Polypharmacy in Psychiatry: An In-depth Examination of Drug-drug Interactions and Treatment Challenges.

Polypharmacy in psychiatry is an in-depth examination of drug-drug interactions and treatment challenges that explores the intricate landscape of psychiatric polypharmacy, a practice involving the prescription of multiple medications to individuals with mental health disorders. This review is based on the critical aspects of drug-drug interactions and the associated treatment challenges. Psychiatric polypharmacy is motivated by the complexity of mental health conditions, where monotherapy may be insufficient. While it offers potential benefits, the practice raises concerns related to drug interactions that can compromise safety and efficacy. The review delves into the prevalence and clinical indications for psychiatric polypharmacy, thoroughly analyzing drug interactions, treatment challenges, and strategies for mitigation. Real-world case studies illustrate the complexities and outcomes of managing complex medication regimens, while emerging trends in personalized medicine, advancements in psychopharmacology, multidisciplinary approaches, and digital health solutions offer a glimpse into the future of psychiatric polypharmacy. This examination underscores the importance of a patient-centered, evidence-based approach in optimizing psychiatric polypharmacy to achieve therapeutic benefits while minimizing risks.

Assessment of thermal damage for plasmonic photothermal therapy of subsurface tumors.

Plasmonic photothermal therapy (PPTT) involves the use of nanoparticles and near-infrared radiation to attain a temperature above 50 °C within the tumor for its thermal damage. PPTT is largely explored for superficial tumors, and its potential to treat deeper subsurface tumors is dealt feebly, requiring the assessment of thermal damage for such tumors. In this paper, the extent of thermal damage is numerically analyzed for PPTT of invasive ductal carcinoma (IDC) situated at 3-9 mm depths. The developed numerical model is validated with suitable tissue-tumor mimicking phantoms. Tumor (IDC) embedded with gold nanorods (GNRs) is subjected to broadband near-infrared radiation. The effect of various GNRs concentrations and their spatial distributions [viz. uniform distribution, intravenous delivery (peripheral distribution) and intratumoral delivery (localized distribution)] are investigated for thermal damage for subsurface tumors situated at various depths. Results show that lower GNRs concentrations lead to more uniform internal heat generation, eventually resulting in uniform temperature rise. Also, the peripheral distribution of nanoparticles provides a more uniform spatial temperature rise within the tumor. Overall, it is concluded that PPTT has potential to induce thermal damage for subsurface tumors, at depths of upto 9 mm, by proper choice of nanoparticle distribution, dose/concentration and irradiation parameters based on the tumor location. Moreover, intravenous administration of nanoparticles seems a good choice for shallower tumors, while for deeper tumors, uniform distribution is required to attain the necessary thermal damage. In the future, the algorithm may be extended further, involving 3D patient-specific tumors and through mice model-based experiments.

Gold nanoblackbodies-based multifunctional nanocomposite for multimodal cancer therapy.

Multifunctional nanocomposites are of potential use to achieve complete tumor elimination and, thus, to avoid tumor recurrence. Herein, polydopamine (PDA)-based gold nanoblackbodies (AuNBs) loaded with indocyanine green (ICG) and Doxorubicin (DOX) termed as A-P-I-D nanocomposite were investigated for multimodal plasmonic photothermal-photodynamic-chemotherapy. Upon near-infrared (NIR) irradiation, A-P-I-D nanocomposite showed enhanced photothermal conversion efficiency of 69.2% compared to bare AuNBs (62.9%) due to the presence of ICG, along with ROS (1O2) generation as well as enhanced DOX release. On assessment of therapeutic effects on breast cancer (MCF-7) and melanoma (B16F10) cell lines, A-P-I-D nanocomposite showed significantly lower cell viabilities of 45.5% and 24% compared to 79.3% and 76.8% for AuNBs. Fluorescence images of stained cells revealed characteristic signs of apoptotic mode of cell death, with almost complete damage on A-P-I-D nanocomposite + NIR treated cells. Further, on evaluation of photothermal performance through breast tumor-tissue mimicking phantoms, A-P-I-D nanocomposite provided required thermal ablation temperatures within the tumor along with the potential for the elimination of residual cancerous cells through photodynamic therapy and chemotherapy. Overall, this study demonstrates that A-P-I-D nanocomposite + NIR provides better therapeutic outcome on cell lines and enhanced photothermal performance on breast tumor-tissue mimicking phantoms to be a promising agent for multimodal cancer therapy.

Gold nanoblackbodies mediated plasmonic photothermal cancer therapy for melanoma.

Aim: Gold nanoblackbodies (AuNBs)-mediated plasmonic photothermal cancer therapy was investigated through melanoma-bearing mice. Materials & methods: Polydopamine-coated Au nanoclusters were synthesized, termed AuNBs and PEGylated AuNBs (AuNBs-PEG). The photothermal response of AuNBs-PEG was evaluated upon low-intensity broadband near-infrared irradiation (785/62 nm; 0.9 Wcm-2), and cytotoxicity was assessed on B16-F10 cells. Further, the therapeutic potential of intravenously administered AuNBs-PEG was evaluated on B16-F10 melanoma in C57BL/6 mice. Results: AuNBs-PEG showed an excellent photothermal response (photothermal conversion efficiency of 60.3%), robust photothermal stability and no cytotoxicity. For AuNB-mediated plasmonic photothermal therapy, an average temperature of 63°C was attained within 5 min of irradiation, and tumors were eradicated. Conclusion: AuNBs-PEG are promising photothermal agents for treating melanoma through low-intensity broadband near-infrared irradiation.

Polydopamine Coated Gold Nano Blackbodies for Tumor-Selective Spatial Thermal Damage During Plasmonic Photothermal Cancer Therapy.

Plasmonic photothermal therapy (PPTT), which involves nanoparticles and near-infrared radiation (NIR) to generate confined heat, is a potential technique for selective thermal damage of cancerous tissue. Herein, tumor-selective spatial damage characteristics during polydopamine (PDA) coated gold nano blackbodies (AuNBs) mediated PPTT is investigated through a tumor-tissue mimicking phantom. The spatial temperatures during PPTT were measured within the phantom mimicking the optical scattering of superficial invasive ductal carcinoma (injected with AuNBs) surrounded by a region without AuNBs. The phantom was irradiated using broadband NIR radiation (754-816 nm), and spatial temperatures were measured using thermocouples and an infrared thermal camera. The obtained results demonstrate that the tumor region's temperature was elevated to >50°C in about 2.5 minutes and was maintained thereafter for about 6 minutes, which is well sufficient for the thermal ablation of the tumor. While for the region surrounding the tumor, a temperature of about 40-44°C was attained, which is within safe limits for the said exposure duration. Overall, this study demonstrates that for the considered experimental parameters and tumor dimensions, heat-based thermal damage could be confined to the nanoparticle embedded tumor region while maintaining the safe temperature levels for the surrounding region, i.e., 2 mm beyond the tumor boundary.

Undervirilized male infant with in utero exposure to maternal use of high dose antifungal therapy.

BACKGROUND: Antifungals act on fungal sterols structurally similar to human cholesterol. Ketoconazole reversibly suppresses steroidogenesis by inhibiting cytochrome P450 enzymes and interferes with dihydrotestosterone (DHT) activity by binding to the androgen receptor. Hypospadias was reported in infants exposed to nystatin in utero. CASE PRESENTATION: A male infant exposed to antepartum nystatin presented with severe under-undervirilization and transient adrenal corticosteroid abnormalities. He was born in USA at 31 weeks gestation to a mother treated with vaginal Polygynax capsules (nystatin-100,000 international units, neomycin sulphate-35,000 international units and polymyxin B-35,000 international units) for vaginal discharge in the Ivory Coast. She used approximately 60 capsules between the first trimester until delivery. The infant was born with micropenis, chordee, perineo-scrotal hypospadias and bifid scrotum with bilaterally palpable gonads. The karyotype was 46,XY. No Mullerian structures were seen on ultrasound. Serum 17-hydroxyprogesterone (17 OHP) on newborn screening was high (304 ng/ml, normal < 35). Cortisol response to cosyntropin on the 3rd day of life (DOL) was 10 mcg/ml; the subnormal cortisol response may have resulted from prematurity and the predelivery treatment with betamethasone. The elevation of several adrenal corticosteroids was not consistent with any specific enzymatic defect. Hydrocortisone and fludrocortisone were initiated at another hospital for suspected mild glucocorticoid and mineralocorticoid deficiencies. Genetic screening for adrenal and gonadal developmental defects performed when transferred to our care were normal. All medications were gradually discontinued over 5-8 months. Adrenal and testicular responses to cosyntropin and human chorionic gonadotropin (hCG) were normal at 8 months. CONCLUSIONS: We report severe undervirilization in a 46,XY infant born to a mother treated with prolonged and high dose nystatin during pregnancy. This presentation suggests that prolonged antepartum use of high dose nystatin could lead to severe but transient defects in androgen synthesis and/or action possibly by acting as an endocrine disruptor. Further studies are warranted to confirm this finding. Thus, endocrine disruptors should be considered in male newborns with atypical genitalia not explained by common pathologies.

Glucocorticoid Resistance in Premature Adrenarche and PCOS: From Childhood to Adulthood.

CONTEXT: We hypothesize that impaired glucocorticoid sensitivity (GC sensitivity) plays a role in the development of premature adrenarche (PA) and polycystic ovarian syndrome (PCOS) by increasing androgen synthesis. OBJECTIVE: To study glucocorticoid sensitivity in vitro in subjects with PA and PCOS. PATIENTS AND METHODS: Fourteen subjects (10 girls, 4 boys, 6.9 ± 0.6 years) with PA; 27 subjects with PCOS (17 ± 2.5 years) and 31 healthy controls were enrolled in the study. All subjects and controls underwent GC sensitivity analysis in vitro using a fluorescein labeled-dexamethasone (F-DEX) assay. A GC sensitivity index (GCSI) was calculated as area under the curve of the F-DEX assay results. Subjects were classified as GC resistant if the GCSI ≤ 264 and GC sensitive if the GCSI ≥ 386. RESULTS: In the PA group, 8 of 14 subjects were resistant with GCSI of 179.7 ± 39.9, 4 were within the normal range with GCSI of 299.6 ± 27.9, and 2 had increased GC sensitivity with GCSI of 423.5 ± 47.9. In the PCOS group, 18 of 27 subjects were GC-resistant with GCSI of 180.9 ± 58.2, 8 were within the normal range with GCSI of 310.7 ± 26.4, and 1 had increased GCSI of 395.4. In the PCOS GC-resistant subgroup, cortisol was higher compared with PCOS with normal GCSI (P < 0.05). In the combined PCOS plus female control group, GCSI correlated negatively with cortisol and testosterone (P < 0.05). CONCLUSION: GC resistance was found in more than 50% of patients with PCOS and PA. The findings strongly suggest that GC resistance is associated with states of PA and PCOS.

Safety and Efficacy of Brivaracetam in Pediatric Refractory Epilepsy: A Single-Center Clinical Experience.

Brivaracetam is a new antiepileptic drug with limited data in children. The objective of this study was to assess the efficacy/tolerability of brivaracetam. This is a retrospective chart review of children/adolescents with refractory epilepsy treated with brivaracetam from 2016 to 2018. The primary outcome was seizure reduction (decrease in seizure frequency >50%). Twenty-three patients were identified. Mean age at initiation was 12.5 years. Fourteen were females. Epilepsy was focal in 11, generalized in 6, and mixed in 3. Average dose was 3.9 mg/kg/d. The mean duration of treatment was 8.2 months. Eight had greater than 50% decrease in seizure frequency, of which 7 had focal epilepsy, and 1 had Lennox-Gastaut/mixed epilepsy. Two had drowsiness and 3 behavioral complaints. One experienced tingling and dizziness. Our retrospective review suggests that brivaracetam is an effective therapy for refractory focal epilepsy in children older than 4 years of age.

A case of 5,10-methenyltetrahydrofolate synthetase deficiency due to biallelic null mutations with novel findings of elevated neopterin and macrocytic anemia.

We describe a case of 5,10-methenyltetrahydrofolate synthetase (MTHFS) deficiency characterized by microcephaly, global developmental delay, epilepsy, and cerebral hypomyelination. Whole exome sequencing (WES) demonstrated homozygosity for the R74X mutation in the MTHFS gene. The patient had the unexpected finding of elevated cerebrospinal fluid (CSF) neopterin. The novel finding of macrocytic anemia in this patient may provide a clue to the diagnosis of this rare neurometabolic disorder.

Neuropsychological outcome following thalamic stroke in adolescence: an identical twin comparison.

Objective: Medial thalamic stroke in adults commonly results in severe learning and memory impairments and executive dysfunction, particularly during the acute phase. However, there is limited research on the cognitive recovery from thalamic stroke in physically healthy adolescents. This study aimed to fill this gap in the literature by utilizing a monozygotic twin control to investigate the neuropsychological outcomes of bilateral thalamic stroke in adolescence. Method: We evaluated an otherwise healthy 17-year-old male with a history of premature birth, developmental delay, and learning disability 2 and 7 months after he sustained a bilateral medial/anterior thalamic stroke of unknown etiology. His identical twin brother served as a case control. Results: The patient presented with improvements in many cognitive skills between assessments, most notably processing speed. Despite some mild improvement, however, he presented with significant deficits in fine motor speed/coordination, spatial perception, and rapid naming. Additionally, he exhibited persistent, severe deficits in verbal learning and memory. Relative sparing of executive functions (i.e., planning and set-shifting) and attention on standardized measures in this case may be explained by good underlying health, limited extra-thalamic damage, and/or recovery of function. The effects of thalamic injury resulted in minimal adaptive dysfunction or deterrence from academic or athletic success for the presented case. Conclusions: These results suggest risk for deficits in encoding of new verbal information following bilateral thalamic stroke in adolescence, as well as risk for persistent cognitive deficits despite initial improvements. This is consistent with descriptions of anterograde memory impairments in adults with similar lesions.

Paroxysmal Dyskinesias.

Paroxysmal dyskinesias (PD) are hyperkinetic movement disorders where patients usually retain consciousness. Paroxysmal dyskinesias can be kinesigenic (PKD), nonkinesigenic (PNKD), and exercise induced (PED). These are usually differentiated from each other based on their phenotypic and genotypic characteristics. Genetic causes of PD are continuing to be discovered. Genes found to be involved in the pathogenesis of PD include MR-1, PRRT2, SLC2A1, and KCNMA1. The differential diagnosis is broad as PDs can mimic psychogenic events, seizure, or other movement disorders. This review also includes secondary causes of PDs, which can range from infections, metabolic, structural malformations to malignancies. Treatment is usually based on the correct identification of type of PD. PKD responds well to antiepileptic medications, whereas PNKD and PED respond to avoidance of triggers and exercise, respectively. In this article, we review the classification, clinical features, genetics, differential diagnosis, and management of PD.

Cost-Effectiveness of Evaluation of Children With Epilepsy in the Emergency Department: Need for Investment in Patient Education.

We aimed to study cost-effectiveness of seizure evaluation of children with epilepsy in the emergency department (ED). We reviewed epilepsy patients seen at our ED for 1 year. Age, laboratory and neuroimaging results, treatment, disposition, and usefulness of the visit (need for hospitalization, clinical improvement) were analyzed. We identified 330 patients, aged 23 days-21 years, 190 (57.5%) had blood tests, 45 (13.6%) urinalysis, 2 (0.6%) cerebrospinal fluid testing, and 44 neuroimaging studies (13.3%). Tests' positive yield were 41%, 11%, 0%, and 4.5%, respectively. One-third of patients (n = 122) were treated with antiepileptic drugs. Other treatments were administered to 44 (13.3%). One hundred eighteen patients (35.7%) were admitted to our hospital, 208 (63%) discharged to home. Two hundred eight visits were useful (63%). One-third of visits did not provide useful patient care. Their visits were expensive and not very cost-effective. Investment in patient education could decrease unnecessary ED visits.

Thrombocytopenia in Critically Ill Patients: Clinical and Laboratorial Behavior and Its Correlation with Short-term Outcome during Hospitalization.

BACKGROUND: Thrombocytopenia, being among the most common laboratory abnormality, found in Intensive Care Unit (ICU) patients is commonly associated with sepsis and disseminated intravascular coagulation. Declining platelet counts are associated with higher mortality rates. Thus, thrombocytopenia can be used as a prognostic marker in critically ill patients. METHODOLOGY: A prospective observational study was conducted on patients fulfilling the inclusion criteria and were evaluated for complete medical history, clinical, and laboratorial examination. Short-term outcome of the patient was correlated with thrombocytopenia. RESULTS: The incidence of thrombocytopenia in ICU patients was 37.57%, and mortality was 44%. Higher mortality rate was found among patients with acute febrile illnesses, respiratory diseases, and sepsis (P = 0.08, 0.22, 0.41 respectively). The mortality was higher in patients with platelet counts <100,000/µl (P = 0.0008) and whose platelet levels declined on day 3 or 5 (P = 0.0001). CONCLUSIONS: Low as well as declining platelet counts are markers of severity of critical patients and are directly related to prognosis and mortality of patients in ICU.

Bilateral Adrenal Hyperplasia as a Possible Mechanism for Hyperandrogenism in Women With Polycystic Ovary Syndrome.

CONTEXT: Androgen excess may be adrenal and/or ovarian in origin; we hypothesized that a subgroup of patients with polycystic ovarian syndrome (PCOS) may have some degree of abnormal adrenocortical function. OBJECTIVE: The objective of the study was to evaluate the pituitary adrenal axis with an oral low- and high-dose dexamethasone-suppression test (Liddle's test) in women with PCOS. DESIGN: This was a case-control study. SETTING: The study was conducted at the National Institutes of Health Clinical Center. PARTICIPANTS: A total of 38 women with PCOS and 20 healthy volunteers (HV) aged 16-29 years participated in the study. MAIN OUTCOME MEASURES: Urinary free cortisol (UFC) and 17-hydroxysteroids (17OHS) before and after low- and high-dose dexamethasone and assessment of adrenal volume by computed tomography scan were measured. RESULTS: Twenty-four-hour urinary 17OHS and UFC were measured during day 1 to day 6 of the Liddle's test. Baseline UFC levels were not different between PCOS and HVs; on the day after the completion of high-dose dexamethasone administration (d 6), UFC was higher in the PCOS group (2.0 ± 0.7 µg/m(2)·d) than the HV group (1.5 ± 0.5) (P = .038). On day 5, 17OHS and UFC were negatively correlated with adrenal volumes (left side, rp = -0.47, P = .009, and rp = -0.61, P < .001, respectively). PCOS patients above the 75th percentile for UFC and/or 17OHS after high-dose dexamethasone (n = 15) had a significantly smaller total adrenal volume (6.9 ± 1.9 cm(3) vs 9.2 ± 1.8 cm(3), P = .003) when compared with the remaining PCOS patients (n = 22), but they did not have worse insulin resistance or hyperandrogenism. CONCLUSIONS: In a subset of young women with PCOS, we detected a pattern of glucocorticoid secretion that mimicked that of patients with micronodular adrenocortical hyperplasia: they had smaller adrenal volumes and higher steroid hormone secretion after dexamethasone compared with the group of PCOS with appropriate response to dexamethasone.

Efficacy and Tolerability of Lacosamide in the Treatment of Children With Refractory Generalized Epilepsy.

Lacosamide is FDA-approved in patients 17 years or older with partial-onset epilepsy. We evaluated the efficacy and tolerability of lacosamide in children with refractory generalized epilepsy. We retrospectively reviewed records of 21 children with refractory generalized epilepsy treated with lacosamide in our institution from 2009-2013 divided into 2 subgroups- I, Lennox-Gastaut Syndrome, and II, other generalized epilepsies. Efficacy was defined as seizure freedom or ≥50% seizure reduction. Descriptive data analysis including seizure freedom was compared using c(2) analysis. There were eleven females and ten males with a mean age, of 11.9 years. Five patients became seizure free, nine had ≥50% seizure reduction, and seven had no response. Group I: seven had ≥50% improvement, one did not respond. Group II: five became seizure free, two had ≥50% improvement, five had no response. Lacosamide is effective and well tolerated in children with refractory generalized epilepsy particularly patients with Lennox-Gastaut Syndrome.

A Patient With Atypical Multiple Sulfatase Deficiency.

BACKGROUND: Multiple sulfatase deficiency is an autosomal recessive lysosomal storage disorder characterized by the absence of several sulfatases and resulting from mutations in the gene encoding the human C (alpha)-formylglycine-generating enzyme. There have been a variety of biochemical and clinical presentations reported in this disorder. PATIENT DESCRIPTION: We present a 4-year-old girl with clinical findings of microcephaly, spondylolisthesis and neurological regression without ichthyosis, coarse facies, and organomegaly. RESULTS: The child's magnetic resonance imaging demonstrated confluent white matter abnormalities involving the periventricular and deep cerebral white matter with the U-fibers relatively spared. Biochemical testing showing low arylsulfatase A levels were initially thought to be consistent with a diagnosis of metachromatic leukodystrophy. The diagnosis of multiple sulfatase deficiency was pursued when genetic testing for metachromatic leukodystrophy was negative. CONCLUSION: This child illustrates the clinical heterogeneity of multiple sulfatase deficiency and that this disorder can occur without the classic clinical features.

A novel 2q37 microdeletion containing human neural progenitors genes including STK25 results in severe developmental delay, epilepsy, and microcephaly.

2q37 microdeletion syndrome is a rare syndrome characterized by neurodevelopmental delay, bone, cardiovascular, and neurological alterations. This syndrome is typically associated with loss of genetic material of approximately 100 genes in the 2q37 band. However, the genes associated with neurodevelopmental phenotype in this syndrome are still unknown. We identified a deleted region of 496 kb by whole genome array CGH in a patient who fulfilled criteria for 2q37 microdeletion syndrome with developmental delay, microcephaly, hypoplasia of the corpus callosum, hand wringing, toe walking, and seizures. The deleted segment contains genes that are highly expressed in the developing human cortical plate and the subventricular zone (SVZ) in vivo and human neural progenitors in vitro, including SEPT2, THAP4, ATG4B, PPP1R7, and STK25. Network analysis revealed that STK25 was the most interacting gene associated with neural development in this deletion. Our report narrows the likely causative genomic region for microcephaly and neurodevelopmental delay in 2q37 microdeletion syndrome to a small genomic region enriched with neural progenitor genes that may represent an important locus for the development of the human cortex and corpus callosum.

EEG Duration: The Long and the Short of It.

Current American Clinical Neurophysiology Society guidelines require a minimum of 20 minutes of artifact-free EEG recording; however, the optimum duration for routine EEGs is not established. Our hypothesis was that an EEG recording of 40 minutes' duration would yield more information than a 20-minute EEG in capturing epileptiform abnormalities and in obtaining sleep. We retrospectively studied 150 consecutive EEGs of 40 minutes' duration performed at St Christopher's Hospital for Children. Although the majority (89%) of interictal EEG abnormalities can be identified within the first 20 minutes of a routine EEG, extending the time of a routine EEG increases the yield significantly by identifying an additional 11% of abnormal studies (P = .0001), precluding the need for further long-term monitoring in these patients. Forty-three percent of interictal epileptiform abnormalities were found during sleep. We recommend that routine EEGs be performed for 40 minutes, whenever possible, to improve yield in a cost-effective manner.