Layout 1 Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 The complexity of schizophrenia presents a formidable challenge for clinicians and researchers alike, especially when addressing cases that resist traditional pharmacological interventions.1,2 Schizophrenia, affecting roughly 1% of the population, frequently manifests with debilitating symptoms such as delusions and hallucinations, which in many cases remain unresponsive to conventional treatments like antipsychotics.3 Approximately 30% of patients with schizophrenia do not achieve adequate symptom relief from standard treatments, which involve failing two or more antipsychotic trials.1,4 Such patients are often prescribed clozapine, the most effective antipsychotic medication available. However, clozapine is reserved for cases of treatment-resistant schizophrenia because it carries the risk of agranulocytosis, a potentially life-threatening condition characterized by dangerously low levels of white blood cells.5,6 Even with clozapine treatment, only about 30% to 60% of patients experience improvement.5 For individuals who don’t respond to or cannot tolerate clozapine, alternative treatments are limited and often ineffective.7 Since schizophrenia imposes a substantial societal burden due to management costs and psychosocial impacts, there is an urgent need for improved methods of symptom control.8-12 Deep brain stimulation is emerging as a promising non- pharmacological option, particularly for cases resistant to conventional therapies.13 Its success in neuropsychiatric conditions such as Parkinson’s disease,14 treatment-resis- Abstract The complexity of schizophrenia, particularly in cases resistant to traditional pharmacological treatments, poses significant challenges for clinicians and researchers. This systematic review synthesizes existing evidence on the effectiveness of deep brain stimulation in treating treatment- resistant schizophrenia. Utilizing the PRISMA 2020 guidelines, a comprehensive literature search was conducted in March 2025 using the “Connected Papers” tool and other sources such as Web of Science, PubMed, PsycINFO, Embase, and Scopus, focusing on studies related to “deep brain stimulation,” “treatment-resistant schizophrenia,” and “refractory schizophrenia.” Four studies met the eligibility criteria, revealing that deep brain stimulation targeting specific brain regions, particularly the nucleus accumbens, can lead to significant symptomatic improvements in approximately 30% of patients unresponsive to conventional antipsychotics. Despite ten adverse events recorded across thirteen procedures, deep brain stimulation offers potential benefits for select individuals. While not universally superior to existing treatments, deep brain stimulation could inform clinical practice and decision-making, highlighting its role in multidisciplinary treatment frameworks. The findings underscore the importance of innovative therapeutic approaches in psychiatry and suggest broader implications for neuromodulation techniques across various psychiatric and neurological disorders, promoting personalized and effective treatment paradigms in mental healthcare. Key Words: deep brain stimulation, electrical stimulation of the brain, treatment-resistant schizophrenia, refractory schizophrenia, schizophrenia. Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Mohsen Khosravi Department of Psychiatry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran; Health Promotion Research Center, Zahedan University of Medical Sciences, Zahedan, Iran; Community Nursing Research Center, Zahedan University of Medical Sciences, Zahedan, Iran. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 341 - Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 tant depression,15 obsessive-compulsive disorder,16 sub- stance use disorders,17 and Tourette syndrome18 suggests that deep brain stimulation could effectively modulate dysfunctional brain circuits in schizophrenia, offering hope for improved management of the disorder.13 Pioneer- ing studies have notably highlighted the possibility of using deep brain stimulation to target specific brain re- gions, such as the nucleus accumbens (likely the strongest candidate for deep brain stimulation electrode placement in schizophrenia), the subgenual anterior cingulate cortex, the ventral tegmental area, the substantia nigra pars retic- ulata, and the habenula.13 These regions have been con- nected to the modulation of dopaminergic, glutamatergic, and GABAergic pathways, which may provide insights into the neurochemical underpinnings of schizophrenia.19 However, deep brain stimulation has been minimally ex- plored as a treatment for treatment-resistant schizophrenia. An early study from the 1950s reported intense rage and fear during amygdala stimulation in a patient with schizo- phrenia, but subsequent research on this application of deep brain stimulation was lacking until recent years.20 Accordingly, this systematic review aims to synthesize ex- isting evidence regarding the effectiveness of deep brain stimulation in treating treatment-resistant schizophrenia, addressing both the observed clinical benefits and the challenges to the widespread implementation of this ther- apeutic approach. By examining the nuances of stimula- tion techniques, patient selection criteria, and the neurobiological mechanisms involved, this review will il- luminate promising avenues for future research while ac- knowledging the ongoing ethical discussions regarding informed consent and the management of adverse effects associated with surgical interventions. Furthermore, as our understanding of the underlying pathophysiology of schizophrenia continues to evolve, there is a pressing need for innovative approaches that encompass multidiscipli- nary perspectives and integrate findings from neuroimag- ing, clinical evaluations, and patient-reported outcomes. Therefore, this review not only highlights the necessity for rigorous methodological designs in deep brain stimu- lation trials but also calls for a collaborative effort to un- ravel the patient-specific factors that might enhance the precision and effectiveness of deep brain stimulation as a viable treatment for those suffering from this complex and often debilitating disorder. Materials and Methods Search strategy The study adhered to the PRISMA 2020 checklist and conducted a systematic review of the literature in March 2025 using “Connected Papers” (www.connectedpapers.com)—a visual exploration tool that accesses data from the Semantic Scholar Paper Cor- pus, which is licensed under ODC-BY, as well as other sources such as Web of Science, PubMed, PsycINFO, Em- base, and Scopus.21 The search focused on studies related to “deep brain stimulation,” “treatment-resistant schizo- phrenia,” and “refractory schizophrenia,” employing spe- cific Boolean modifiers to refine the results. Two inde- pendent researchers evaluated the titles and abstracts of potential articles, selecting those that met the eligibility criteria for further analysis. When primary evaluators dis- agreed about including a study, a third evaluator was con- sulted to make the final decision. Eligibility criteria The study focused on original research articles related to treatment-resistant schizophrenia and deep brain stimula- tion treatment, excluding other disorders, non- deep brain stimulation treatments, non-human studies, and review ar- ticles. The selected articles were peer-reviewed and in- cluded case reports, case series, or randomized trials in English. There was no exclusion based on the publication date. Data extraction Two authors created a citation list by screening titles and abstracts, and then independently evaluated full-text ar- ticles based on agreed-upon eligibility criteria. They ex- tracted data on the country, study design, number of patients, participant characteristics, minimum duration of illness, target location(s), primary outcome measure(s), length of follow-up, mean score improvement, responders (i.e., those with a Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) reduc- tion of ≥25%), and the number and time to resolution of transient/serious adverse events for comparison. Due to the small number of patients in eligible studies, they couldn’t quantitatively assess the strength of the evidence. Three primary scales were used: the PANSS, the BPRS, and the Scale for the Assessment of Negative Symptoms (SANS). PANSS is a 30-item scale that assesses positive symptoms, negative symptoms, and general psychopathol- ogy, with each item rated from one to seven to indicate symptom severity.22 BPRS examines up to 24 psychotic symptoms, also using a one-to-seven rating system for severity.23 SANS evaluates negative symptoms with a 25- item scale scored from zero to five per item.24 Quality assessment Two authors independently evaluated the risk of bias for each study’s outcome, following AHRQ guidelines.25 Results Study selection A comprehensive search of “Connected Papers” yielded 90 titles. No additional articles were identified from other sources such as Web of Science, PubMed, PsycINFO, Em- base, and Scopus. A bibliometric co-authorship analysis using VOSviewer (version 1.6.20) revealed that 195 authors met the minimum threshold of one document per author, as presented in Figure 1. After removing duplicates, 77 unique titles remained. Following a screening process based on ti- tles and abstracts, ten articles were shortlisted. However, further evaluation led to the exclusion of two review ar- ticles, one study protocol, a repetitive longitudinal study, a - 342 - http://www.connectedpapers.com Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 case report, and a case series due to data similarity with a randomized trial. Ultimately, four articles met the eligibility criteria and were included in the final selection, as depicted in Figure 2. Study design In a review of four selected studies, one was a pilot ran- domized crossover clinical trial, two were case series, and one was a case report focusing on deep brain stimulation for treatment-resistant schizophrenia. A total of 13 patients (6 females and 7 males) were involved across these studies, although one patient was excluded due to complications but was later replaced by another patient. The studies aimed to treat both positive and negative symptoms using deep brain stimulation and assessed the effects over varying follow-up periods. Wang et al.26 intended a 12-month stimulation period but faced deviations, with one patient receiving only 10 months of stimulation. The other studies reported stim- ulation durations of 12 months.27,28 The randomized trial al- lowed continued stimulation until clinical stability was achieved, followed by a double-blind crossover phase for patients with significant improvement (≥ 25% PANSS re- duction).29 Subsequently, these eight patients, including the replacement case, successfully completed a three-year fol- low-up.30 The study examined four different brain regions in 13 pa- tients: the subgenual anterior cingulate cortex (n = 4), nu- cleus accumbens (n = 6), habenula (n = 2), and substantia nigra pars reticulata (n = 1), all linked to the pathophysi- ology of schizophrenia. The subgenual anterior cingulate cortex is part of the default mode network, which controls the brain’s resting state. Some studies suggest that patients with schizophrenia exhibit decreased deactivation of this network during tasks, although this remains debated.31-33 There is more consensus regarding dopamine dysregula- tion in schizophrenia. A proposed model indicates that ab- normal excitatory input from the hippocampus to the nucleus accumbens causes the ventral tegmental area to be released from ventral pallidal inhibition, leading to ex- cessive dopamine release back into the nucleus ac- cumbens.34-37 The dopamine system can also be directly targeted through the substantia nigra, a key brain structure involved in dopamine regulation. In schizophrenia, re- duced cortical function decreases striatal inhibition of the substantia nigra, resulting in increased dopamine release to the striatum and inhibited thalamic activity, amplifying cortical dysfunction.38,39 Additionally, the habenula’s in- hibitory inputs to the substantia nigra and ventral tegmen- tal area are questioned for their role in schizophrenia, as habenular dysfunction can cause excessive dopamine re- lease from these areas.40,41 Outcomes The study involved 13 patients undergoing stimulation for an average of 26.61 ± 12.36 months (see Table 1). Twelve patients showed improvement in their outcome measures, whereas one patient’s condition deteriorated.26-30 Despite initial improvements in their PANSS score by 10.8% at six months and 20.3% at seven months, this patient was even- - 343 - Figure 1. The bibliometric analysis of co-authorship using VOSviewer: (a) network visualization based on document weights; (b) overlay visualization based on document weights and average publishing year, with a minimum score of 2014 and a maximum of 2022; (c) density visualization of 30 clusters, 933 links, and a total link strength of 1056. Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 tually withdrawn due to a psychotic episode after ten months. At this point, their PANSS score had decreased by 9.5% from the baseline, with significant increases in both positive (69.2%) and negative (4.3%) symptoms, leading to their hospitalization.26 Out of the twelve patients with lower outcomes at follow- up, only four (one person from each brain stimulation region) showed significant improvement, achieving a reduction of 25% or more in PANSS or BPRS scores. The other pa- tients exhibited varied levels of symptom improvement. - 344 - Figure 2. PRISMA flow diagram. Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 - 345 - Table 1. Characteristics of the articles included. Authors (year) Corripio et al., Wang et al., Cascella et al., Bioque et al., 202029/Aibar-Durán 202026 202128 202327 et al., 202330* Country Spain China United States Spain Study design Randomized clinical Case series Case report Case series trial Number of patients 8 2 1 2 Median age (year) / 43 / 62.5% 23.5 / 0% 35 / 100% 49 / 0% Female (%) Minimum duration of 5 4 16 19 illness (year) Electrode placement Bilateral NAc (n=4) Bilateral Hb Bilateral SNr Bilateral NAc Bilateral sgACC (n=4) Length of follow-up 36 10 to 12 12 12 (months) Primary outcome PANSS PANSS BPRS, SANS PANSS measure(s) Mean score Bilateral NAc T-PANSS: 11.1% BPRS: 52.38% T-PANSS: 21.76% improvement (%) T-PANSS: 17% P-PANSS: -7.7% SANS: Not specified P-PANSS: Not specified P-PANSS: 19.75% N-PANSS: 13.7% N-PANSS: Not specified N-PANSS: 10% G-PANSS: 14.35% G-PANSS: Not specified G-PANSS: 19.75% Bilateral sgACC T-PANSS: 15.5% P-PANSS: 17.75% N-PANSS: 9.75% G-PANSS: 16.5% Responders (i.e., Bilateral NAc T-PANSS: 1 BPRS: 1 T-PANSS: 1 those with a PANSS T-PANSS: 0 P-PANSS: 1 SANS: Not specified P-PANSS: Not specified or BPRS reduction P-PANSS: 3 N-PANSS: 1 N-PANSS: Not specified of ≥25%) N-PANSS: 0 G-PANSS: 0 G-PANSS: Not specified G-PANSS: 2 Bilateral sgACC T-PANSS: 1 P-PANSS: 2 N-PANSS: 1 G-PANSS: 1 *Durán et al.’s study summarizes the outcomes of the participants in Corripio et al.’s study after a three-year follow-up. Although in Corripio et al.’s study one patient was withdrawn due to serious complications (n=7), in Durán et al.’s study this vacancy was filled by another patient (n=8). BPRS, brief psychiatricrating scale; Hb, habenula; NAc, nucleus accumbens; PANSS, positive and negative syndrome scale; T-PANSS, PANSS total score; P-PANSS, PANSS positive subscale; N-PANSS, PANSS negative subscale; G-PANSS, PANSS general psychopathology subscale; SANS, scale for the assessment of negative symptoms; sgACC, subgenual anterior cingulate cortex; SNr, substantia nigra pars reticulata. Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 One patient with a subgenual anterior cingulate cortex im- plant and another with a nucleus accumbens implant showed increased negative PANSS scores.29 Meanwhile, a patient implanted in the substantia nigra pars reticulata experienced a substantial reduction in positive symptoms but only slight reductions in some negative symptoms. This same patient also had mixed results in cognitive testing, with decreased performance in verbal and visuospatial learning/memory but improved performance in verbal fluency.28 In a crossover phase trial involving deep brain stimulation for schizophrenia, only three of the original seven patients participated. One patient with a nucleus accumbens implant began with active stimulation, while two others with a sub- genual anterior cingulate cortex implant started without it. Both patients in the no-stimulation group experienced wor- sened symptoms and were withdrawn before completing the crossover. The patient who commenced with stimula- tion also reported worsening negative symptoms when the stimulation was turned off but completed the trial. However, these symptoms persisted even after resuming stimulation. A fourth patient with a nucleus accumbens implant qual- ified for the crossover phase but declined to participate; this patient’s symptoms had previously worsened during an ac- cidental lapse in stimulation. Overall, when stimulation was turned off, all four participating patients exhibited worsened symptoms compared to their condition during active stim- ulation.29 This pattern, along with the overall improvement observed in 12 out of 13 patients across various studies, in- dicates that deep brain stimulation could be a promising treatment for refractory schizophrenia.26-30 Quality assessment The risk of bias for each study is comprehensively eval- uated and detailed in Table 2. - 346 - Table 2. Assessment of risk of bias in each study. Authors (year) Corripio et al., Wang et al., Cascella et al., Bioque et al., 202029/Aibar-Durán 202026 202128 202327 et al., 202330 Selection bias Randomization Yes Not applicable Not applicable Not applicable Accounted for No No No No confounding Performance bias Accounted for Yes No No No concurrent intervention/ unintended exposure Fidelity to Yes Yes Yes Yes intervention protocol Attrition bias Missing data handled Yes No Not applicable Not applicable appropriately Detection bias Interventions defined Yes Yes Yes Yes using reliable measures Outcomes defined Yes Yes Yes Yes using reliable measures Outcome assessors No No No No blinded Reporting bias Outcomes prespecified Yes No No No Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 Adverse events In the four studies, ten adverse events were recorded across thirteen procedures. Eleven adverse events occurred, with six classifieds as serious.26-30 Most of the serious adverse events were observed in a single randomized trial, primarily affecting one patient.29 This patient was scheduled to re- ceive nucleus accumbens deep brain stimulation, but due to postoperative complications, including a right internal capsule hemorrhage and subsequent device infection, they did not undergo stimulation. This necessitated complete hardware removal three months after surgery. Although the patient did not suffer permanent neurological deficits, they experienced seizures that were manageable with antiepilep- tic drugs. Another significant serious adverse event in- volved mood instability with occasional suicidal thoughts, which correlated with the patient’s discontinuation of their antipsychotic regimen (see Table 3). Previously, a combi- nation of antipsychotics and deep brain stimulation had shown symptom reduction for this patient.29 Five transient adverse events were experienced by individ- uals during the deep-brain stimulation procedure.28,29 Ini- tially, akathisia occurred when the stimulation was shifted from unilateral to bilateral but was effectively resolved by reverting to unilateral stimulation. Secondly, one individual experienced occasional electrical sensation in the trunk and head following specific body movements, which were miti- gated by switching the stimulation from unipolar to bipolar mode. Thirdly, confusion arose after a right-sided perioper- ative hemorrhage but subsided naturally after four days without intervention.29 Another case involved increased ap- petite over three months, resulting in a significant weight gain of 33 pounds (15 kg), which also resolved itself over time. Lastly, one patient showed decreased performance in verbal and visuospatial learning and memory tests; ho- wever, the details surrounding this final event were not specified.28 Discussion Striking a balance between innovative therapeutic strategies and established treatment protocols is crucial in addressing the complexities of treatment-resistant schizo- phrenia. Within this context, the systematic review elu- cidates the efficacy of deep-brain stimulation as a potential intervention. Findings indicate that deep brain stimulation effectively alleviates symptoms in a significant proportion of individuals with treatment-resistant schizophrenia, with approximately 30% of patients reporting symptomatic re- lief, particularly in positive symptoms such as hallucina- tions and delusions.26-30 The outcomes align with previous studies that demonstrate similar efficacy rates for deep brain stimulation in treating refractory neuropsychiatric conditions.14-18 Despite reports that higher amplitudes of nucleus accumbens stimulation can exacerbate psychotic symptoms when treating severe depression,42 a random- ized trial in treatment-resistant schizophrenia found that four patients did not experience worsening symptoms with higher stimulation parameters.29,30 This finding is sup- ported by earlier evidence where an individual with ob- sessive-compulsive disorder and a history of psychosis also showed no symptom worsening with increased stim- ulation amplitude.27 These observations suggest that higher nucleus accumbens stimulation may not univer- sally exacerbate psychotic symptoms in depression or ob- sessive-compulsive disorder patients. One of the key mechanisms by which deep brain stimulation may be ef- fective in treating treatment-resistant schizophrenia is its ability to modulate the activity of specific brain regions associated with the disorder. Studies have shown that elec- trical stimulation can influence the flow of impulses through neural pathways, potentially restoring the balance and proper functioning of the affected brain circuits.43,44 In addition to its direct impact on brain activity, deep brain stimulation may also have indirect effects on the underly- ing pathophysiology of schizophrenia. Some research sug- gests that the technique may have neuroprotective properties, potentially slowing or even reversing the pro- gressive neurodegeneration observed in schizophrenia.44,45 Furthermore, deep brain stimulation has been associated with improvements in cognitive function and overall qual- ity of life in some patients with schizophrenia.47,48 The im- provements in scores on other scales, such as the Calgary Depression Scale for Schizophrenia, the Hamilton Depres- sion Rating Scale, the Quality-of-Life Scale, and the WHO-5 Well-Being Index, further underscore the poten- tial multidimensional benefits of deep brain stimulation. These benefits extend beyond mere symptom manage- ment to enhance overall functional outcomes. Neverthe- less, despite its potential benefits, the precise mechanism by which deep brain stimulation exerts its therapeutic ef- fects in treatment-resistant schizophrenia remains largely unknown, necessitating further investigation to fully un- derstand and optimize this treatment modality.29,30 Given the heterogeneity of treatment-resistant schizophre- nia, different structures may be the ideal targets for deep- brain stimulation, depending on the specific symptoms. The findings from this review reiterate and support data pre- sented in earlier investigations, where heterogeneous re- sponses to different targets—such as the nucleus accumbens versus the subgenual anterior cingulate cortex—highlight critical implications for personalized medicine.29,49 In par- ticular, results showing that the nucleus accumbens plays a predominant role in symptom improvement for treatment- resistant schizophrenia29,30 align with existing literature that emphasizes the need for careful patient selection and opti- mization of stimulation parameters to maximize therapeutic benefits.50,53 This finding serves as a seal of approval for current theories on the disease’s pathophysiology, which propose that overactivity of the hippocampus increases in- hibitory signals from the nucleus accumbens to the ventral pallidum. This reduces inhibition on the ventral tegmental area, leading to increased dopamine release back onto the nucleus accumbens and producing the disease’s positive symptoms.34,37 Nonetheless, significant variability in re- sponse rates across studies necessitates further exploration into the underlying neurobiological mechanisms driving these differences, particularly as previous research identifies dopamine-glutamate-GABA interactions as pivotal in the pathology of schizophrenia.26-20,54,57 - 347 - Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 - 348 - Table 3. Adverse events reported in each study. Authors (year) Corripio et al., Wang et al., Cascella et al., Bioque et al., 202029/Aibar-Durán 202026 202128 202327 et al., 202330 Number of 8 2 1 2 procedures Transient adverse No transient No transient adverse events adverse events were events were reported reported related to related to the surgery, the surgery, implanted hardware, or implanted hardware, neurostimulation or neurostimulation Electrode placement (i) NAc (i) SNr (ii) NAc (ii) SNr (iii) NAc Adverse events (i) Akathisia occurred (i) An increased after changing the appetite for three stimulation from months, resulting in a unilateral to bilateral weight gain of 33 (ii) An occasional pounds over this electrical sensation period, reaching a in the trunk and head total weight of 314 triggered by specific pounds (142 kg) body movements and a body mass (iii) Confusion index of 54 kg/m² following a right-sided (ii) Decreased peri-operative performance on tests hemorrhage of verbaland visuospatial learning/ memory Number of adverse (i) 1 (i) 1 events (ii) 1 (ii) 1*** (iii) 1 Time to resolution (i) Eventually, this (i) It resolved after adverse event was 3 months and without resolved when the any intervention stimulation was (ii) Not specified changed back to unilateral (ii) Switching the stimulation from unipolar to bipolar mode led to a resolution of the symptoms (iii) It recovered after four days and without any intervention Serious adverse events No serious adverse No serious adverse events were reported events were reported related to the surgery, related to the surgery, implanted hardware, implanted hardware, or or neurostimulation neurostimulation To be continued on next page Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 - 349 - Table 3. Continued from previous page. Authors (year) Corripio et al., Wang et al., Cascella et al., Bioque et al., 202029/Aibar-Durán 202026 202128 202327 et al., 202330 Electrode placement (i) NAc (i) Hb (ii) NAc (iii) NAc (iv) NAc (v) NAc Adverse events (i) Daily mood (i) Aggravated fluctuations, psychotic impulsive behavior, symptoms and occasional requiring suicidal thoughts hospitalization (ii) Perioperative internal capsule hemorrhage (iii) Device infection (iv) Seizures occurred six months after being withdrawn from the trial (v) Behavioral changes consistent with hypomania and psychotic symptoms occurred after a total of 11 months of stimulation Number of adverse (i) 1* (i) 1 events (ii) 1 (iii) 1 (iv) 1 (v) 1** Time to resolution (i) Mood fluctuations (i) It was resolved were hard to manage after the removal with mood stabilizers of the generator and changes in deep and electrodes brain stimulation parameters, but they improved after the reinstatement of the antipsychotic medication aripiprazole (ii) It was resolved after the removal of the generator and electrodes (iii) It was resolved after the removal of the generator and electrodes (iv) Seizure attacks were controlled with anticonvulsant medication (v) Responded to treatment with antipsychotics in the inpatient setting *The number of recurrences of suicidal thoughts was not specified. **The patient stopped their antipsychotic medication before exhibiting hypomanic and psychotic symptoms, along with an initial reduction in stimulation parameters due to some improvement. ***The patient showed decreased performance during follow-up, but it remains uncertain if this trend will persist. Hb, habenula; NAc, nucleus accumbens; SNr, substantia nigra pars reticulata. Effectiveness of deep brain stimulation in alleviating treatment-resistant schizophrenia: a systematic review Eur J Transl Myol 35 (3) 14206, 2025 doi: 10.4081/ejtm.2025.14206 Limitations The study underscores significant limitations, primarily due to the scarcity of evidence, which makes a meta-analysis unfeasible. Of the thirteen patients included, eight were from the same trial, which could potentially introduce bias. The review highlights the potential of deep brain stimula- tion for treating treatment-resistant schizophrenia, while emphasizing the need for larger, randomized trials to facili- tate target-specific analyses. In addition, all patients studied were on antipsychotic medication during deep brain stim- ulation treatment, with no known cases of deep brain stim- ulation being used alone for treatment-resistant schizophrenia. Clinical implications and future directions As the clinical landscape evolves, the implications of these findings emphasize the importance of personalized treat- ment approaches that consider individual symptom profiles and the specific mechanisms underlying each patient’s con- dition. Moreover, the concurrent observation of serious ad- verse events in around 15% of patients highlights the need for careful monitoring and individualized adjustment of stimulation parameters to mitigate risks. Additionally, the analysis underscores the necessity for multidisciplinary col- laboration among psychiatrists, neurosurgeons, and neu- rologists to ensure optimal patient selection and treatment planning, thereby maximizing therapeutic benefits while minimizing potential complications.58 Future research should focus on larger, multi-center trials to substantiate these findings and explore the underlying mechanisms of deep brain stimulation more thoroughly. This includes in- vestigating the neural pathways involved in symptom relief and the relationship between specific stimulation sites and clinical outcomes to refine targeting strategies. Further- more, incorporating advanced imaging techniques may en- hance our understanding of how deep brain stimulation interacts with brain circuits associated with schizophrenia symptoms. Conclusions The systematic review on the efficacy of deep brain stim- ulation for treatment-resistant schizophrenia has high- lighted several key findings regarding this intervention. Primarily, evidence indicates that deep brain stimulation, when targeting certain brain regions, particularly the nu- cleus accumbens, can lead to significant symptomatic improvements in patients who have not responded to conventional antipsychotic treatments. Specifically, a re- sponse rate of approximately 30% was reported, with 4 out of 13 patients showing marked improvement in pos- itive symptoms such as hallucinations and delusions, as indicated by a reduction of 25% or more in PANSS or BPRS scores. It seems that the potential of deep brain stimulation as a treatment modality for treatment-resis- tant schizophrenia heralds a paradigm shift in mental health care, emphasizing the need for a more nuanced approach to treatment. As we continue to unravel the complexities of the disorder, integrating evidence from emerging research can lead to the development of stan- dardized guidelines for implementing deep brain stimu- lation in clinical practice, paving the way for improved outcomes for individuals grappling with the debilitating effects of treatment-resistant schizophrenia. By address- ing both clinical efficacy and methodological integrity, the future of treatment-resistant schizophrenia treatment can offer renewed hope and a pathway toward recovery for those in need. Funding The author did not receive any specific funding for this work. Conflict of interest The author declares that he has no conflict of interest. Ethics approval and consent to participate Not applicable. Corresponding author Mohsen Khosravi, Department of Psychiatry, School of Medicine, Zahedan University of Medical Sciences, Zahe- dan, Ira. ORCID: 0000-0003-2970-6309 E-mail: dr_khosravi2016@yahoo.com References 1. Khosravi M. Ursodeoxycholic acid augmentation in treatment-refractory schizophrenia: a case report. J Med Case Rep 2020;14:137. 2. Khosravi M. Quetiapine versus Clozapine in Treating Psychiatric Patients with Severe COVID-19: A Neto- sis-Based Opinion. Electron J Gen Med 2021;18: em301. 3. Velligan DI, Rao S. The epidemiology and global bur- den of schizophrenia. 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Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 29 July 2025. Accepted: 9 August 2025. Early access: 5 September 2025. - 352 - https://doi.org/10.1088