Cutaneous adverse reaction during lithium treatment: a case report and updated systematic review with meta-analysis

OBJECTIVES: To present a new case of adverse cutaneous reaction during lithium treatment and to update the systematic review and meta-analysis of the incidence of this adverse reaction. METHODS: We conducted a systematic search (performed in September 2016) for peer-reviewed articles in English indexed in Medline (2011-present). Meta-analytical estimates were obtained using the "Metafor" package. CASE PRESENTATION: Ms. H., a 31-year-old Caucasian woman with BD1, was admitted to the inpatient unit for a full-blown psychotic episode and treated with carbamazepine 400 mg q.d., lithium carbonate 450 mg q.d., and risperidone 4 mg q.d. with clinical improvement. After 12 days from the start of psychopharmacological treatment, she manifested a cutaneous reaction that motivated the stop of carbamazepine treatment, as well as the increase in lithium carbonate dose (750 mg q.d.). Risperidone dose remained unvaried. Since the skin lesion persisted after 8 days from withdrawal of carbamazepine, the private practitioner stopped also lithium carbonate treatment (de-challenge), maintaining risperidone treatment. The cutaneous reaction resolved spontaneously after six days from withdrawal of lithium carbonate. Subsequently, the worsening of psychopathological conditions motivated a new admission during which lithium carbonate was reintroduced (16 days after its suspension) (re-challenge). On the following day, we observed an itching erythematous maculopapular rash involving the trunk, the four limbs, and the oral mucosa. CONCLUSIONS: Our case of an erythematous maculopapular rash during lithium treatment was the first to present a challenge-de-challenge-re-challenge sequence that suggests causality. Although meta-analysis does not point to an increased rate of adverse skin reaction during lithium treatment, clinicians should not neglect to monitor cutaneous symptoms during lithium treatment

The Role of Copper Overload in Modulating Neuropsychiatric Symptoms

Copper is a transition metal essential for growth and development and indispensable for eukaryotic life. This metal is essential to neuronal function: its deficiency, as well as its overload have been associated with multiple neurodegenerative disorders such as Alzheimer’s disease and Wilson’s disease and psychiatric conditions such as schizophrenia, bipolar disorder, and major depressive disorders. Copper plays a fundamental role in the development and function of the human Central Nervous System (CNS), being a cofactor of multiple enzymes that play a key role in physiology during development. In this context, we thought it would be timely to summarize data on alterations in the metabolism of copper at the CNS level that might influence the development of neuropsychiatric symptoms. We present a non-systematic review with the study selection based on the authors’ judgement to offer the reader a perspective on the most significant elements of neuropsychiatric symptoms in Wilson’s disease. We highlight that Wilson’s disease is characterized by marked heterogeneity in clinical presentation among patients with the same mutation. This should motivate more research efforts to disentangle the role of environmental factors in modulating the expression of genetic predisposition to this disorder

Lithium and its effects: does dose matter?

Background: Decades of clinical research have demonstrated the efficacy of lithium in treating acute episodes (both manic and depressive), as well as in preventing recurrences of bipolar disorder (BD). Specific to lithium is its antisuicidal effect, which appears to extend beyond its mood-stabilizing properties. Lithium's clinical effectiveness is, to some extent, counterbalanced by its safety and tolerability profile. Indeed, monitoring of lithium levels is required by its narrow therapeutic index. There is consensus that adequate serum levels should be above 0.6 mEq/L to achieve clinical effectiveness. However, few data support the choice of this threshold, and increasing evidence suggests that lithium might have clinical and molecular effects at much lower concentrations. Content: This narrative review is aimed at: (1) reviewing and critically interpreting the clinical evidence supporting the use of the 0.6 mEq/L threshold, (2) reporting a narrative synthesis of the evidence supporting the notion that lithium might be effective in much lower doses. Among these are epidemiological studies of lithium in water, evidence on the antisuicidal, anti-aggressive, and neuroprotective effects, including efficacy in preventing cognitive impairment progression, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), of lithium; and (3) revieweing biological data supporting clinically viable uses of lithium at low levels with the delineation of a mechanistic hypothesis surrounding its purported mechanism of action. The study selection was based on the authors' preference, reflecting the varied and extensive expertise on the review subject, further enriched with an extensive pearl-growing strategy for relevant reviews and book sections. Conclusions: Clinical and molecular effects of lithium are numerous, and its effects also appear to have a certain degree of specificity related to the dose administered. In sum, the clinical effects of lithium are maximal for mood stabilisation at concentrations higher than 0.6 mEq/l. However, lower levels may be sufficient for preventing depressive recurrences in older populations of patients, and microdoses could be effective in decreasing suicide risk, especially in patients with BD. Conversely, lithium's ability to counteract cognitive decline appears to be exerted at subtherapeutic doses, possibly corresponding to its molecular neuroprotective effects. Indeed, lithium may reduce inflammation and induce neuroprotection even at doses several folds lower than those commonly used in clinical settings. Nevertheless, findings surrounding its purported mechanism of action are missing, and more research is needed to investigate the molecular targets of low-dose lithium adequately

Melkersson–Rosenthal syndrome: A case report

Melkersson–Rosenthal syndrome (MRS) is a rare disorder with a still unknown etiology. It is defined by three main symptoms, which are orofacial granulomatosis (OFG), facial palsy, and fissured tongue. It generally presents in young people, during the second or third decade, and its incidence in the entire population is about 1%. We focus our attention on a 69-year-old man who came to us with an important swelling of the upper lip. His anamnesis revealed that he suffered from a facial palsy four times in his life and at the physical examination we attested the presence of scrotal tongue. We suspected a misdiagnosed MRS and we searched the web in order to give him a diagnosis and a therapy. We found that OFG is the most common symptom of MRS and that it can show as a non complete form, where the three main symptoms cannot occur simultaneously. We also prescribed a therapy based on the use of topic steroids and antiviral, according to literature. After the positive response to the therapy and according to data found in the most recent literature, we can assume that our patient suffers from a misdiagnosed MRS for about 40 years

Pharmacokinetic Markers of Clinical Outcomes in Severe Mental Illness: A Systematic Review

The term severe mental illness (SMI) encompasses those psychiatric disorders exerting the highest clinical burden and socio-economic impact on the affected individuals and their communities. Pharmacogenomic (PGx) approaches hold great promise in personalizing treatment selection and clinical outcomes, possibly reducing the burden of SMI. Here, we sought to review the literature in the field, focusing on PGx testing and particularly on pharmacokinetic markers. We performed a systematic review on PUBMED/Medline, Web of Science, and Scopus. The last search was performed on the 17 September 2022, and further augmented with a comprehensive pearl-growing strategy. In total, 1979 records were screened, and after duplicate removal, 587 unique records were screened by at least 2 independent reviewers. Ultimately, forty-two articles were included in the qualitative analysis, eleven randomized controlled trials and thirty-one nonrandomized studies. The observed lack of standardization in PGx tests, population selection, and tested outcomes limit the overall interpretation of the available evidence. A growing body of evidence suggests that PGx testing might be cost-effective in specific settings and may modestly improve clinical outcomes. More efforts need to be directed toward improving PGx standardization, knowledge for all stakeholders, and clinical practice guidelines for screening recommendations

Pharmacological Treatment of Bipolar Depression: A Review of Observational Studies

The persistence of depressive morbidity is frequent in bipolar disorder, and the pharmacological management of this symptomatology often lacks effectiveness. This systematic review aimed to summarize the results of the naturalistic observational studies on the pharmacological treatment of bipolar depression published through April 2022. The certainty of evidence was evaluated according to the GRADE approach. In sum, 16 studies on anticonvulsants, 20 on atypical antipsychotics, 2 on lithium, 28 on antidepressants, and 9 on other compounds were found. Lamotrigine, quetiapine, aripiprazole, and ketamine were the most investigated compounds. Overall, the results support the recommendations regarding the effectiveness of lamotrigine and quetiapine. In contrast to the current recommendations, aripiprazole was shown to be effective and generally well tolerated. Additionally, SSRIs were shown to be effective, but, since they were associated with a possibly higher switch risk, they should be used as an adjunctive therapy to mood stabilizers. Lithium was only studied in two trials but was shown to be effective, although the serum concentrations levels were not associated with clinical response. Finally, ketamine showed divergent response rates with a low certainty of evidence and, so far, unclear long-term effects. Heterogeneity in diagnosis, sample sizes, study designs, reporting of bias, and side effects limited the possibility of a head-to-head comparison

Telemedicine: Issues in the Analysis of Its Use in Elderly People and in People with Disabilities, According to the Perspective of the Clinical Psychology of Disability

The recent COVID-19 pandemic has led to a sudden increase in the speed of the digitization process, which has affected several areas of life (public administration, schools, universities, and healthcare, and extending to so-called "digital citizenship") [...]

Digital determinants of health as a way to address multilevel complex causal model in the promotion of Digital health equity and the prevention of digital health inequities: A scoping review

Background: With the progressive digitization of health services and the current spread of Telemedicine and e-Health, it became clear that promoting Digital health equity (DHE) is necessary to support health potential, to avoid that some individuals can incur in unintended inequities. In this paper, we address the complex causal process(es) that may generate risk of inequities, considering the so-called “Digital Determinants of health” (DDoH) and their relationship with determinants of health (DoH). Design and methods: We conducted a scoping review, according to methodological framework proposed in PRISMA-ScR guidelines, on the definition of DDoH (Scopus, Pubmed and Web of Science electronic databases). Inclusion criteria: papers on the definition of DDoH, no time limits, all study designs eligible. Results: There is an agreement on the link between DDoHs and “digital divide” and on their effects on a wide range of health, functioning outcomes, both as barriers and as facilitators. Authors proposed to modify or integrate with DDoHs the “Rainbow model” or other conceptual models on DoH. To promote DHE, authors suggest considering a multidimensional complex causal model, with interdependence among the different levels and the mutually reinforcing effects. Conclusion: To study DDoH and their relationship with main determinants of health could be a way to address the complex causal model in the promotion of DHE. However, as they act in a multidimensional causal context, any intervention may consider the interdependence among different involved levels, within them, and the mutually reinforcing effects. Further research is needed to gain a more complete picture of the field

Telemedicine, e-Health, and Digital Health Equity: A Scoping Review

Background: With the progressive digitization of people's lives and in the specific healthcare context, the issue of equity in the healthcare domain has extended to digital environments or e-environments, assuming the connotation of “Digital Health Equity” (DHE). Telemedicine and e-Health, which represent the two main e-environments in the healthcare context, have shown great potential in the promotion of health outcomes, but there can be unintended consequences related to the risk of inequalities. In this paper, we aimed to review papers that have investigated the topic of Digital Health Equity in Telemedicine and e-Health [definition(s), advantages, barriers and risk factors, interventions]. Methods: We conducted a scoping review according to the methodological framework proposed in PRISMA-ScR guidelines on the relationship between Digital Health Equity and Telemedicine and e-Health via Scopus and Pubmed electronic databases. The following inclusion criteria were established: papers on the relationship between Digital Health Equity and Telemedicine and/or e-Health, written in English, and having no time limits. All study designs were eligible, including those that have utilized qualitative and quantitative methods, methodology, or guidelines reports, except for meta-reviews. Results: Regarding Digital Health Equity in Telemedicine and e-Health, even if there is no unique definition, there is a general agreement on the idea that it is a complex and multidimensional phenomenon. When promoting Digital Health Equity, some people may incur some risk/s of inequities and/or they may meet some obstacles. Regarding intervention, some authors have proposed a specific field/level of intervention, while other authors have discussed multidimensional interventions based on interdependence among the different levels and the mutually reinforcing effects between all of them. Conclusion: In summary, the present paper has discussed Digital Health Equity in Telemedicine and e-Health. Promoting equity of access to healthcare is a significant challenge in contemporary times and in the near future. While on the one hand, the construct “equity” applied to the health context highlights the importance of creating and sustaining the conditions to allow anyone to be able to reach (and develop) their “health potential”, it also raises numerous questions on “how this can happen”. An overall and integrated picture of all the variables that promote DHE is needed, taking into account the interdependence among the different levels and the mutually reinforcing effects between all of them

IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation

: Giant cell glioblastoma (GC-GBM) is a rare variant of IDH-wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between IDH-wt and IDH-mutant GBM. The lack of an objective definition, specifying the percentage of giant cells required for this diagnosis, may account for the absence of a definite molecular profile of this variant. This study aimed to clarify the molecular landscape of GC-GBM, exploring the mutations and copy number variations of 458 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI) in 39 GBMs dichotomized into having 30-49% (15 cases) or\u2009 65\u200950% (24 cases) GCs. The type and prevalence of the genetic alterations in this series was not associated with the GCs content (<\u200950% or 65\u200950%). Most cases (82% and 51.2%) had impairment in TP53/MDM2 and PTEN/PI3K pathways, but a high proportion also featured TERT promoter mutations (61.5%) and RB1 (25.6%) or NF1 (25.6%) alterations. EGFR amplification was detected in 18% cases in association with a shorter overall survival (P\u2009=\u20090.004). Sixteen (41%) cases had a TMB\u2009>\u200910 mut/Mb, including two (5%) that harbored MSI and one with a POLE mutation. The frequency of RB1 and NF1 alterations and TMB counts were significantly higher compared to 567 IDH wild type (P\u2009<\u20090.0001; P\u2009=\u20090.0003; P\u2009<\u20090.0001) and 26 IDH-mutant (P\u2009<\u20090.0001; P\u2009=\u20090.0227; P\u2009<\u20090.0001) GBMs in the TCGA PanCancer Atlas cohort. These findings demonstrate that the molecular landscape of GBMs with at least 30% giant cells is dominated by the impairment of TP53/MDM2 and PTEN/PI3K pathways, and additionally characterized by frequent RB1 alterations and hypermutation and by EGFR amplification in more aggressive cases. The high frequency of hypermutated cases suggests that GC-GBMs might be candidates for immune check-point inhibitors clinical trials