Tic disorders typically begin in childhood and often improve by adulthood, but some individuals continue to experience tic symptoms into adult life. Tic disorders frequently co-occur with Attention-deficit/hyperactivity disorder (ADHD), and in such cases α2-adrenergic agonists are recommended as a treatment as they can address both conditions. However, evidence in adults with ADHD and comorbid tic disorders is limited, as most studies have focused on pediatric populations. Here, we present three adult male patients with childhood-onset ADHD and chronic tic symptoms who showed a rapid and significant improvement in tics with low-dose extended-release guanfacine (GXR) monotherapy. These cases suggest that GXR can effectively treat both ADHD and tic symptoms in adults-a finding that has not been well documented in prior adult studies.
Interoception has been reported to be associated with several psychiatric disorders, including addiction. Alexithymia refers to difficulties in identifying and describing one's own emotions and has also been linked to addictive disorders. However, the relationship between self-reported interoceptive sensitivity and alexithymia in patients with addiction remains insufficiently understood, particularly when current distress and functional impairment are considered. In this study, we examined the relationship between the Body Perception Questionnaire-Body Awareness very short form Japanese version (BPQBAVSFJ), the Toronto Alexithymia Scale-20 (TAS-20), and the Distress and Impact Thermometer (DIT) in 94 patients with addiction. BPQBAVSFJ was significantly correlated with TAS-20 (Pearson r = 0.405, p < 0.001; Spearman rho = 0.458, p < 0.001). This association remained significant after adjustment for age, sex, distress, and impact (B = 0.271, 95% CI = 0.105-0.438, p = 0.002). Distress showed a weak bivariate association with BPQBAVSFJ, whereas impact did not. In the multivariable model, neither distress nor impact independently predicted BPQBAVSFJ. No significant differences in BPQBAVSFJ were observed among the six addiction subtypes or between substance-related and behavioral addictions after adjustment for age and sex. These findings suggest that self-reported interoceptive sensitivity in patients with addiction may be more closely associated with alexithymia than with current distress or functional impairment.
Electroconvulsive therapy (ECT) is considered relatively safe and effective for severe psychiatric disorders during pregnancy, but evidence regarding neuromuscular blockers for ECT in pregnancy remains limited. We report a 30-year-old primigravida admitted at 30 weeks of gestation with severe major depressive disorder and persistent suicidal ideation despite pharmacotherapy. ECT was initiated at 32 weeks and 2 days of gestation. The first five sessions used succinylcholine. Owing to a nationwide shortage in Japan, the muscle relaxant was switched to rocuronium from the sixth session, with neostigmine and atropine used for reversal during the two antepartum rocuronium sessions. Serial cardiotocographic monitoring before and after each of the seven antepartum ECT sessions showed a transient decrease in fetal heart rate variability after ECT in all sessions and a transient increase in fetal heart rate baseline in five of the seven sessions (Sessions 1, 2, 3, 5, and 7), while fetal well-being was maintained throughout. Spontaneous vaginal delivery occurred at 37 weeks and 0 days, five days after the seventh ECT session. The infant developed respiratory failure shortly after birth and required ventilatory support for two days, but subsequently recovered without complications. Postpartum ECT was resumed for five additional sessions using rocuronium reversed with sugammadex, and the patient achieved clinical remission. This case suggests the feasibility of rocuronium with neostigmine reversal as an alternative to succinylcholine for ECT during late pregnancy when succinylcholine is unavailable, provided that multidisciplinary management and fetal monitoring are available.
AIM:Anxious distress is common in major depressive disorder (MDD), but real-world data are limited on its burden and relationship to depressive symptom domains. This study examined the prevalence and symptom-domain correlates of self-reported anxious distress in MDD outpatients. METHODS:This cross-sectional study used routinely collected questionnaire and clinical data from Dokkyo Medical University Hospital. Depressive severity was assessed using the Japanese version of the Quick Inventory of Depressive Symptomatology (QIDS-J). Anxious distress was assessed using five self-rated items aligned with the Clinically Useful Depression Outcome Scale-Anxious Distress (CUDOS-A) and DSM-5 framework. Of 309 respondents, the primary analytic cohort comprised 206 participants with QIDS-J total scores of 6 or higher and complete anxious-distress item data. RESULTS:A lower anxious-distress threshold (at least two items scored > = 2) was met by 153 participants (74.3%), and a stringent threshold (at least two items scored > = 3) by 85 (41.3%). QIDS-J total score correlated with anxious-distress burden (r = 0.614 for > = 2 count, r = 0.669 for > = 3 count, and r = 0.697 for summed score; all p < 0.001). In forced-entry Poisson models, sad mood, negative self-view, and psychomotor symptoms were associated with anxious-distress burden. Post hoc decomposition suggested that this psychomotor association was driven mainly by psychomotor agitation rather than retardation. CONCLUSION:Self-reported anxious distress was common among MDD outpatients and was closely associated with depressive severity and specific symptom domains, supporting further evaluation of anxious distress as a clinically relevant psychopathological dimension in MDD.
BACKGROUND:Sexual dysfunction is a common comorbidity in patients with epilepsy; it correlates with seizure frequency and right temporal lobe epilepsy and affects quality of life (QOL). Despite its clinical significance, sexual dysfunction is often underassessed in clinical practice. Brivaracetam (BRV), an anti-seizure medication (ASM) introduced in recent years, is considered to have few psychiatric side effects, and no association with sexual dysfunction has been reported to date. We report a case of temporal lobe epilepsy in which the patient exhibited increased libido following the initiation of BRV. CASE PRESENTATION:A woman in her 70s with drug-resistant temporal lobe epilepsy, weekly focal seizures, and mild cognitive impairment was treated with brexpiprazole (BXP) for delusions of theft. BRV (50 mg/day) was initiated due to worsening epileptic seizures. Three weeks later, she developed persistent, intrusive sexual urges accompanied by self-stimulatory behavior (e.g., genital touching). She initially concealed these symptoms due to embarrassment but disclosed them at the follow-up 1 month later. Given the temporal association with BRV initiation, the drug was discontinued, resulting in marked improvement within 2 weeks and subsequent resolution. Throughout the course of treatment, no changes were observed in seizure frequency, cognitive function, or other ASMs. DISCUSSION:Previous reports have described increased libido with levetiracetam, which shares the same mechanism of action with BRV. Genetic factors, such as reduced striatal dopamine receptor density associated with DRD2/ANKK1 polymorphisms may contribute to psychiatric side effects. In this case, BRV-associated modulation of neurotransmission may have interacted with a vulnerable dopaminergic system, as indicated by the need for BXP. Preexisting bilateral hippocampal atrophy may also have provided a structural substrate resembling a pharmacologically induced incomplete Klüver-Bucy syndrome. Clinicians should be aware that patients may hesitate to report such symptoms and should actively monitor for changes in libido after initiating BRV.
INTRODUCTION:Benzodiazepines (BZDs) are associated with dependence, tolerance, withdrawal, and various adverse effects, and switching to other drug classes is often recommended. Although non-BZD hypnotics are reported in package inserts to have similar but less frequent adverse events, real-world patients often have complex psychiatric and medical backgrounds, and the actual frequency of subjective adverse events may differ substantially from that reported in package inserts. This study aimed to elucidate subjective symptoms potentially related to psychotropic medications using real-world patient data. METHODS:This prospective cohort study included patients at the Akebono Clinic who were taking a single hypnotic agent. A total of 314 patients were analyzed. Insomnia severity was assessed using the Athens Insomnia Scale, and 11 self-reported adverse events were evaluated. RESULTS:The frequency of insomnia was 72% for non-BZDs, 52% for BZDs, and 70% for dual orexin receptor antagonists (DORAs) (significantly lower for BZDs; p = 0.0036). Among the 11 self-reported symptoms, two items (thirst and nightmares) were reported as "always" or "often" by more than 10% of patients; three items (constipation, head heaviness/headache, and abnormal behavior during sleep) by 5%-10%; and four items (lightheadedness, vertigo, abdominal pain, and tremor) by 3%-5%. There were no differences in adverse-event frequencies among non-BZDs, BZDs, and DORAs. Multivariate analyses showed that adverse events were associated with female sex, age < 60 years, and schizophrenia, depression, and anxiety disorders, but not with hypnotic drug classes. CONCLUSIONS:Subjective adverse events in patients taking hypnotics occurred more frequently than those reported in package inserts, indicating a clear discrepancy between controlled trial data and real-world clinical experience. Because adverse events were more strongly associated with patient characteristics-such as psychiatric comorbidities, physical conditions, and concomitant medications-than with hypnotic drug class, routine assessment of subjective symptoms through interviews or questionnaires is essential in clinical practice.
Behavioral tests in mice and other animals are widely used to study anxiety and to evaluate the efficacy of anxiolytic compounds. However, the validity of behavioral tests used to assess anxiety-like behavior has been questioned because their results are often inconsistent and not readily replicated across studies. We developed a simple falling-trap test to examine whether the number of falls could serve as an index of anxiety-like behavior. The test is designed to produce falls from an elevated path, based on the hypothesis that less-anxious mice would be more prone to fall. Male C57BL/6N mice were given vehicle or chlordiazepoxide (CDP), and their behavior was evaluated using both the novel test and the elevated plus maze (EPM). The outcomes were the number of falls in the falling-trap test and open-arm time in the EPM. In the falling-trap test, CDP-treated mice did not show a statistically significant increase in the number of falls compared with control mice. In contrast, CDP significantly increased open-arm time in the EPM. Thus, under the present experimental conditions, these findings did not support the hypothesis that the number of falls in the falling-trap test could serve as a measure of anxiety-like behavior. Further studies are needed to determine the conditions under which this assay could be useful and to establish its reliability and validity.
Multiple sclerosis (MS) can present with neurological and psychiatric symptoms that may overlap with those of schizophrenia, making differentiation difficult particularly because their typical onset ages are similar. We present the case of a woman in her 50s who developed persecutory delusions and a subjective sense of being under surveillance in Year X-31 and was diagnosed with schizophrenia. Despite the long-term antipsychotic treatment, the patient's symptoms persisted and worsened. In Year X-1, brain magnetic resonance imaging revealed multiple white matter lesions, and then cerebrospinal fluid analysis revealed oligoclonal bands, leading to a diagnosis of MS. Treatment with ofatumumab was initiated. Owing to persistent psychiatric symptoms, clozapine was administered, which showed partial effectiveness. This case highlights the clinical overlap between schizophrenia and MS and suggests that comorbid MS pathology may be clinically relevant in the context of treatment resistance and cognitive impairment. Similarities in symptoms and disease course raise the possibility that a subset of patients with schizophrenia may share pathophysiological features with MS. In addition, postmortem studies, including our previous and current observations, provide hypothesis-generating support for partially overlapping MS-like changes in some patients with schizophrenia. Clinicians should consider the possibility of comorbid MS in patients with treatment-resistant schizophrenia, particularly when atypical clinical or neurological features are present.
AIM:Treatment-resistant schizophrenia (TRS) is a clinically important subtype of schizophrenia, but its cognitive characteristics remain incompletely understood. The Wisconsin Card Sorting Test (WCST) is widely used to assess executive dysfunction in schizophrenia, although conventional summary analyses may overlook trial-by-trial behavioral adaptation. This study aimed to examine whether recent trial outcome modulates subsequent responding differently between TRS and non-TRS patients during the WCST. METHODS:We analyzed WCST data from 41 outpatients with schizophrenia, including 13 patients with TRS and 28 with non-TRS. Conventional subject-level indices, including perseveration rate and outcome-dependent reaction time (RT) adjustment, were first compared between groups. We then performed trial-level linear mixed-effects analyses using log-transformed RT as the dependent variable, with previous trial correctness, treatment resistance, their interaction, age, and sex as fixed effects. Additional sensitivity analyses included models with by-subject random slopes for previous trial correctness and analysis in an age-matched sample. RESULTS:Conventional summary analyses showed no significant group differences in perseveration rate or RT measures. In the primary model, previous trial correctness significantly modulated subsequent RT, and the interaction between previous trial correctness and TRS suggested a group difference in outcome-dependent RT modulation. Specifically, the RT difference between trials following error and correct responses appeared smaller in TRS patients than in non-TRS patients. However, sensitivity analyses using by-subject random slopes and an age-matched sample showed similar directions and magnitudes of the interaction but did not reach statistical significance. CONCLUSION:Conventional WCST summary analyses did not distinguish TRS from non-TRS patients, whereas trial-level modeling provided preliminary evidence for possible alteration of outcome-dependent response adjustment in TRS. These findings suggest that dynamic behavioral phenotypes may provide a useful complement to standard neuropsychological indices in characterizing cognitive heterogeneity in schizophrenia, but replication in larger samples is needed.
Synergistic "Double Brake" Model on the Spinal Defecation Center in Clozapine-Induced Constipation. Real-world data shows BZDRs increase laxative risk in schizophrenia. Mitigating the central GABAergic brake via sedative optimization and maintaining gut microbiota homeostasis prevents fatal Ogilvie's syndrome.
BACKGROUND:Nonadherence to antipsychotics affects nearly half of patients with schizophrenia, leading to rehospitalization, suicidality, and reduced quality of life. Optimizing treatment adherence is critical to prevent disease relapses, which can be life-threatening. This review provides an updated status of innovative efforts in ensuring treatment adherence and the challenges associated. It also addresses future directions to improve treatment outcomes among patients with schizophrenia. METHODS:A narrative review was thoroughly conducted by retrieving peer-reviewed articles from PubMed, Google Scholar, ScienceDirect, and Web of Science. Articles relevant to the aim of the review and published in English were reviewed and analyzed. A total of 76 articles were included in the final report. RESULTS:Digital pills have demonstrated adherence detection rates reaching above 95%. Wearable devices such as smart watches collect real-time behavioral and physiological data such as sleep patterns, heart rate variability, and physical activity that reflect adherence or emerging relapse. These metrics enable clinicians to customize interventions according to the patient adherence profile, allowing shared decision-making during treatment. Besides, the biomarker-based monitoring system provides more precise tracking, thus reducing the risk of an unsuitable treatment switch. Aptamer-based technologies also provide ultrasensitive and noninvasive adherence monitoring through the detection of antipsychotics in body fluids. CONCLUSION:Integration of wearable and biomarker data enables clinicians to make evidence-based pharmacological decisions while treating schizophrenic patients. Artificial intelligence promises to facilitate this integration by forecasting medication lapses and suggesting personalized solutions. To fully revolutionize adherence in schizophrenia treatment, pharmacists, psychiatrists, bioengineers, and policymakers should collaborate to address ethical, infrastructural, and financial barriers present in this practice.
This study investigates the relationship between problematic Internet use (PIU) and family rules regarding Internet use among children and adolescents. Although the Internet offers valuable development opportunities, excessive use is associated with adverse outcomes. Family-related factors have been discussed in relation to PIU prevention; however, empirical evidence regarding the establishment and maintenance of family rules remains limited. Data were obtained from a large-scale administrative survey conducted in Japan, including 8534 elementary and junior high school students. PIU was assessed using the Young Diagnostic Questionnaire. Family rules were classified according to their presence, the rule-setting process (parents only, parents and children collaboratively, or children), and the degree of adherence. Associations between family rules and PIU were examined using logistic regression analyses adjusted for sex, grade, and time spent on the Internet on weekdays and holidays. The results indicated that having previously established but no longer maintained family rules was associated with higher odds of PIU. In contrast, collaboratively established rules between parents and children were associated with lower odds of PIU, whereas rules determined by parents alone were associated with higher odds of PIU. Additionally, lower adherence to family rules was associated with higher odds of PIU. Collectively, these findings suggest that not only the presence of family rules but also the process through which they are established and adhered to are associated with PIU among children and adolescents. Accordingly, collaborative rule-setting and rule adherence may be relevant family processes to consider in future longitudinal and intervention research on PIU.
BACKGROUND:Educational interventions are widely used to promote guideline-concordant psychiatric practice. However, it remains unclear whether participants' subjective satisfaction translates into actual changes in clinical behavior (CB). This study examined the association between subjective assessment (SA) scores of the EGUIDE training programs for schizophrenia and major depressive disorder (MDD) and CB. METHODS:In this multicenter observational study, we analyzed data from psychiatrists who participated in the EGUIDE training program. SA scores were obtained immediately after training using standardized questionnaires assessing satisfaction with program content, knowledge, skills, and future clinical intentions. CB was evaluated using self-report measures of guideline-concordant practice in general, schizophrenia-specific, and MDD-specific domains. Associations between SA and CB scores were examined using Spearman's rank correlation coefficients. RESULTS:A total of 1399 psychiatrists were included in the analysis. The comprehensive SA score showed a significant positive correlation with the comprehensive CB score (r = 0.19, p < 0.001). Likewise, schizophrenia- and MDD-specific SA scores were positively correlated with all CB domains, including general guideline use and disorder-specific practices (ρ = 0.14-0.19, all p < 0.001). Although effect sizes were small, the associations were consistent across disorders and clinical domains. CONCLUSIONS:Higher satisfaction with guideline-based educational programs was associated with greater self-reported guideline-concordant CBs, suggesting that positive educational experiences may support improvements in psychiatric practice at the national level.
INTRODUCTION:Psychosis in epilepsy may be difficult to diagnose when altered consciousness, antiseizure medication changes, and psychotropic adverse effects coexist. CASE PRESENTATION:We report a man in his late 50s with longstanding drug-resistant epilepsy and recurrent psychosis. His documented convulsive seizures were classified as tonic-clonic seizures of unknown onset; epilepsy type and etiology could not be assigned. During admission for medication adjustment, reduced responsiveness and fluctuating alertness developed. EEG showed generalized rhythmic epileptiform activity at 2-3 Hz with evolution, and EEG/awareness improved after intravenous diazepam before fosphenytoin was introduced, supporting nonconvulsive status epilepticus. After treatment with fosphenytoin/phenytoin and improvement of nonconvulsive status epilepticus (NCSE), continuous EEG monitoring was performed to assess the phenytoin response and monitor electrographic recurrence. Serum antiseizure medication levels measured at multiple time points, together with MRI, blood tests, and the clinical course, made overt intoxication, acute structural or metabolic disease, and dementia with Lewy bodies less likely. After epileptiform activity attenuated and antipsychotics were withdrawn, psychosis re-emerged without EEG evidence of ongoing status epilepticus. The course was interpreted as interictal psychosis with a possible alternative psychosis component. Aripiprazole improved psychosis but caused akathisia/dyskinesia, requiring cross-titration to brexpiprazole. Levetiracetam reduction was limited by worsening EEG abnormalities. DISCUSSION AND CONCLUSION:This case emphasizes the need for a low threshold for EEG, structured diagnostic reasoning, and careful monitoring of pharmacokinetic interactions when treating psychosis in drug-resistant epilepsy.
Serum Aβ oligomer positivity may indicate neurodegenerative vulnerability and may be associated with poorer antidepressant treatment response in middle-aged and late-life depression. Further validation using amyloid PET, tau biomarkers, standardized treatment protocols, and longitudinal cognitive follow-up is needed.
INTRODUCTION:Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with distressed behaviors and psychological challenges. This study aims to evaluate the change in health-related quality of life (HRQoL), anxiety, and sleep quality in autistic individuals prescribed cannabis-based medicinal products (CBMPs). METHOD:This observational case series analyzed data from the UK Medical Cannabis Registry on autistic adults treated with CBMPs. Demographic and clinical data were collected at baseline, with patient-reported outcome measures assessed up to 18 months. Primary outcomes included changes in anxiety (GAD-7), sleep quality (SQS), and HRQoL (EQ-5D-5L). Secondary outcomes included the incidence of adverse events. Statistical significance was indicated by p < 0.050. RESULTS:One-hundred and thirty individuals met the inclusion criteria. GAD-7 (p < 0.001) and SQS (p < 0.001) scores improved from baseline to 18 months. EQ-5D-5L index values showed improvement from baseline (0.43 ± 0.30) to 18 months (0.51 ± 0.32, p < 0.001), and PGIC scores increased from 1 month (5.43 ± 1.49) to 18 months (5.65 ± 1.32, p = 0.013). Twenty-five participants (19.23%) reported a total of 232 (178.46%) adverse events, with most being mild (n = 88; 67.69%) or moderate (n = 99; 76.15%). CONCLUSION:Treatment with CBMPs was associated with improvements in HRQoL, anxiety, and sleep outcomes in autistic patients over an 18-month period. Given the absence of a control group, these findings represent associations rather than proven treatment effects. Further high-quality randomized controlled trials are needed to confirm the long-term efficacy and safety of CBMPs in ASD.
Although sleep deprivation (SD) is clinically associated with numerous neuropsychiatric disorders, its underlying molecular correlates remain unclear. Because extended wakefulness is accompanied by increased neuronal activity and network firing, SD may be associated with a hyperactive neural state. This study aimed to test the hypothesis that SD shares transcriptomic signatures induced by neuronal hyperexcitation and to identify the gene pathways and cell types associated with these signatures. Publicly available transcriptomic datasets were analyzed, including 32 SD and 23 neuronal hyperexcitation transcriptomic datasets. These datasets were systematically compared using the Running Fisher algorithm across multiple mouse brain regions and rodent neuronal hyperexcitation models. The analysis revealed significant positive transcriptomic overlaps between SD and neuronal hyperexcitation models (p ≤ 0.05 in 73% of cross-model comparisons). In addition, neuronal hyperexcitation datasets collected within 1-12 h after seizure induction showed stronger transcriptomic similarity to SD than those collected 24 h or later. The shared transcriptomic signature was significantly enriched for pathways associated with neuronal plasticity, immune response, and inflammation. Key overexpressed genes common to both conditions included immediate early genes (IEGs) such as Egr1, Fos, and Arc, as well as inflammation-associated genes such as Ptgs2 and Junb. Comparisons between SD single-cell and neuronal hyperexcitation datasets indicated that the shared signature was most strongly enriched in microglia and neurons, with additional contributions from endothelial cells and astrocytes. Microglia showed enrichment of stress- and immune-response genes, neurons exhibited IEG and plasticity-related signatures, and endothelial cells expressed metabolism-associated genes. Together, these findings indicate that SD is associated with a transcriptomic state resembling acute neuronal hyperexcitation, characterized by activation of neuronal plasticity-, neuroinflammatory-, and metabolism-related pathways. This shared molecular signature provides a transcriptomic framework linking sleep loss to molecular processes implicated in neuropsychiatric disorders and suggests that acute neuronal hyperexcitation-related molecular processes may contribute to SD-associated brain dysfunction.
Psychedelics such as psilocybin and lysergic acid diethylamide (LSD) exert hallucinogenic effects through stimulation of serotonin 5-HT2A receptors (5-HT2ARs) in the cerebral cortex. In recent years, numerous reports have demonstrated that psychedelics are effective in treating various psychiatric disorders such as major depressive disorder (MDD), treatment-resistant depression (TRD), and anxiety-related disorders. We have previously reported that administration of psilocin, the active metabolite of psilocybin, produces antidepressant-like effects in mice. Furthermore, we found that this effect is mediated by 5-HT2AR activation. Since depression and other psychiatric disorders often lead to impairments in social behavior (e.g., social avoidance), the present study examined the effects of psilocin on social avoidance behavior in mice subjected to chronic social defeat stress (CSDS), a widely used model that closely models human psychosocial stress. Mice exposed to CSDS exhibited social avoidance behavior, whereas psilocin administration before the onset of CSDS had little effect on this behavior. In contrast, psilocin administration after the completion of CSDS ameliorated social avoidance in CSDS-exposed mice. This effect was blocked by pretreatment with a 5-HT2AR antagonist, indicating that psilocin exerts its therapeutic effects through 5-HT2AR activation. Taken together, psilocin exerts therapeutic effects on social avoidance behavior after stress through activation of 5-HT2AR, but not preventive effects when administered before stress, suggesting that psilocin may promote stress resilience rather than resistance.
BACKGROUND:G protein-coupled receptors, the largest class of cell surface receptors, are ubiquitously expressed throughout the body. Different subtypes of G protein α subunits activate distinct intracellular signaling pathways and mediate opioid analgesic effects. However, the contributions of these Gα subunits remain unclear. We conducted a hypothesis-generating, two-stage candidate gene association study to identify potential genetic loci related to pain processing and opioid analgesia, focusing on genes encoding G protein α subunits. METHODS:To identify candidate single-nucleotide polymorphisms (SNPs) in seven genes encoding G protein α subunits, we analyzed postoperative opioid consumption, pain intensity, and opioid responsiveness in two exploratory cohorts [laparoscopy-assisted colectomy (n = 350) and mandibular plastic surgery (n = 354)]. For identified candidate SNPs, we further evaluated opioid responsiveness in a confirmatory cohort of 89 patients with cancer pain. We also conducted a preliminary sensitivity analysis adjusting for relevant covariates. RESULTS:Two SNPs (rs10781468 in the GNAQ gene and rs308049 in the GNA11 gene) showed significant associations in both exploratory cohorts. Patients with postoperative pain who were homozygous for the minor allele of rs10781468 exhibited higher opioid sensitivity or lower pain severity. In the confirmatory cohort, homozygosity for the major allele of rs10781468 was significantly associated with increased opioid sensitivity for cancer pain management under the dominant model (p = 0.025) and the genotypic model (p = 0.020), whereas rs308049 was not. The observed phenotypes and associated genetic models differed across cohorts, and sensitivity analyses continued to demonstrate some significant associations. CONCLUSIONS:As a hypothesis-generating investigation, we suggest that rs10781468 may serve as a potential candidate marker of responsiveness to opioid analgesics. Our findings should be validated in a large-scale study with a homogeneous pain type in which the opioid administration protocol is controlled to further examine the association observed in this exploratory study.
ABSTRACT Background Bipolar disorder (BD) is a chronic psychiatric condition that requires careful pharmacological management. Ensuring treatment effectiveness, safety, adherence, and proper monitoring is essential, especially in pediatric, pregnant, and cognitively impaired patients. Objective To review the available evidence on treatment outcomes, safety, adherence, and monitoring in bipolar disorder. Methods A literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar. A comprehensive review of systematic reviews, meta‐analyses, cohort studies, clinical trials, and case reports was performed. This review was guided by the Scale for the Assessment of Narrative Review Articles (SANRA) criteria. The findings were synthesized qualitatively. Results This review highlights important challenges and therapeutic considerations in bipolar disorder management. Medication adherence and laboratory monitoring compliance were generally poor. Sleep disturbances were associated with poorer functional outcomes. Combination therapy reduced the risk of manic and depressive recurrence but may lower overall functioning in some patients. Lithium showed favorable long‐term outcomes, including reduced sickness absence and lower mortality, whereas pregabalin was linked to poorer occupational outcomes. Untreated bipolar disorder during pregnancy was associated with prematurity and low birth weight. Mechanistically, lithium, valproate, and emerging agents may modulate neuroplasticity and intracellular signaling pathways; however, evidence for cognitive improvement remains limited and inconsistent. Conclusion Lithium and combination therapies improve relapse prevention, cognitive outcomes, and mortality. However, adverse effects and poor adherence remain challenges. Individualized strategies, regular monitoring, and tailored interventions are essential to optimize care.
