53,54, but few studies have involved the examination of associations among IL-6 levels, GMV alterations in the frontal lobe and hippocampus, and cognitive impairment in such patients.
Lithium can reduce the oxidative inflammatory response, at least in part through the inhibition of glycogen synthase kinase-3β (GSK-3β) expression; this effect contributes to its efficacy in the treatment of mood disorders27,31,43,44,55,56,57,58. Through its effect on GSK-3β, lithium reduces transcription factor activity, thereby reducing the production of pro-inflammatory mediators [including interferon (IFN)-γ and IL-6] and increasing that of anti-inflammatory cytokines58,59,60,61; GSK-3β inhibition has the opposite effects61,62,63,64. Lithium’s inhibition of GSK-3β also leads to the reduction of pro-inflammatory cytokine production via the reduced activation of the signal transducer and activator of transcription62,63. In patients with bipolar disorder, 30- and 90-day lithium regimens reduced the levels of inflammatory markers, including IL-658,64,65. Similarly, an ex vivo study showed that lithium reduced the IL-6 production of lipopolysaccharide-stimulated monocytes from patients with bipolar disorder ex vivo66,67,68,69,70,71,72,73,74,75,76. Moreover, the effects of lithium on GSK-3β cascade (AKT/FoxO3a/β-catenin, AKT/GSK-3β/β-catenin, oxidative stress, and inflammatory factor pathway) activity are neuroprotective. These cascades play critical roles in brain development and were found to impair cognitive function in a murine model of schizophrenia, and their inhibition enhances frontal-lobe neural activity, improving cognitive function67,68,70,75,76. Lithium also improves cognitive performance by increasing the cortical N-acetyl-aspartate concentration69,74.
This evidence converges to support the association of cognitive impairment in schizophrenia with GMV reduction and increases in the IL-6 level. Lithium improves such impairment by regulating IL-6. Exploration of the relationships among these factors will provide useful information guiding the development of strategies to reduce cognitive impairment in schizophrenia, especially first-episode schizophrenia in drug-naive patients. In this double-blind randomized controlled study, we used an IL-6 immunoassay, 3.0-T magnetic resonance imaging (MRI), and the MATRICS Consensus Cognitive Battery (MCCB) to investigate the associations among the IL-6 level, GMV alterations, and cognitive impairment in drug-naive patients with first-episode schizophrenia. We hypothesized that: 1) a 24-week regimen of low-dose lithium adjunct to antipsychotic agent use would improve patients’ cognitive performance relative to placebo and 2) that the improved cognitive performance would correlate with alterations of the GMV and/or IL-6 level.
Methods
Participants and group allocation
For this study, we enrolled 100 consecutive drug-naive patients with first-episode schizophrenia who were treated at the psychiatry departments of Tianjin Fourth Center Hospital, Tianjin Anding Hospital, and Wenzhou Seventh Peoples Hospital, between December 2019 and December 2022. The inclusion criteria were: 1) hospital visitation due to the experience of schizophrenic symptoms for the first time, 2) diagnosis with schizophrenia according to the Structured Clinical Interview for DSM-IV axis 1 disorders (SCID-I) by two senior psychiatrists77,78,79, and 3) no antipsychotic use prior to hospital visitation. The exclusion criteria were: 1) psychotic symptoms not meeting the DSM-IV criteria for schizophrenia, 2) diagnosis of personality disorder, 3) history of a mental disorder induced by physical factors (e.g., severe premenstrual syndrome), 4) history of substance abuse, 5) neurological or other severe physical disease that could influence mental status, 6) MRI contraindication, and 7) refusal to participate in the study. The patients were randomly allocated to two groups receiving placebo and low-dose (250 mg/day) lithium, respectively, adjunct to antipsychotic agents (n = 50/group, duration = 24 weeks). All patients received antipsychotic agents to alleviate schizophrenia symptoms. Their liver, thyroid, and kidney functions were monitored weekly. This study was approved by the ethics committees of the three hospitals (Tianjin Fourth Center Hospital IRB no. 2018KY09), and was conducted in compliance with the Declaration of Helsinki. All participants volunteered to take part in this study and provided informed consent.
Clinical assessment
A research assistant arranged clinical visits and MRI examinations for potentially eligible participants. At the patient visits, two attending psychiatrists collected demographic and clinical information, performed clinical assessments with SCID-I administration, and established schizophrenia diagnoses80. The Positive and Negative Syndrome Scale (PANSS)81 was used to assess schizophrenic symptom severity and the MCCB82 was used to assess cognitive performance.
IL-6 measurement
Serum samples were collected from the patients and stored at −80 °C. Researchers blinded to participants’ group allocation measured serum IL-6 levels using a Quantikine® immunoassay (R&D Systems, Inc., Minneapolis, MN, USA) according to the manufacturer’s instructions. The intra- and inter-assay coefficients of variability were 1.6–4.2% and 3.3–6.4%, respectively83,84,85.
MRI examination and image processing
All study participants underwent 3.0-T MRI examination (Discovery MR750; General Electric, Milwaukee, WI, USA) 24 h after clinical assessment. They were given instructions to assure examination effectiveness and safety. T1-weighted (magnetization-prepared rapid acquisition gradient echo) sequences were performed with the following parameters: repetition/echo time (TR/TE), 8.2/3.2 ms; inversion time, 450 ms; flip angle (FA), 12°; field of view (FOV), 256 × 256 mm; matrix, 256 × 256; slice thickness, 1 mm (no gap); and 188 sagittal slices. An experienced clinician screened the images for anatomical abnormalities and artifacts. The T1-weighted images were then processed automatically [with skull dissection, bias field correction, and alignment to Montreal Neurological Institute (MNI) standard space (template 152)] using the Computational Anatomy Toolbox 12 (CAT12, build 1184; Structural Brain Mapping Group, Jena University Hospital, Germany) extension of Statistical Parametric Mapping 12 (Institute of Neurology, University College London, London, UK) in MATLAB (2018b; MathWorks, Inc., Natick, MA, USA). GM/white matter/cerebrospinal fluid segmentation was performed. Group-specific templates were created using a DARTEL algorithm and used as a reference for the non-linear warping and normalization of the segmented images in native space. The CAT12 default parameters and a DARTEL algorithm were used to preprocess the structural MRI data, with bias correction, clarification of tissue type, spatial registration, normalization, and segmentation. For all images, the CAT12 “check data quality using covariance” procedure was executed for quality control.
GMV calculation
Following segmentation, affine registration to MNI space and nonlinear deformation (using exponentiated Lie algebra) of the GM concentration maps were performed. The data were resampled (cubic voxel size, 3 mm3), and voxel-wise GMVs were determined by multiplying the GM map data by the non-linear determinants from spatial normalization. The GM images were smoothed with a 6-mm3 full-width-at-half-maximum Gaussian kernel and preprocessed spatially, yielding smoothed maps for statistical analysis. Whole-brain GMV alteration ratios were calculated for the two groups as follows: pretreatment – posttreatment whole-brain GMV/pretreatment whole-brain GMV.
Statistical analysis
Demographic and clinical variables (age, sex, antipsychotic agent dosage, and educational level) were compared between groups using the SPSS software (version 23.0 for Windows; IBM Corporation, Armonk, NY, USA). Continuous variables are expressed as means ± standard deviations and categorical values are expressed as numbers and percentages. They were compared between groups using repeated-measures analysis of variance, the Mann–Whitney test, Student’s t test, and the chi-squared test Bonferroni correction for multiple testing was performed and the significance level was set to P < 0.05. The threshold of P < 0.05 was also used for cluster-level familywise error–corrected data after the application of an initial cluster-forming threshold of P < 0.01. Analysis of covariance was performed to compare the changes in variables from baseline to 24 weeks, adjusted by the baseline levels, between groups. Partial correlation analysis16,18,26,29,86 was performed to examine the relationships of cognitive performance to alterations in the whole-brain GMV and IL-6 level and between the latter, with adjustment for age, education level, schizophrenia duration, total PANSS score, and antipsychotic agent dosage (chlorpromazine equivalent).
Results
Participant characteristics
In total, 73 patients (37 in the lithium group and 36 in the placebo group) with a mean age of 22.5 ± 2.6 years and mean illness duration of 3.7 ± 1.2 months completed the study. Data from 27 patients were excluded due to the presence of major artifacts or anatomical abnormalities on MR images, failure to meet the CAT12 image quality criteria, or treatment termination. Chi-squared and t tests revealed no difference in baseline demographic or clinical characteristics or cognitive performance between the excluded and included patients. The 24 weeks’ cumulative antipsychotic agent dose did not differ significantly between the lithium and placebo groups (105,336.00 ± 8276.25 mg and 106,158.00 ± 8588.287 mg, respectively). The categories of antipsychotic agents and doses are listed in Table 1. No adverse renal event occurred during the study period. The patients’ demographic and baseline clinical characteristics are provided in Table 2.
Decreases in PANSS and MCCB scores
PANSS scores decreased significantly after treatment in both groups (Tables 2–5), with no significant difference between groups. MCCB scores in the processing speed and working memory domains improved significantly in both groups; the verbal learning score also improved significantly after treatment in the lithium group, but only processing speed and working memory were significant in placebo group. The alteration rates of MCCB scores in attention/vigilance, working memory, reasoning/problem solving, and social cognition scores changed more in the lithium group than in the placebo group (Table 5). However, no significant within- or between-group difference in the composite MCCB score was observed.
GMV alterations
At baseline, GMVs did not differ significantly between groups (Fig. 1). After 24 weeks of treatment, they were significantly lower in the placebo group than in the lithium group (P < 0.001; Fig. 2).
Relative to baseline, the lithium group showed GMV reductions mainly in the bilateral occipital, parietal, temporal, and frontal lobes, and GMV increases mainly in the left dorsal frontal, lateral parietal, and occipital lobes and bilateral frontal and parietal lobes and thalamus. This group showed 0.46% whole-brain GMV reduction (P < 0.001; Fig. 3). The placebo group showed GMV reductions mainly in the bilateral cingulated gyrus and posterior occipital, temporal, parietal, and frontal lobes and GMV increases mainly in the bilateral prefrontal, left parietal and frontal, and right temporal lobes. This group showed 1.03% whole-brain GMV reduction (P < 0.001; Fig. 4).
IL-6 alterations
The IL-6 level differed significantly between the lithium and placebo groups after treatment (Tables 3 and 4). Compared with baseline, this level decreased significantly by 64.01% in the lithium group and 55.64% in the placebo group; the IL-6 reduction ratio differed significantly, favoring the lithium group (Table 5).
Correlations among the IL-6 level, whole-brain GMV alterations, and cognitive performance
In the lithium group, the whole-brain GMV reduction ratio correlated with the IL-6 reduction ratio (r = −0.19, P = 0.040), verbal learning improvement ratio (r = −0.17, P = 0.025), working memory improvement ratio (r = −0.15, P = 0.030), and processing speed (r = −0.14, P = 0.036). The IL-6 reduction ratio correlated with the verbal learning (r = −0.30, P = 0.031) and working memory (r = −0.21, P = 0.043) improvement ratios in this group. In the placebo group, the whole-brain GMV reduction ratio correlated only with the working memory improvement ratio (r = −0.24, P = 0.019) and the IL-6 reduction ratio correlated with the working memory (r = −0.17, P = 0.022) and verbal learning (r = −0.15, P = 0.011) improvement ratios.
Discussion
Our findings showed that a low-dose lithium regimen adjunct to antipsychotic agent use improved some cognitive domains (processing speed, working memory, and verbal learning) in drug-naive patients with first-episode schizophrenia, but resulted in no significant improvement in global cognition. However, our data provide clues for further investigation to identify the ideal treatment strategy to reduce cognitive impairment in patients with schizophrenia.
The PANSS score reductions in both groups indicate that the relief of the patients’ schizophrenic symptoms can be attributed mainly to the antipsychotic agents. Regarding the improvement of the processing speed and working memory in the placebo group, some research has shown that the second-generation antipsychotics used in this study reduce cognitive impairment87, such as risperidone, quetiapine, olanzapine and aripiprazole, but results have been inconsistent88. Our results suggest that the antipsychotics had protective effects in specific cognition domains, but the lithium group showed more extensive benefits for cognitive performance.
Reductions of the whole-brain GMV and IL-6 level were associated with improved processing speed, working memory, and verbal learning in both groups. The observed whole-brain GMV reduction (despite increases in some brain regions) is consistent with reports that antipsychotic agents can cause brain impairment while alleviating schizophrenic symptoms89,90. Given the known positive effects of antipsychotics on cognition, the effect of lithium on cognitive impairment possibly have been synergistic, and lithium did not enhance the alleviation of schizophrenic symptoms. In contrast, low-dose lithium has been found to protect against mild cognitive impairment (MCI) and dementia by increasing the GMV91,92. A review showed that lithium increases the GMV by preventing inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction via the phosphatidylinositol-3 (PI3)/Akt/GSK-3β and PI3/Akt/cAMP response element-binding protein/brain-derived neurotrophic factor signaling pathways93. Our results are inconsistent with these findings, as regional GMV increases did not overcome the reduction of the whole-brain GMV. The reason for this discrepancy is unclear, and further research on the effects of lithium on the whole-brain GMV is needed.
We observed substantial reductions of the IL-6 level in both groups in this study, consistent with previous findings26,94,95. Our finding that this reduction was significantly greater in the lithium group than in the placebo group is consistent with the lithium-induced reduction of the IL-6 level via PI3K/Akt/GSK-3β pathway regulation observed in animal models of cognitive impairment, including mouse models of MCI and dementia62,96,97,98,99,100,101,102. The mechanism by which lithium reduces cognitive impairment in patients with dementia, MCI, and schizophrenia has not been explored thoroughly, and our results provide a clue for further study.
We cannot fully explain the complex correlations among whole-brain GMV and IL-6 level reductions and cognitive alterations observed in this study. They may be related to mechanisms involving the PI3K/Akt/GSK-3β pathway, homeostasis, the genetic modulation of lithium-induced neural progenitor proliferation, neurotrophic effects, oxidative stress, and/or inflammatory factors22,26,42,43,44,45,62,96,97,98,99,100,101,102,103,104,105,106,107,108,109. These correlations imply the occurrence of counterintuitive phenomena; for example, adjunct lithium and antipsychotic agent treatments may both induce whole-brain GMV reduction. A decrease in the IL-6 level is usually associated with increased GMV22,110,111,112, but we observed reductions of both. Further research is needed to clarify these complex relationships and underlying mechanisms.
Strengths and limitations
The main strength of the present study is that it was conducted with drug-naive patients with first-episode schizophrenia, thereby avoiding the potentially biasing influence of medications. This work, however, has several limitations. First, we did not examine the factors underlying the complex correlations among whole-brain GMV and IL-6 level reduction and cognitive alterations. Second, we focused on IL-6 alterations, although other inflammatory factors such as IL-12, IL-1β, tumor necrosis factor-α, and C-reactive protein have crucial effects on the GMV and cognitive performance of patients with schizophrenia, which may explain the inconsistencies between our data and previous findings. Third, the benefits of lithium use in the treatment of schizophrenia have not been fully acknowledged72,73; we observed no adverse event in this study, but the benefits and risks of this treatment strategy need to be examined further. Fourth, the second antipsychotic agents used in some cases after the failure of primary agents to alleviate schizophrenic symptoms differed among patients in this study; although the dosages were normalized to chlorpromazine equivalents, different agents target different symptoms of schizophrenia and the diversity of antipsychotic agent regimens may have confounded our study. Finally, whether lithium interacts with antipsychotic agents remains unclear, and potential underlying mechanisms need further study. Further well-designed studies with large samples are needed to clarify these discrepancies.
Conclusion
The two treatments administered in this study improved specific domains of the cognitive performance of drug-naive patients with first-episode schizophrenia. Low-dose lithium adjunct to antipsychotic agent use had a nearly significant effect on the reduction of cognitive impairment relative to placebo. The patterns of correlation among GMV, and IL-6 level reduction and improved cognitive performances differed between treatment groups.
Data availability
The datasets used and analyzed in the current study are available from the corresponding author Chuanjun Zhuo on reasonable request. Anonymized data supporting the findings of this study are available upon reasonable request from the corresponding author for research purposes exclusively.
References
Briend, F. et al. Hippocampal glutamate and hippocampus subfield volumes in antipsychotic-naive first episode psychosis subjects and relationships to duration of untreated psychosis. Transl. Psychiatry 10, 137 (2020).
Feng, N. et al. Working memory processing deficit associated with a nonlinear response pattern of the anterior cingulate cortex in first-episode and drug-naive schizophrenia. Neuropsychopharmacology 48, 552–559 (2023).
Fett, A. J., Reichenberg, A. & Velthorst, E. Lifespan evolution of neurocognitive impairment in schizophrenia—A narrative review. Schizophr Res. Cogn. 28, 100237 (2022).
Javitt, D. C. Cognitive impairment associated with schizophrenia: from pathophysiology to treatment. Annu. Rev. Pharmacol. Toxicol. 63, 119–141 (2023).
Keefe, R. S., Eesley, C. E. & Poe, M. P. Defining a cognitive function decrement in schizophrenia. Biol. Psychiatry 57, 688–691 (2005).
Zhao, X. et al. Facial emotion perception abilities are related to grey matter volume in the culmen of cerebellum anterior lobe in drug-naive patients with first-episode schizophrenia. Brain Imaging Behav. 16, 2072–2085 (2022).
Heinrichs, R. W. & Zakzanis, K. K. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 12, 426–445 (1998).
Martínez, A. L., Brea, J., Rico, S., de Los Frailes, M. T. & Loza, M. I. Cognitive deficit in schizophrenia: from etiology to novel treatments. Int. J. Mol. Sci. 22, 9905 (2021).
Mould, A. W., Al-Juffali, N., von Delft, A., Brennan, P. E. & Tunbridge, E. M. Kalirin as a novel treatment target for cognitive dysfunction in schizophrenia. CNS Drugs 36, 1–16 (2022).
Sohal, V. S. Transforming discoveries about cortical microcircuits and gamma oscillations into new treatments for cognitive deficits in schizophrenia. Am. J. Psychiatry 179, 267–276 (2022).
Vita, A. et al. European Psychiatric Association guidance on treatment of cognitive impairment in schizophrenia. Eur. Psychiatry 65, e57 (2022).
Zierhut, K. C. et al. Distinct structural alterations independently contributing to working memory deficits and symptomatology in paranoid schizophrenia. Cortex. 49, 1063–1072 (2013).
Li, Q. et al. Disassociated and concurrent structural and functional abnormalities in the drug-naive first-episode early onset schizophrenia. Brain Imaging Behav. 16, 1627–1635 (2022).
Palaniyappan, L. et al. Voxel-based morphometry for separation of schizophrenia from other types of psychosis in first episode psychosis. Cochrane Database Syst. Rev. 2015, Cd011021 (2015).
Sun, T. et al. Distinct Associations of Cognitive Impairments and Reduced Gray Matter Volumes in Remitted Patients with Schizophrenia and Bipolar Disorder. Neural Plast. 2020, 8859388 (2020).
Mohan, V. et al. Patterns of Impaired Neurocognitive Performance on the Global Neuropsychological Assessment, and Their Brain Structural Correlates in Recent-onset and Chronic Schizophrenia. Clin. Psychopharmacol. Neurosci. 21, 340–358 (2023).
Fan, Y. et al. Grey matter volume and its association with cognitive impairment and peripheral cytokines in excited individuals with schizophrenia. Brain Imaging Behav. 16, 2618–2626 (2022).
Torres, U. S. et al. Patterns of regional gray matter loss at different stages of schizophrenia: a multisite, cross-sectional VBM study in first-episode and chronic illness. Neuroimage Clin. 12, 1–15 (2016).
Hulshoff Pol, H. E. et al. Volume changes in gray matter in patients with schizophrenia. Am. J. Psychiatry 159, 244–250 (2002).
Frodl, T. & Amico, F. Is there an association between peripheral immune markers and structural/functional neuroimaging findings? Prog. Neuropsychopharmacol. Biol. Psychiatry 48, 295–303 (2014).
Halstead, S. et al. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry 10, 260–271 (2023).
Williams, J. A. et al. Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders: A Mendelian Randomization Study. JAMA Psychiatry 79, 498–507 (2022).
King, S. et al. Early life Adversity, functional connectivity and cognitive performance in Schizophrenia: the mediating role of IL-6. Brain Behav. Immun. 98, 388–396 (2021).
Kogan, S., Ospina, L. H. & Kimhy, D. Inflammation in individuals with schizophrenia—Implications for neurocognition and daily function. Brain Behav. Immun. 74, 296–299 (2018).
Zhang, L. et al. The effect of minocycline on amelioration of cognitive deficits and pro-inflammatory cytokines levels in patients with schizophrenia. Schizophr. Res. 212, 92–98 (2019).
Patlola, S. R., Donohoe, G. & McKernan, D. P. The relationship between inflammatory biomarkers and cognitive dysfunction in patients with schizophrenia: a systematic review and meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 121, 110668 (2023).
Dunleavy, C., Elsworthy, R. J., Upthegrove, R., Wood, S. J. & Aldred, S. Inflammation in first-episode psychosis: the contribution of inflammatory biomarkers to the emergence of negative symptoms, a systematic review and meta-analysis. Acta Psychiatr. Scand. 146, 6–20 (2022).
Huang, Z. et al. Predictive effect of Bayes discrimination in the level of serum protein factors and cognitive dysfunction in schizophrenia. J. Psychiatr. Res. 151, 539–545 (2022).
Adamowicz, D. H. et al. Associations between inflammatory marker profiles and neurocognitive functioning in people with schizophrenia and non-psychiatric comparison subjects. J. Psychiatr Res. 149, 106–113 (2022).
Çakici, N. et al. Altered peripheral blood compounds in drug-naive first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis. Brain Behav. Immun. 88, 547–558 (2020).
Upthegrove, R. & Khandaker, G. M. Cytokines, oxidative stress and cellular markers of inflammation in schizophrenia. Curr. Top Behav. Neurosci. 44, 49–66 (2020).
Yan, J. et al. Network Association of Biochemical and Inflammatory Abnormalities With Psychiatric Symptoms in First-Episode Schizophrenia Patients. Front. Psychiatry 13, 834539 (2022).
Gómez-Rubio, P. & Trapero, I. The Effects of Exercise on IL-6 Levels and Cognitive Performance in Patients with Schizophrenia. Diseases. 7, 11 (2019).
Frydecka, D. et al. Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation. Eur. Arch. Psychiatry Clin. Neurosci. 265, 449–459 (2015).
Bonilha, L. et al. Neurocognitive deficits and prefrontal cortical atrophy in patients with schizophrenia. Schizophr. Res. 101, 142–151 (2008).
Esquivel-Rendón, E. et al. Interleukin 6 Dependent Synaptic Plasticity in a Social Defeat-Susceptible Prefrontal Cortex Circuit. Neuroscience. 414, 280–296 (2019).
Leschak, C. J. et al. Ventromedial prefrontal cortex activity differentiates sick from healthy faces: associations with inflammatory responses and disease avoidance motivation. Brain Behav. Immun. 100, 48–54 (2022).
Masetto Antunes, M., Godoy, G., Masi, L. N., Curi, R. & Barbosa Bazotte, R. Prefrontal cortex and hippocampus inflammation in mice fed high-carbohydrate or high-fat diets. J. Med. Food 25, 110–113 (2022).
Sedaghat, K., Naderian, R., Pakdel, R., Bandegi, A. R. & Ghods, Z. Regulatory effect of vitamin D on pro-inflammatory cytokines and anti-oxidative enzymes dysregulations due to chronic mild stress in the rat hippocampus and prefrontal cortical area. Mol. Biol. Rep. 48, 7865–7873 (2021).
Suwaluk, A. & Chutabhakdikul, N. Long-term effects of prenatal stress on the development of prefrontal cortex in the adolescent offspring. J. Chem. Neuroanat 125, 102169 (2022).
Zalcman, S. et al. Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res. 643, 40–49 (1994).
Zhou, X., Tian, B. & Han, H. B. Serum interleukin-6 in schizophrenia: a system review and meta-analysis. Cytokine. 141, 155441 (2021).
Fond, G., Lançon, C., Korchia, T., Auquier, P. & Boyer, L. The role of inflammation in the treatment of schizophrenia. Front. Psychiatry 11, 160 (2020).
Roomruangwong, C. et al. The Role of Aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: the IRS-CIRS Theory of Schizophrenia. Mol. Neurobiol. 57, 778–797 (2020).
Zhang, X. Y. et al. Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J. Clin. Psychiatry. 65, 940–947 (2004).
Yu, X. et al. Fingolimod ameliorates schizophrenia-like cognitive impairments induced by phencyclidine in male rats. Br. J. Pharmacol. 180, 161–173 (2023).
Fang, X., Wang, Y., Chen, Y., Ren, J. & Zhang, C. Association between IL-6 and metabolic syndrome in schizophrenia patients treated with second-generation antipsychotics. Neuropsychiatr Dis. Treat. 15, 2161–2170 (2019).
Goldsmith, D. R. et al. Association of baseline inflammatory markers and the development of negative symptoms in individuals at clinical high risk for psychosis. Brain Behav. Immun. 76, 268–274 (2019).
Nikkheslat, N. et al. Childhood trauma, HPA axis activity and antidepressant response in patients with depression. Brain Behav. Immun. 87, 229–237 (2020).
Behrens, M. M., Ali, S. S. & Dugan, L. L. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J. Neurosci. 28, 13957–13966 (2008).
Behrens, M. M. & Sejnowski, T. J. Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex? Neuropharmacology. 57, 193–200 (2009).
Donegan, J. J., Girotti, M., Weinberg, M. S. & Morilak, D. A. A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex. J. Neurosci. 34, 953–962 (2014).
Fillman, S. G. et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol. Psychiatry 18, 206–214 (2013).
Lin, K. Y. et al. Memantine abolishes the formation of cocaine-induced conditioned place preference possibly via its IL-6-modulating effect in medial prefrontal cortex. Behav. Brain Res. 220, 126–131 (2011).
Beurel, E. & Jope, R. S. Inflammation and lithium: clues to mechanisms contributing to suicide-linked traits. Transl. Psychiatry 4, e488 (2014).
Fernandes, M. S. et al. Lithium is able to minimize olanzapine oxidative-inflammatory induction on macrophage cells. PLoS One 14, e0209223 (2019).
Leung, M. et al. Gray matter in first-episode schizophrenia before and after antipsychotic drug treatment. Anatomical likelihood estimation meta-analyses with sample size weighting. Schizophr. Bull. 37, 199–211 (2011).
Rapaport, M. H., Guylai, L. & Whybrow, P. Immune parameters in rapid cycling bipolar patients before and after lithium treatment. J. Psychiatr. Res. 33, 335–340 (1999).
Jope, R. S., Yuskaitis, C. J. & Beurel, E. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem. Res. 32, 577–595 (2007).
Martin, M., Rehani, K., Jope, R. S. & Michalek, S. M. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6, 777–784 (2005).
Yuskaitis, C. J. & Jope, R. S. Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal 21, 264–273 (2009).
Beurel, E. & Jope, R. S. Lipopolysaccharide-induced interleukin-6 production is controlled by glycogen synthase kinase-3 and STAT3 in the brain. J. Neuroinflammation 6, 9 (2009).
Rowse, A. L. et al. Lithium controls central nervous system autoimmunity through modulation of IFN-γ signaling. PLoS One 7, e52658 (2012).
Woodgett, J. R. & Ohashi, P. S. GSK3: an in-Toll-erant protein kinase? Nat. Immunol. 6, 751–752 (2005).
Kim, Y. K., Jung, H. G., Myint, A. M., Kim, H. & Park, S. H. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J. Affect Disord 104, 91–95 (2007).
Atre-Vaidya, N. & Taylor, M. A. Effectiveness of lithium in schizophrenia: do we really have an answer? J. Clin. Psychiatry 50, 170–173 (1989).
Campbell, I. H., Campbell, H. & Smith, D. J. Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder. Transl. Psychiatry 12, 350 (2022).
Chatterjee, D. & Beaulieu, J. M. Inhibition of glycogen synthase kinase 3 by lithium, a mechanism in search of specificity. Front. Mol. Neurosci. 15, 1028963 (2022).
Dell’Osso, L., Del Grande, C., Gesi, C., Carmassi, C. & Musetti, L. A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. Neuropsychiatr Dis. Treat 12, 1687–1703 (2016).
Jones, G. H., Rong, C., Shariq, A. S., Mishra, A. & Machado-Vieira, R. Intracellular signaling cascades in bipolar disorder. Curr. Top Behav. Neurosci. 48, 101–132 (2021).
Knijff, E. M. et al. An imbalance in the production of IL-1beta and IL-6 by monocytes of bipolar patients: restoration by lithium treatment. Bipolar Disord 9, 743–753 (2007).
Leucht, S., Helfer, B., Dold, M., Kissling, W. & McGrath, J. J. Lithium for schizophrenia. Cochrane Database Syst. Rev. 2015, Cd003834 (2015).
Leucht, S., McGrath, J. & Kissling, W. Lithium for schizophrenia. Cochrane Database Syst Rev. 3, Cd003834 (2003).
Moore, G. J. et al. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 48, 1–8 (2000).
Snitow, M. E., Bhansali, R. S. & Klein, P. S. Lithium and Therapeutic Targeting of GSK-3. Cells. 10, 255 (2021).
Wan, J. et al. Inhibition of the glycogen synthase kinase 3β-hypoxia-inducible factor 1α pathway alleviates NLRP3-mediated pyroptosis induced by high glucose in renal tubular epithelial cells. Exp. Physiol. 107, 1493–1506 (2022).
First, M. B., Gibson, M., Spitzer, R. L., Williams, J. B. W. & Benjamin, L. S. Structured Clinical Interview For DSM-IV Axis II Personality Disorders (SCID-II). (American Psychiatric Press, Washington, DC., 1997).
First, M. B. Clinical utility: a prerequisite for the adoption of a dimensional approach in DSM. J. Abnorm. Psychol. 114, 560–564 (2005).
Hirschfeld, R. M. et al. Validity of the mood disorder questionnaire: a general population study. Am. J. Psychiatry 160, 178–180 (2003).
First, M. B., Spitzer, R. L., Gibbon, M. & Williams, J. B. Structured clinical interview for DSM-IV-TR Axis I disorders: patient edition: Biometrics Research Department. (Columbia University, New York, NY, 2005).
Kay, S. R., Fiszbein, A. & Opler, L. A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276 (1987).
Shi, C. et al. The MATRICS Consensus Cognitive Battery (MCCB): Co-norming and standardization in China. Schizophr. Res. 169, 109–115 (2015).
Lasseter, H. C. et al. Cross-platform comparison of highly sensitive immunoassay technologies for cytokine markers: Platform performance in post-traumatic stress disorder and Parkinson’s disease. Cytokine X 2, 100027 (2020).
Pierce, M. E. et al. Plasma biomarkers associated with deployment trauma and its consequences in post-9/11 era veterans: initial findings from the TRACTS longitudinal cohort. Transl. Psychiatry 12, 80 (2022).
Komatsu, S. et al. Cholesterol Crystals as the Main Trigger of Interleukin-6 Production through Innate Inflammatory Response in Human Spontaneously Ruptured Aortic Plaques. J. Atheroscler Thromb. (2023). https://doi.org/10.5551/jat.64098.
Maurus, I. et al. Associations between aerobic fitness, negative symptoms, cognitive deficits and brain structure in schizophrenia-a cross-sectional study. Schizophrenia 8, 63 (2022).
Ohi, K., Muto, Y., Sugiyama, S. & Shioiri, T. Safety and Efficacy in Randomized Controlled Trials of Second-Generation Antipsychotics Versus Placebo for Cognitive Impairments in Schizophrenia: A Meta-Analysis. J. Clin. Psychopharmacol. 42, 227–229 (2022).
Takeuchi, H., Thiyanavadivel, S., Fervaha, G. & Remington, G. Neurocognitive Benefits of Second-Generation Antipsychotics Versus Placebo: Insufficient Evidence Based on a Systematic Review. J. Clin. Psychopharmacol. 37, 274–276 (2017).
Mitelman, S. A., Buchsbaum, M. S., Brickman, A. M. & Shihabuddin, L. Cortical intercorrelations of frontal area volumes in schizophrenia. Neuroimage. 27, 753–770 (2005).
Olabi, B. et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol. Psychiatry 70, 88–96 (2011).
Rybakowski, J. K., Suwalska, A. & Hajek, T. Clinical Perspectives of Lithium’s Neuroprotective Effect. Pharmacopsychiatry. 51, 194–199 (2018).
Ferensztajn-Rochowiak, E. & Rybakowski, J. K. The effect of lithium on hematopoietic, mesenchymal and neural stem cells. Pharmacol. Rep. 68, 224–230 (2016).
Ghanaatfar, F. et al. Is lithium neuroprotective? An updated mechanistic illustrated review. Fundam. Clin. Pharmacol. 37, 4–30 (2023).
Martins, P. L. B. et al. Immunoinflammatory and oxidative alterations in subjects with schizophrenia under clozapine: A meta-analysis. Eur. Neuropsychopharmacol. 73, 82–95 (2023).
Enache, D. et al. Peripheral immune markers and antipsychotic non-response in psychosis. Schizophr. Res. 230, 1–8 (2021).
Fenech, R. K. et al. Low-Dose Lithium Supplementation Influences GSK3β Activity in a Brain Region Specific Manner in C57BL6 Male Mice. J. Alzheimers Dis. 91, 615–626 (2023).
Wiseman, A. L. et al. Lithium Provides Broad Therapeutic Benefits in an Alzheimer’s Disease Mouse Model. J. Alzheimers Dis. 91, 273–290 (2023).
Wang, J. et al. Effects of different doses of lithium on the central nervous system in the rat valproic acid model of autism. Chem. Biol. Interact 370, 110314 (2023).
Jeong, E. S. et al. Therapeutic Effects of Hydrogen Gas Inhalation on Trimethyltin-Induced Neurotoxicity and Cognitive Impairment in the C57BL/6 Mice Model. Int. J. Mol. Sci. 22, 13313 (2021).
Toricelli, M., Evangelista, S. R., Buck, H. S. & Viel, T. A. Microdose Lithium Treatment Reduced Inflammatory Factors and Neurodegeneration in Organotypic Hippocampal Culture of Old SAMP-8 Mice. Cell Mol. Neurobiol. 41, 1509–1520 (2021).
Wilson, E. N. et al. NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats. J. Alzheimers Dis. 73, 723–739 (2020).
Wang, R., Zhang, Z., Kumar, M., Xu, G. & Zhang, M. Neuroprotective potential of ketamine prevents developing brain structure impairment and alteration of neurocognitive function induced via isoflurane through the PI3K/AKT/GSK-3β pathway. Drug Des Devel Ther. 13, 501–512 (2019).
Nemoto, T., Yanagita, T., Kanai, T. & Wada, A. Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: the role of GSK-3beta in the maintenance of steady-state levels of insulin receptor signaling molecules and Na(v)1.7 sodium channel in adrenal chromaffin cells. J. Pharmacol. Sci. 109, 157–161 (2009).
Wada, A. Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades. J. Pharmacol. Sci. 110, 14–28 (2009).
Tingskov, S. J. et al. Tamoxifen Affects Aquaporin-3 Expression and Subcellular Localization in Rat and Human Renal Collecting Ducts. Cells. 12, 1140 (2023).
George, M. Y. et al. Design and evaluation of chrysin-loaded nanoemulsion against lithium/pilocarpine-induced status epilepticus in rats; emphasis on formulation, neuronal excitotoxicity, oxidative stress, microglia polarization, and AMPK/SIRT-1/PGC-1α pathway. Expert. Opin. Drug Deliv. 20, 159–174 (2023).
Wolter, J. M. et al. Cellular Genome-wide Association Study Identifies Common Genetic Variation Influencing Lithium-Induced Neural Progenitor Proliferation. Biol. Psychiatry 93, 8–17 (2023).
Chumakov, E., Dorofeikova, M., Tsyrenova, K. & Petrova, N. A Cross-Sectional Study on Associations Between BDNF, CRP, IL-6 and Clinical Symptoms, Cognitive and Personal Performance in Patients With Paranoid Schizophrenia. Front. Psychiatry 13, 943869 (2022).
Miyamoto, S., Miyake, N., Jarskog, L. F., Fleischhacker, W. W. & Lieberman, J. A. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol. Psychiatry 17, 1206–1227 (2012).
Quidé, Y. et al. Systemic inflammation and grey matter volume in schizophrenia and bipolar disorder: Moderation by childhood trauma severity. Prog. Neuropsychopharmacol. Biol. Psychiatry 105, 110013 (2021).
Lizano, P. et al. Association of Choroid Plexus Enlargement With Cognitive, Inflammatory, and Structural Phenotypes Across the Psychosis Spectrum. Am. J. Psychiatry 176, 564–572 (2019).
Kalmady, S. V. et al. Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naive schizophrenia: evidence for differential susceptibility? PLoS One 9, e96021 (2014).
Funding
This work was sponsored by grants from the National Natural Science Foundation of China (82171503 to C.J.Z. and 81871052 C.J.Z.).
Author information
Authors and Affiliations
Contributions
C.J.Z., S.H. and G.C. conceived and designed the research; L.Y., Z.C. and H.T. collected the data and conducted the research; C.C., L.W., X.M. and R.L. analyzed and interpreted the data; wrote the initial draft of the manuscript; G.C., C.J.Z. and H.T. revised the manuscript; C.J.Z. and H.T. had primary responsibility for the manuscript’s final content. All authors read and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
This study was approved by the ethics committees of three hospitals (Tianjin Fourth Center Hospital, Tianjin Anding Hospital, and Wenzhou Seventh Peoples Hospital), and was conducted in compliance with the Declaration of Helsinki. All participants volunteered to take part in this study and gave written informed consent.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Zhuo, C., Hu, S., Chen, G. et al. Low-dose lithium adjunct to atypical antipsychotic treatment nearly improved cognitive impairment, deteriorated the gray-matter volume, and decreased the interleukin-6 level in drug-naive patients with first schizophrenia symptoms: a follow-up pilot study. Schizophr 9, 71 (2023). https://doi.org/10.1038/s41537-023-00400-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41537-023-00400-w