Depressive and anxiety disorders often co-occur with insomnia, creating complex treatment challenges. Although clinical guidelines recommend psychotherapy as first-line treatment for these comorbid conditions, limited access to psychological services in primary healthcare facilities in China often leads to heavy reliance on pharmacological therapy. To the appropriateness of psychotropic medications for patients with insomnia comorbid with depressive or anxiety disorders at primary healthcare facilities in China. This cross-sectional study included patients with documented diagnoses of insomnia comorbid depressive or anxiety disorders in 2022 at all 67 primary healthcare facilities in Dongcheng District, Beijing, China. The primary outcome was the prescribing rate of guideline-recommended psychotropic medications. Among 842 patients with insomnia and depressive disorders and 1014 patients with insomnia and anxiety disorders, over 90% received psychotropic medications. Benzodiazepines were the most frequently prescribed classes (55.9 and 69.6%), followed by non-benzodiazepine hypnotics (42.5 and 42.4%), whereas medications recommended by the guideline, including antidepressants with sedative effects, selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, were used infrequently. Only 29.9% of patients with insomnia and depressive disorders and 11.5% of those with insomnia and anxiety disorders received guideline-recommended pharmacotherapy, with lower concordance among older adults. Guideline-recommended pharmacotherapy for insomnia comorbid with depressive or anxiety disorders was rarely implemented at primary care in China. This highlights the need to facilitate evidence-based practices and improve management of comorbid mental health conditions, particularly for older adults.

IntroductionMDD is often managed with antidepressants that may carry a fall risk. Limited data exist comparing fall risk across individual SNRIs. Therefore, this study aimed to determine the fall rates associated with SNRIs.MethodsData were drawn from Merative MarketScan Medicare Supplemental claims (January 1, 2015 to November 30, 2021), including adults 65 years and older prescribed an SNRI (ie, duloxetine, venlafaxine, desvenlafaxine, milnacipran, levomilnacipran). The index date was the first prescription claim. Patients were followed up to 1 month after their last prescription to identify falls, using International Classification of Diseases (ICD) 9th Revision and ICD-10 codes. Fall-related injuries were identified using trauma codes. Descriptive statistics and odds ratios (95% CI) were calculated to compare fall rates between agents. Propensity score weighting adjusted for potential selection bias.ResultsA total of 79 256 patients met eligibility (68% female; mean age: 75 years). Duloxetine (66%) and venlafaxine (30%) were the most prescribed. The overall fall rate was approximately 1% with duloxetine having the highest (1.1%), and venlafaxine having the lowest rate (0.68%). Injuries occurred in 79% of fall cases. After adjusting for age, sex, and comorbidities, the odds ratio for falling with venlafaxine versus duloxetine was 0.69 (95% CI = 0.56, 0.83), indicating a 31% odds reduction with venlafaxine compared with duloxetine.DiscussionVenlafaxine appears to have a lower fall risk than duloxetine. Further studies are needed to determine clinical significance and assess fall-related costs to support safer SNRI use in older adults.

Chronic pain is among the most devastating and poorly understood symptoms after traumatic brain injury (TBI). Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior work, we found that TBI induces a two-stage pain dysregulation involving acute mechanical hindpaw hypersensitivity that resolves by 28 days post-injury (DPI), followed by chronic failure of descending control of nociception (DCN) lasting up to 180 DPI. However, the impact of sex on the dysfunction of endogenous pain control systems after TBI has not been explored. Using a lateral fluid percussion model of TBI in male and female rats, we assessed mechanical nociceptive responses using von Frey fibers and tested pharmacological interventions targeting established descending pain modulatory systems. We employed the selective noradrenergic (NA) reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists' prazosin (α1-adrenoceptors) and atipamezole (α2-adrenoceptors), and the serotonin 5-HT3 receptor antagonist, ondansetron. Findings revealed that acute hindlimb hypersensitivity involved enhanced descending serotonergic pain facilitation via the 5-HT3 receptor in both sexes. In uninjured rats, pain control relies on descending NA inhibitory signaling via spinal α2-adrenoceptors. Boosting noradrenaline in the acute phase after TBI with reboxetine reduced acute mechanical pain, but studies with selective adrenoceptor antagonists revealed a persistent switch from an α2- to an α1-adrenoceptor-driven antinociceptive pathway after TBI in both males and females. Acute phase mechanical pain resolved by 28 DPI, exposing a chronic phase of DCN failure up to 180 DPI. Reboxetine treatment restored the DCN response in female TBI rat via α1-adrenoceptor but failed in male TBI rats. Restoration of the DCN response in male TBI rats was restored by enhancing serotonin signaling with escitalopram. These results demonstrate key differences in the susceptibility of endogenous pain modulatory pathways and the adaptations of those pathways between male and female rats after TBI. These findings suggest that sex needs to be considered when designing mechanism-based therapies for pain after TBI.

Dose-dependent pharmacological mechanisms within the Neuroscience-based Nomenclature: a new concept to facilitate neuroscience-based prescribing.

Serotonin reuptake inhibition and intracerebral hemorrhage risk after ischemic stroke: A multicenter retrospective study.

Tramadol is a widely used analgesic with a unique dual mechanism of action, combining weak μ-opioid receptor agonism with inhibition of norepinephrine and serotonin reuptake. It is frequently prescribed for various acute and chronic pain conditions. Evaluating prescribing trends can provide valuable insight into clinical practice patterns and inform institutional pain management strategies and policy development. To assess tramadol prescribing patterns over a one-year period in a university-based health system and compare them to overall opioid prescribing. A retrospective review was conducted using electronic medical record (EMR) data from January 1, 2024, to December 31, 2024. The number of tramadol prescriptions was quantified quarterly and compared to the total number of opioid prescriptions (including tramadol) during the same period. No identifiable patient information was collected. A total of 17,660 tramadol prescriptions were written in 2024. Quarterly breakdowns were: Q1 - 4,347; Q2 - 4,382; Q3 - 4,369; Q4 - 4,562. Overall, tramadol prescriptions accounted for 25.9% of the 68,212 total opioid prescriptions written during the year. Tramadol constituted over one-quarter of all opioid prescriptions in this academic medical center. Prescribing remained stable across all quarters, with a slight increase observed in Q4. These findings highlight tramadol's significant role in opioid prescribing practices for acute and chronic pain management.

Burning Mouth Syndrome (BMS) is a complex chronic neuropathic orofacial pain disorder characterized by a persistent burning or dysesthetic sensation in the oral cavity without an identifiable organic cause. The management of BMS has evolved beyond symptom relief to focus on achieving full functional recovery (FFR), which encompasses restoring patients to their usual activities without restrictions, addressing both physical and psychological dimensions. Key pharmacological treatments such as clonazepam and capsaicin are explored in detail, alongside the potential of newer agents like various classes of antidepressants (including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin and noradrenaline reuptake inhibitors, vortioxetine) and antiepileptics showing promise in addressing the multifactorial nature of BMS. Non-pharmacological interventions, such as cognitive-behavioral therapy (CBT), low-level laser therapy (LLLT), and transcranial magnetic stimulation (TMS), are highlighted for their potential to complement pharmacological treatments. These interventions aim to modify pain perception, reduce psychological burdens, and enhance overall quality of life. Lifestyle modifications, including dietary changes, stress management techniques, improved sleep hygiene, and regular physical activity, are essential components of a holistic treatment plan that addresses modifiable risk factors affecting brain health. The integration of telemedicine and digital health resources is proposed to enhance patient management and accessibility to multidisciplinary care. This review provides a comprehensive update on all available therapeutic approaches for BMS, encompassing pharmacological treatments, non-pharmacotherapeutic interventions, and lifestyle optimization strategies, offering a holistic perspective on managing this condition.

Objectives: Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are widely prescribed, and growing evidence highlights the clinical and methodological challenges of withdrawal during discontinuation. This study aimed to provide a comprehensive bibliometric map of SSRI/SNRI withdrawal research to clarify production patterns, citation structures, thematic evolution, and global collaboration. Methods: A comprehensive search of the Web of Science Core Collection (1995–2025) identified 652 original articles on SSRI/SNRI withdrawal, discontinuation, or tapering. Records were analyzed using the bibliometrix package in R for performance metrics, co-citation and keyword networks, and country–institution collaboration structures. Results: The corpus comprised 652 documents published in 308 journals, citing 18,957 references, with an annual growth rate of 7.79%. Articles received a mean of 41.6 citations. The Journal of Clinical Psychiatry (22 articles; h=20) and Journal of Clinical Psychopharmacology (18; h=14) were the most influential sources. Highly cited documents ranged from 270 to 730 citations, predominantly from Lancet, Pediatrics, The New England Journal of Medicine, and American Journal of Psychiatry. Keyword frequency was led by “depression” (n=172), “fluoxetine” (n=153), and “antidepressants” (n=152). The United States produced 240 articles (36.8%; 12,904 citations), forming the central hub of the collaboration network. Conclusions: SSRI/SNRI withdrawal research shows concentrated authorship, journal anchoring, and geographically centralized knowledge production, with emerging themes in tapering, pregnancy outcomes, and pharmacogenetics.

Phytochemical investigation on the aerial parts of Oreomecon nudicaulis resulted in the identification of eight new benzylisoquinoline-derived secondary metabolites, including four unusual C-6-N-17 bond cleaved isopavine alkaloids oreonudines A-D (1-4), two isopavine alkaloids oreonudines E (5) and F (6), one rhoeadine alkaloid oreonudine G (7), and one morphinane alkaloid oreonudine H (8), along with 10 previously reported analogues 9-18. Their structures were determined by comprehensive spectroscopic and spectrometric analyses, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. In vitro studies using HT22 mouse hippocampal neuronal cells revealed that the previously reported compounds 12, 15, and 16 exhibited potent inhibition of serotonin (5-HT) and/or norepinephrine (NE) reuptake. Among them, mecoquitupline (15) showed significant inhibitory activity against 5-HT (88.0%) and NE (58.8%) reuptake, outperforming the tricyclic antidepressant amitriptyline (53.6% and 35.5%, respectively), and notably activated the neurotrophic BDNF/CREB signaling pathway. Molecular docking and drug affinity responsive target stability (DARTS) assays further confirmed the binding of 15 to both serotonin transporter (SERT) and norepinephrine transporter (NET). In contrast, 12 and 16 selectively inhibited NE and 5-HT reuptake, respectively, by targeting the corresponding transporters. These findings highlight mecoquitupline (15) as a promising dual-action antidepressant candidate with potent activity.

Depression is one of the most prevalent mental disorders globally. World Health Organization (WHO) data shows that approximately 3.5%5% of the global population suffers from depression, and the incidence rate is increasing annually. Its peak age of onset is concentrated in late adolescence to middle age, especially among those aged 1529. Depression has become a major risk factor for disability and suicide. This article summarizes and compiles the main causes of depression, its significant impact on individuals and society, and innovative treatment methods proposed by some scholars. This article primarily employs a literature review method, compiling several articles to demonstrate the causes and solutions of depression. The research concludes that the development of depression includes, but is not limited to, congenital genetic factors, interpersonal relationships, and academic pressure. It can be treated with selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (SNRIs).

Abstract Introduction Sexual side effects from a selective serotonin reuptake inhibitor (SSRI)/serotonin and norepinephrine reuptake inhibitor (SNRI) typically resolve upon discontinuation. Post-SSRI Sexual Dysfunction (PSSD) is identified in patients without history of sexual dysfunction prior to SSRI/SNRI use and, after cessation of the medication, continue to have symptoms of bothersome sexual dysfunction for ≥ 6 months, with no obvious alternative pathophysiologic risk factors. Objective To perform a retrospective chart review of men diagnosed with PSSD to assess frequency and severity of sexual symptoms and biologic pathophysiologies. Methods Charts of men between 2009-2024 with various sexual dysfunctions who met inclusion criterion for PSSD were reviewed. Patients with a history of ED following blunt penile/perineal trauma, 5-alpha reductase inhibitor use, or exposure to ≥2 vascular risk factors were excluded. Data collected included age, responses on validated instruments (IIEF, SDS-R, PHQ-9), hormone blood test values, results of quantitative sensory testing, and vascular testing utilizing grayscale and duplex Doppler ultrasound during complete smooth muscle relaxation with erection hardness scale grade 3-4. Using Fuji version 1.53, percent hypoechoic area in proximal, mid-shaft, distal regions were analyzed and compared to 2 control populations of men without PSSD but with ED from either 1) blunt penile/perineal trauma or 2) vascular risk factor exposure. Two-way ANOVA followed by post-hoc pairwise comparisons between groups within each penile region were performed using Tukey’s test. Results A total of 43 men, mean age 27.6 y (range 16-43), met inclusion/exclusion criteria, making this the largest chart review of PSSD to date. Patients reported multiple sexual health concerns, including ED (88%), reduced genital sensation (92%, n=39), low libido (mean desire domain 4.0) and orgasmic dysfunction (mean orgasm domain 6.0) with significant distress (mean SDS-R score 37.4) (Table 1). The mean IIEF of patients presenting with ED (n = 38) from PSSD was 8.8±8.0, consistent with severe ED. Testosterone, dihydrotestosterone, estradiol, prolactin, LH, FSH, and sex hormone binding globulin values in this patient cohort were not consistent with hormonal pathophysiology. Grayscale ultrasound findings revealed erectile tissue inhomogeneity with percent hypoechoic area similar to the older (65.6±8.5 y) controls (n=16) with vasculogenic ED, and significantly greater (p<0.0001) than the similar age cohort (32.1±8.3 y) with ED from perineal/penile trauma (n=15) (Figure 1). Duplex Doppler ultrasound findings (n=30) revealed a mean peak systolic velocity of 32.2±10.8 cm/s and end diastolic velocity values of 1.1±1.8 cm/s. Quantitative sensory testing including vibration, heat and cold perception threshold testing, revealed 89% (n=37) of patients had abnormal results. Conclusions PSSD occurring in young, healthy men is associated with severe ED, and multiple other persistent sexual dysfunctions. The biologic pathophysiology of ED is hypothesized to result from an intracavernosal drug effect of the oral SSRI/SNRI leading to increased oxygen radical formation causing cavernosal smooth muscle apoptosis in affected patients. This results in erectile tissue inhomogeneity throughout the entire penile shaft, causing persistent ED in a young population without vascular risk factors. The biologic pathophysiology of changes in libido, sensation and orgasm are hypothesized to be related to SSRI/SNRI-induced altered central neurotransmitter activity. Disclosure No

Increases in brain catecholamine levels counteract memory deficits and reduces Aβ deposition in 5XFAD male mice.

Noradrenergic dysregulation in the locus coeruleus: Implications for neuropsychiatric disease pathophysiology- A systematic review.

Depression is a significant comorbidity of epilepsy that affects both quality of life and seizure control. Selective serotonin reuptake inhibitors (SSRIs) are the recommended first-line treatment for depression in patients with epilepsy; however, the optimal management strategies for SSRI-resistant depression in this population remain unclear. We conducted a 10-year retrospective analysis of epilepsy patients with SSRI-resistant depression who were treated by either switching to a serotonin norepinephrine reuptake inhibitor (SNRI) or augmenting with aripiprazole. We compared demographic factors, seizure characteristics, and treatment outcomes between the two groups. Our study included 33 epilepsy patients with SSRI-resistant depression who switched to SNRIs and 36 patients who were treated with aripiprazole augmentation. There were no significant differences in demographic factors, seizure characteristics, mean initial depression scores, or seizure freedom between the groups. However, patients receiving aripiprazole augmentation showed higher retention rates than those switching to SNRIs at their last follow-up (28/36 vs. 13/33, p = .001). Our study suggests that aripiprazole augmentation may be a more favorable option than switching to SNRIs for epilepsy patients with SSRI-resistant depression. Further prospective studies are needed to investigate effective treatment strategies for epilepsy patients with SSRI-resistant depression.

Depression significantly impacts quality of life and prognosis in subjects with cancer. Despite the evidence supporting the role of pharmacotherapy, real-world data on the effectiveness and tolerability of different antidepressant classes in cancer populations remain limited. To assess the effectiveness and tolerability of antidepressant classes and individual agents in oncology patients with major depressive disorder (MDD), and to investigate antidepressant prescription trends. This 6-month retrospective observational study was conducted in 170 oncology outpatients with MDD. Patients received monotherapy with tricyclic antidepressants(TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or a multimodal antidepressant class including only vortioxetine. Psychiatric symptoms were evaluated at baseline and after 1 and 6months. Evaluation included rates of response, remission and changes in rating scales assessing depression, anxiety, suicidality, and agitation. All antidepressant classes showed comparable effectiveness and capability of reducing depression, anxiety, and suicidal ideation over time. Vortioxetine showed a favorable tolerability profile, with no reported adverse effects, whereas SSRIs and SNRIs had higher dropout rates due to side effects. SSRIs were the most prescribed class, followed by multimodal agents. Vortioxetine was the most frequently prescribed individual antidepressant, particularly among patients undergoing chemotherapy. The small sample size and the lack of stratification by cancer type limit the generalizability of the results. Antidepressants were equally effective in treating depression among cancer patients. Vortioxetine emerged as a well-tolerated and preferred option for chemotherapy patients. These findings emphasize the importance of tolerability and drug-interaction profiles in oncology care.

Abstract Purpose of Review Neuropsychiatric disorders frequently co-occur with lower urinary tract symptoms (LUTS) in children, with prevalence rates for behavioral and psychological problems reaching 20–40% in those with elimination disorders. Notably, attention-deficit/hyperactivity disorder (ADHD) affects nearly 25% of children with daytime wetting. This strong association is increasingly understood through shared neurobiological underpinnings. Recent Findings Genetic studies reveal links between specific genes associated with anxiety and nocturnal enuresis, while epigenetics demonstrates how early life stress can induce methylation changes in genes critical for brain development and stress response, influencing bladder function. Neuroimaging has elucidated a common neuroanatomical basis. Brain regions such as the insula, anterior cingulate cortex (ACC), and prefrontal cortex (PFC), vital for both micturition control and executive functions, show structural and functional abnormalities in children with LUTS and neuropsychiatric conditions like schizophrenia and depression. Cortical thinning in the right frontal lobe, for instance, correlates with both urinary incontinence and depression. A distinct clinical phenotype, "wetting without sensory awareness," is often observed in children, reflecting dysfunction in major attention and default mode networks, particularly in ADHD. Pharmacological interventions targeting central neurotransmitter systems, rather than solely peripheral bladder mechanisms, have shown efficacy. Tricyclics, A2 agonists, norepinephrine reuptake inhibitors, and serotonin reuptake inhibitors demonstrate benefit by modulating central pathways affecting bladder control, often through ACC or frontal lobe activation. However, medications like norepinephrine reuptake inhibitors and sympathomimetics, while centrally beneficial, can cause peripheral bladder neck tightening, leading to voiding difficulties. Summary This complex interplay necessitates a holistic, neurobiologically informed approach to diagnosis and management, recognizing LUTS as manifestations of broader neurodevelopmental vulnerabilities.

ABSTRACT Solriamfetol, an emerging drug for the treatment of excessive daytime sleepiness along with narcolepsy and obstructive sleep apnoea. It acts as a dopamine and norepinephrine reuptake inhibitor. The present study aimed to develop a liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method for the estimation of Solriamfetol in spiked human plasma, using 13‐C Solriamfetol as an internal standard (IS). All the chromatographic conditions were optimized to obtain a sharp, symmetrical peak of Solriamfetol in a chromatographic run. The chromatographic conditions include 0.1% formic acid and acetonitrile (30:70) as the mobile phase, a C18 column as the stationary phase. Multiple reaction monitoring mode was selected for ionization and fragmentation, and the maximum sensitivity was achieved in the mass spectrometer. The results of validation parameters showed the developed method as precise, accurate, and robust. The linearity concentration is in the range of 5.0–5220.0 ng/mL with a correlation coefficient of 0.9980. All the stability showed the method's reliability under various conditions. The developed method was successfully applied to spiked human plasma samples and can be further useful for pharmacokinetic profiling. This approach employs a deuterated IS, which provides more accuracy and reduces matrix effects compared with existing LC‐MS and high‐performance LC methods. This method addresses the need for a sensitive and selective analysis of Solriamfetol, providing valuable insights into its pharmacological profile for the treatment of sleep‐related disorders.

Atomoxetine is a selective norepinephrine reuptake inhibitor prescribed for the management of attention-deficit hyperactivity disorder (ADHD). Untreated ADHD can significantly damage a woman's well-being and often worsens during postpartum. As a result, physicians often recommend continued medication therapy during pregnancy and postpartum; however, there is limited data evaluating the safety of atomoxetine's transfer into human milk. The InfantRisk Center's Human Milk Biorepository collected milk samples from 10 lactating participants who were treated with atomoxetine 40 to 100mg daily. The concentrations of atomoxetine in milk were quantified using liquid chromatography-tandem mass spectrometry. The mean atomoxetine concentration in milk was 12ng/mL at an adjusted daily dose of 80mg, resulting in a relative infant dose (RID) of 0.19%. To estimate a worst-case scenario, the maximum concentration of 39ng/mL was used to simulate a worst-case scenario RID of 0.65%. There were no reported adverse effects in the breastfed infants. The transfer of atomoxetine into human milk is minimal, with a 0.19% RID, well below the 5% safety threshold for psychoactive medications. The minimal transfer suggests that maternal atomoxetine use poses a very low risk to breastfed infants, making it a suitable choice for medication management of ADHD in lactating women.

Chronic postoperative neuropathic pain is a common and sometimes disabling problem. Mainstay pharmacological management involves gabapentinoids, tricyclic anti-depressants and serotonin and norepinephrine reuptake inhibitors. Past this, guidance is limited. There is good evidence for the use of high-concentration capsaicin patch in non-operative causes of neuropathic pain. This systematic review aimed to evaluate the evidence base for the high-concentration (8%) capsaicin patch for postoperative neuropathic pain. We carried out a systematic search of 4 databases (Ovid MEDLINE, Embase, Cochrane Library and https://ClinicalTrials.gov) from inception to 3rd July 2025 to identify randomised controlled trials investigating the effectiveness of high-concentration capsaicin patch for postoperative neuropathic pain. The primary outcome was pain improvement, with adverse events being the secondary outcome. Study selection was performed independently by two reviewers using the Rayyan platform. 487 studies were identified. After screening, only one randomised controlled trial on 46 participants met inclusion criteria. The high-concentration capsaicin patch did not significantly improve postoperative neuropathic pain compared to an inactive placebo patch. However, the certainty of evidence was graded as very low using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We also found 2 ongoing trials without published results. This systematic review identified a clear gap in the literature regarding the use of high-concentration capsaicin patches for chronic postoperative neuropathic pain. High-quality studies are needed to expand the existing evidence base. Based on our findings, we propose several recommendations to guide future research in this area.

Introduction: Treatment-resistant depression (TRD) is a chronic and severe form of major depressive disorder with limited therapeutic options. One-third of TRD patients fail to respond to pharmacological and psychotherapeutic interventions. Deep Brain Stimulation (DBS) is a promising therapy for TRD patients, but its clinical results have been highly variable in multiple studies focused on single target interventions, suggesting suboptimal targeting of the circuits implicated in TRD. Connectomics approaches have emerged to enable an individualized planning of symptom-specific circuits targeting in TRD with promising results. We report a case of Multitarget DBS involving six neural tract including subgenual cingulate cortex, Brodmann area 25 (SGC25) and anterior limb of the internal capsule (ALIC) with distal extension toward the nucleus accumbens (NAc) stimulation.Clinical description: A 34-year-old woman presented with a chronic psychiatric history dating back to age 10, when she developed disordered eating behaviors, bulimia nervosa type 1 and later anorexia nervosa at 15 years managed with limited success. Over the ensuing years, she experienced recurrent major depressive episodes, generalized anxiety disorder, panic attacks, social phobia, and agoraphobia. Despite multiple evidence-based psychiatric interventions—including cognitive behavioral therapy and sequential pharmacotherapy with selective and multiple serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors—her symptoms remained refractory or transient improvement. At evaluation, affective lability, anhedonia, hopeless, and intrusive anxiety are presented persistently. Given the TRD diagnostic, a multidisciplinary team recommended an innovative multitarget DBS approach using Multiple Independent current control (MICC).Discussion: This case illustrates the potential of simultaneous modulation of interconnected affective and cognitive circuits implicated in TRD. The ALIC-NAc target was selected to precisely modulate anxiety and reward-related networks, while the SGC25 was chosen to engage affective regulation pathways including medial forebrain bundle (MFB), dorsal longitudinal fasciculus (DLF), and anterior thalamic radiation (ATR), all described with antidepressant effect in DBS for TRD. MICC technology enabled tailored stimulation according to TRD individual evolution explaining the observed multidomain symptomatic improvement across scales. At four-month follow-up, Hamilton Depression Rating Scale (HDRS-17) scores improved by 65%, Montgomery–Åsberg Depression Rating Scale (MADRS) by 70%, with additional improvement in Beck inventory depression and anxiety scales (BDI and BAI).Conclusions: This novel single-case study supports the feasibility and clinical benefit of multitarget MICC-DBS guided by connectomics in TRD. Individualized modulation of SGC25 and ALIC-NAc may improve cognitive and anxiety predominant symptoms in TRD patients. Further studies are needed to replicate these findings in a well-selected cohort of TRD patients to validate the individualized multitarget MICC-DBS modulation and its progressive capacity to improve symptoms in TRD. Coronal postoperative MRI with tractography overlay demonstrating bilateral multitarget DBS electrode trajectories. Directional Cartesia™ leads were placed in the SGC25, while linear Vercise™ leads traversed the ALIC with distal contacts in the NAc. Patient-specific tractography highlights key white matter pathways: MFB (blue), ATR (green), and DLF (red), confirming engagement of fronto-limbic and reward circuits relevant to depression and anxiety modulation. (Figure 1).