CerefolinNAC (CFLN-NAC) contains L-methylfolate (6 mg), methylcobalamin (2 mg), and N-acetylcysteine [NAC] (600 mg) [Pamlab 2017]. Dizziness and lightheadedness have not heretofore been described with use of CFLN-NAC.

Case Study: A 64 year old right-handed female was started on CFLN-NAC for smell and taste issues. Over a three day period, she experienced a gradual increase in dizziness. This was a non-vertiginous lightheadedness, so severe that she was unable to walk, and would lie down the entire day to alleviate the dizziness. It was associated with nausea, but without any vomiting or falls. The dizziness would come and go, last for several hours, and was 9/10 in severity.

She admits to a past history of epochs of vertigo. The vertigo occurred three times with nausea and vomiting 13 years, 11 years, and 4 years prior to presentation. She also developed a constant, bilateral, high-pitched tinnitus 14 years prior to presentation, which obstructs her hearing. It is level 3/10 in intensity during the night and in the quiet. There were no alleviating or aggravating factors. Acupuncture was without effect, and she denies any ear pain. After ceasing CFLN-NAC for three days, a gradual reduction of dizziness to baseline ensued.

Abnormalities in Physical Examination: General: Decreased blink frequency and hypokinesia. Cranial Nerve III, IV, VI: Saccadization of horizontal eye movements. Motor Examination: Tone: 1+ cogwheel rigidity in both upper extremities, left more than right. Drift Test: Bilateral Abductor Digiti Minimi sign with cerebellar spooning. Reflexes: Absent quadriceps femoris and Achilles bilaterally. Positive Hoffman reflex bilaterally. Neuropsychiatric Testing: Go-No-Go Test: 6/6 (normal). Animal Fluency Test: 19 (normal). Reliable Digit Span: 10 (normal). Clock Drawing Test: 4 (normal). Center for Neurologic Study Lability Scale: 10 (normal). Other: Audiometry and Fiberoptic Endoscopy: normal. MRI of the brain with and without contrast was normal.

None of the individual components in CFLN-NAC have been reported to precipitate dizziness [Pamlab 2017]. The non-vertiginous nature of the dizziness makes it unlikely to be due to vestibular involvement, raising the spectre of this drug having an impact on the autonomic nervous system. While a nocebo effect could be in action, this is unlikely since dizziness was not presented as a potential side effect on initiation of the medication. In addition, methylcobalamin can cause hyperviscosity syndrome, but due to an absence of visual disturbances and altered mental status, it is also improbable. The relatively rapid onset with initiation and resolution upon discontinuation of this medication strongly suggests that it is not a coincidence, rather an origin for the dizziness. Those who are treated with CFLN-NAC should be queried as to new onset dizziness. For those already dizzy, one should consider other treatment options.

Smell and Taste Treatment and Research Foundation

Meningitis causes inflammation of the meninges and when bacteria are not the cause may be considered aseptic. Drug-induced aseptic meningitis (DIAM) can arise from the use of certain medications. The pathophysiology of DIAM is not well understood. Within the antiepileptic medication class, only lamotrigine, carbamazepine, and levetiracetam have been associated with DIAM via documented cases. Common presentation of DIAM involves fever, headache, meningismus, and mental status changes (abnormal consciousness and focal neurological deficits). Other clinical features may include neck stiffness, photophobia, nausea, vomiting, abdominal pain, bone pain, hypotension, edema (facial and optic nerve), rash, and seizures. Case reports of DIAM with varying or limited symptomology exist. Therefore, the presentation alone will not allow for a DIAM diagnosis, prompting further analysis and diagnostic exclusion.

A middle-aged male presented with a 48-hour history of confusion, disorientation, unresponsiveness, and hypersomnolence. Past medical history included hypertension, hyperlipidemia, type-2 diabetes, and seizures. Home medication included chlorthalidone, levetiracetam, lisinopril, metformin, potassium chloride, rosuvastatin with no medication allergies reported. Upon admission, the patient denied fever, headache, nausea, neck pain, vomiting, and rash. Somnolence, dysarthria, and obtundation were noted during the physical evaluation. Hospital medications included home medications along with enoxaparin, correctional dose insulin lispro, and IV lactated ringers. Vitals and labs were unremarkable. On hospital day (HD) 1 the MRI scan was unremarkable, ruling out a demyelinating process. Serology tests (ie, ANA and dsANA) were negative. Neurology was consulted, and a lumbar puncture was performed. On HD-2 AEIM was suspected, prompting levetiracetam discontinuation and lacosamide initiation (50 mg by mouth twice daily). The CSF analysis was notable for pleocytosis (lymphocytic predominance at 96%), elevated protein (100 mg/dL), and slightly elevated glucose (79 mg/dL). The CSF VDRL was negative, ruling out neurosyphilis. Bacterial meningitis was ruled out based on the CSF analysis (WBC 144 × 103 and glucose) and the lack of bacterial growth on gram stain. Inasmuch, antibiotic therapy was not initiated. Empiric acyclovir 1000 mg IV every 8 hours was initiated as viral meningitis had not been eliminated, due to the lack of viral meningeal PCR testing. By HD-3, the CSF culture resulted without growth and the patient was alert and oriented. By HD-4 the patient was discharged, having received 6 doses of IV acyclovir, with 7 more days of oral therapy.

In 2018, McDonald et al documented the first case of probable levetiracetam-related antiepileptic induced meningitis (AEIM). The mainstay of treatment is discontinuing the offending agent. Resolution of symptoms is typically 2 to 3 days after drug discontinuation as seen in this patient case report. Symptomatic resolution within days of stopping the suspected offending drug has been observed in all reported cases of AEIM where 1 to 2 weeks is generally seen with viral meningitis. Applying the Naranjo Scale yields a score of 4, which indicates possible levetiracetam-induced meningitis in this adult patient. Providers should be cognizant when prescribing antiepileptics to assess and monitor for aseptic meningitis that may appear with atypical symptoms.

No funding

Priming stimulation, which involves high-frequency repetitive transcranial magnetic stimulation (rTMS) followed by low-frequency, has been shown to enhance neural response and is one of the novel paradigms found beneficial in adult patients with depression and has not been studied in late-life depression (LLD). This study aims to compare the effect of adjunctive priming vis-a-vis no priming rTMS over right dorso-lateral prefrontal cortex (DLPFC), on treatment of LLD.

This trial is registered in Clinical Trial Registry-India (CTRI) on www.ctri.nic.in. CTRI registration number: CTRI/2020/08/027230. Forty patients of LLD who are symptomatic after an adequate antidepressant trial will be randomized into 2 groups (active priming and sham priming rTMS); each receiving 10 sessions of rTMS over 2 weeks. Patients will remain blind to treatment allocation. Assessments will be done using Hamilton rating scale for depression, Geriatric Depression Scale, Hamilton rating scale for Anxiety, Somatic Symptom Severity Scale 8, Hindi Mental Status Examination, and Clinical Global Impression scale at baseline, week 1, 2, and 4. Side effect checklist will be applied after each session in both groups and at the end of 4 weeks.

Data will be analyzed using statistical software Statistical Package for Social Sciences. Both the groups (active and sham groups) will be compared at the four given timepoints. Also, the baseline characteristics will be compared with the 3 follow-up points for any change.

The findings of the study will give an insight to the possible role of priming to augment the effect of low-frequency rTMS in LLD.

Major depressive disorder (MDD) has been ranked among the top causes worldwide of years lived with disability. In this study we assessed meaningful change for the PHQ-9 and the SDS and determined the meaningful change threshold (MCT) using anchor-based methods, which could be used to compare meaningful differences in patients within different treatment arms.

TRANSFORM-1 (NCT02417064) and -2 (NCT0241858) were Phase 3 trials that evaluated the efficacy and safety of fixed and flexible doses of esketamine nasal spray (56 mg or 84 mg) in combination with newly initiated oral antidepressant (ESK+AD) vs oral antidepressant + placebo nasal spray (AD+PBO) in TRD patients. Patient Reported Outcomes (PROs) were integrated into these trials to evaluate the patient perspective of treatment using instruments capturing concepts of importance to patients. The 9-item Patient Health Questionnaire (PHQ-9) is a PRO instrument used to assess self-reported depression symptoms and the Sheehan Disability Scale (SDS) is a PRO for self-reported function and disability. Blinded trial data (combined treatment groups) from TRANSFORM-1 was used for the anchor-based analysis. The Clinical Global Impression - Severity (CGI-S) was used as an anchor and patients were classified into response groups depending on their level of change over the course of the study. Patients were classified among all possible change categories (15 levels, ranging from -7 to 7 where negative change scores indicate improvement). Cumulative Distribution Function (CDF) curves of change from baseline to day 28 were generated using unblinded data from TRANSFORM-2 to visualize the range of responses demonstrated in the respective treatment groups for the PHQ-9 and SDS. MCT values were used to as thresholds to evaluate percentage of responders in each treatment group.

In anchor-based analyses using TRANSFORM-1 combined treatment groups, the correlation between change on the CGI-S and change on the PHQ-9 at Day 28 was high (> 0.60) with anchor-based MCTs ranging from 5 to 8 points. The magnitude of change (standardized effect size estimate within-subject change) for patients improving was exceptionally high (> 0.80). Similar results were observed on the SDS: high correlation of CGI-S and SDS at Day 28 (0.75), moderate SES (0.66), with suggested MCT ranging from 3 to 7 with an MCT value of 5 pts. CDF curves from TRANSFORM-2 showed clear separation between the ESK+AD vs AD+PBO across a number of responder definitions inclusive of those identified with the anchor-based analyses.

The current study is the first to derive an MCT on the PHQ-9 and SDS in TRD to measure meaningful change from the perspective of the patient using regulatory-preferred psychometric anchor-based methodology. These analyses assist with interpretation of meaningfulness of esketamine phase 3 clinical trial results from the patient perspective.

Study was funded by Janssen Global Services, LLC.

Objectives for this survey are to determine similarities or differences in treatment goals reported by psychiatrists, patients with schizophrenia (SCZ) and caregivers in the US, as well as whether goals differed by patients currently on an oral antipsychotic (OAP) or long-acting injectable (LAI), and whether goals differed by age.

This was a real-world, cross-sectional survey of US psychiatrists, patients =18 years old diagnosed with SCZ, and caregivers. Data was collected using the Disease Specific Programme (DSP) methodology. Psychiatrists (n=120) completed detailed record forms for next 8 outpatients and 2 inpatients matching inclusion criteria. The same patients and their caregivers, if present, were invited by their psychiatrist to voluntarily complete a separate survey.

Responses on treatment goals were collected from psychiatrists for all patients included in the analysis (n=1161), patients (n= 542) and caregivers (n=130). Among 3 top goals, psychiatrists, patients and caregivers concurred that “decrease in disease symptoms” is most important (63%, 64%, 68% respectively). For psychiatrists and caregivers, second was “decrease in hospitalization for relapse” (41%, and 38% respectively), whereas for patients, it was “thinking clearly” (47%). Of the 3 least important goals, psychiatrists, patients and caregivers agreed with “sexual problems” (59%, 43%, 44%, respectively) and “weight gain” (38%, 44%, 38%, respectively).

When asked which goals were met by current medication, patients responded “decrease in disease symptoms” (68%) and “thinking clearly” (39%). However, caregivers responded “thinking clearly” (30%) was not met by current medication. Caregivers most important goals, “decrease in disease symptom” (70%) and “decrease in hospitalization for relapse” (41%), were met. Additional analyses of patients on OAPs and LAIs, did not show differences in goals. However, “decrease in disease symptoms” was numerically more important for patients on LAIs vs OAPs according to psychiatrists (68% vs 62%) and caregivers (77% vs 70% respectively). Caregivers responded “decrease in hospitalization for relapse” was met for 63% patients currently on an LAI and 35% OAP. No major differences in treatment goals were observed by patient age (18–35 vs 36–65 vs >65 years).

There is consensus among US psychiatrists, patients and caregivers on the most important treatment goal “decrease in disease symptoms”, regardless of patients’ current medication or age. For patients, “thinking more clearly” was second, compared with “decrease in hospitalization due to relapse”, for psychiatrists and caregivers. All agreed that least important treatment goals, related to AEs, were “weight gain” and “sexual problems”. More caregivers agreed “decrease in hospitalization for relapse” was met by patients on LAIs vs OAPs. These findings may help with discussions between psychiatrists, patients and caregivers.

Lundbeck LLC and Otsuka Pharmaceutical Development & Commercialization, Inc.

A double-blind, randomized, active-controlled, parallel-group, noninferiority trial (NCT03345342) demonstrated that paliperidone palmitate once-every-6-months (PP6M) was noninferior to paliperidone palmitate once-every-3-months (PP3M) in preventing relapse in clinically stable adults with schizophrenia. This post hoc analysis assessed efficacy and safety following transition to PP6M from paliperidone once-monthly (PP1M) versus PP3M.

Adults with schizophrenia who were clinically stable on moderate/high doses of PP1M or PP3M were randomly assigned 1:2 to dorsogluteal PP3M or PP6M treatment for 12 months. The primary efficacy measure was time to relapse during the 12-month DB phase. Secondary endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale (PANSS) total and subscale scores, Clinical Global Impression-Severity (CGI-S) scale score, and Personal and Social Performance (PSP) scale score. Safety was assessed by treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory tests.

Of 702 patients in the study, 231 transitioned from PP1M to PP6M and 247 transitioned from PP3M to PP6M. Low relapse rates for PP6M were observed regardless of transition pathway (PP1M/PP6M: 7.8%; PP3M/PP6M: 7.3%). Changes from DB baseline to endpoint in PANSS total, PSP, and CGI-S scores were similar between transition groups. In the DB phase, ≥1 TEAE was observed in 61.0% and 63.2% of patients in the PP1M/PP6M and PP3M/PP6M, groups, respectively.

Adults with schizophrenia who transitioned to PP6M from either PP1M or PP3M experienced similarly low relapse rates. Additionally, symptom and functionality scores supported the primary analysis and, along with TEAE incidences, were comparable between transition groups.

Deutetrabenazine is FDA approved for tardive dyskinesia (TD) based on two 12-week, placebo-controlled studies evaluating safety and efficacy in patients with baseline Abnormal Involuntary Movement Scale (AIMS) score ≥6. Deutetrabenazine reduced overall AIMS scores compared with placebo in ARM-TD (–3.0 vs –1.6, P=0.019) and AIM-TD (24 mg/day, –3.2 vs –1.4, P=0.003; 36 mg/day, –3.3 vs –1.4, P=0.001). This analysis assessed Minimal Clinically Important Difference (MCID) in AIMS score in patients with TD treated with deutetrabenazine.

MCID is the smallest change from baseline in AIMS score that is meaningful for patients. MCID analyses were performed based on Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) as anchors described by Hauser et al., where MCID is the difference between patients treated with deutetrabenazine who were minimally improved and patients treated with placebo who were unchanged. Additional MCID definitions were explored: difference between patients who demonstrated treatment improvement versus those who did not (Method 2); difference between patients who demonstrated treatment success versus those who did not (Method 3).

295 patients were analyzed. Based on PGIC, the suggested MCID was –2.8. Results were similar for Method 2 (75% of patients had treatment improvement; MCID = –2.8) and Method 3 (38% of patients had treatment success; MCID = –2.6). Based on CGIC, the suggested MCID was –2.6. Results were similar for Method 2 (76% of patients had treatment improvement; MCID = –2.8) and Method 3 (41% of patients had treatment success; MCID = –3.0). Therefore, the suggested MCID for deutetrabenazine is –3.

The MCID for change in AIMS score based on PGIC and CGIC for deutetrabenazine was –3 regardless of the analytical method. Findings suggest an AIMS score reduction of ~3 is associated with clinically meaningful improvement in TD symptoms.

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Chronic insomnia (CI) often co-occurs with depression and anxiety, and treatment may positively impact mood. This ongoing study collected real-world data on changes in insomnia, depression, and anxiety symptoms among adults with CI treated with a prescription digital therapeutic (PDT) delivering cognitive-behavioral therapy for insomnia (CBT-I; Somryst®, previously SHUTi).

This prospective, single-arm, pragmatic clinical study enrolled adults (≥18 years) in the US with CI and mobile device access. The PDT consists of six core modules completed over 6–9 weeks. In this interim analysis, participants completed the Insomnia Severity Index (ISI), 8-item Patient Health Questionnaire (PHQ-8), and Generalized Anxiety Disorder-7 scale (GAD-7) and other self-reported outcomes—at screening (baseline/prior to Core 1), end of treatment (Day 63), and 6-month follow-up (Day 243).

Mean ISI scores decreased (p<0.0001) from baseline (n=991) to post-treatment (n=777;18.8 vs 11.3) and to Day 243 (n=193; 18.8 vs 12.1). Mean GAD-7 scores improved from baseline to Day 63 (n=744; p<0.0001, Cohen’s d = 0.48) and to Day 243 (n=186; p<0.0001, d = 0.45). Similarly, PHQ-8 scores improved from baseline to Day 63 (n=747; p<0.001, d = 0.76) and to Day 243 (n=186; p<0.0001, d = 0.60). These patterns persisted across baseline anxiety and depressive severity levels among people with any baseline depressive or anxiety symptoms (all p<0.05 for depression, all p<0.0001 for anxiety), with large effect sizes observed for severe anxiety (d=1.43 Day 63, d=1.55 Day 243) and for moderate to severe depression (d range = 0.96-1.51).

In this study, treatment with digital CBT-I was associated with significant reductions in ISI, anxiety, and depression at posttreatment and at 6 months. The largest observed decreases in GAD-7 and PHQ-8 scores were among people with more severe baseline mood symptoms.

Pear Therapeutics (US), Inc.

Recent guidance from UK health authorities strongly cautions against the use of valproic acid (VPA) in persons under 55 because of reevaluated risk of teratogenicity.

To summarize the extant literature documenting VPA-associated anatomical, behavioral, and cognitive teratogenicity.

Pubmed, Medline, Cochrane Library, PsychInfo, Embase, Scopus, Web of Science, and Google Scholar were searched in accordance with PRISMA guidelines. Collected data covered study design, participant characteristics, anatomical, behavioral, or cognitive effects, and folic acid outcomes.

122 studies were identified meeting inclusion comprised of studies evaluating anatomical (n = 67), behavioral (n = 28), and cognitive (n = 47) teratogenicity. Twenty studies were identified reporting on the risk mitigation effects of folic acid supplementation. Prenatal VPA exposure is associated with anatomical teratogenicity including major congenital malformations (odds ratio [OR] 2.47–9.30; p < 0.005). Behavioral teratogenicity including autism (OR 1.70–4.38), impaired motor development (OR 7.0), and ADHD (OR 1.39) are also significantly associated with VPA exposure. VPA was associated with intellectual disability and low IQ (hazard ratio [HR] 2.4–4.48, verbal intelligence: Spearman’s ρ = −0.436, respectively). Teratogenic effects were dose-dependent across all domains and were significant when compared with controls and other antiepileptic drugs (eg, carbamazepine, lamotrigine, and levetiracetam). Folic acid supplementation does not significantly reduce the hazard associated with VPA.

VPA is significantly associated with anatomical, behavioral, and cognitive teratogenicity. Folic acid supplementation does not abrogate the risk of teratogenicity associated with VPA exposure. Available evidence supports recommendations to reduce VPA exposure in women of reproductive age.

Human resource management is an important field that directly impacts the development of enterprises and the quality of employees’ work. With the rapid growth of society and the intensification of competition, enterprises are facing more and more pressure, and employees are also under more work pressure. Therefore, optimizing the enterprise’s human resource management system to relieve the psychological pressure of new and old employees has become an urgent research topic.

Based on the analysis and dismantling of the existing human resource management model, this study improves the structural modules that can be optimized, such as the suitable working environment and resource support provided by the company, the promotion system obtained by employees, and reasonable welfare benefits. The improved and optimized human resource management mode was compared with the traditional one under the same conditions, and SPSS23.0 software was used for correlation detection. This paper explores the relieving effect of the optimal management mode on the psychological stress of employees.

The employees who accepted the optimal management mode were more satisfied, the number of employees with psychological stress decreased significantly, and the self-evaluation score was higher. The difference was significant (P<0.05). Employees who accept the traditional management mode have no noticeable effect on relieving psychological pressure and low overall satisfaction.

The optimal human resource management model proposed in this study explicitly affects the psychological pressure of new and old employees and improves job satisfaction and performance.

Flibanserin, a serotonin antagonist currently indicated for treatment of female sexual dysfunction disorder, has not heretofore been described to worsen cerebellar function. Such a case is presented.

A 60-year-old woman, 8 months prior to presentation, had an acute onset of fainting and hitting her head into a wall without loss of consciousness. She could not stand up, had left-sided weakness, and vomiting, with garbled, slow speech and severe headache. Findings in the emergency room showed a left cerebellar parenchymal hemorrhage of 3.2 x 3.1 x 2 cm with the epicenter at the dentate nucleus, extending medially towards midline into the cerebellar vermis, with surrounding perilesional edema extending into the middle cerebellar peduncle. Also, 5.2 cm of the hemorrhage extended from the petrous of the tentorium to the cerebellar vermis. Moreover, a ventral left thalamic hemorrhage with subependymal clot at the foramen of Monroe extended into the dependent portion of lateral ventricles without midline shift. Post one month of physical therapy, speech, walking, and coordination improved but she continued to have delayed speech and trouble getting up, with a wide stance.

Neurologic Examination: Cranial Nerve (CN) Examination: CN XI: Sternocleidomastoid hypertrophy, horizontal titubation. Motor examination: Drift test: L pronator drift with L abductor digiti mini sign. Gait examination: heel walking, dystonic posture of L hand. Tandem gait: unstable, wide based. Cerebellar examination: Both (B) finger-to-nose dysmetria, Left > Right. Slow rapid alternating movements (RAM) L Upper Extremity (UE). Due to absent sexual desire she started 100 mg of flibanserin nightly. Maintaining this for 5 weeks, her coordination markedly worsened with poor balance and a need for a cane to ambulate. She would stumble, with a wider gait, and found climbing stairs challenging. Physical examination displayed worse cerebellar function: prominent horizontal titubation. Finger-to-nose—dysmetria L>R. Decreased RAM, L UE. Markedly positive Holmes Rebound phenomenon, Bilateral UE. Tandem gait: unstable. A week post stopping flibanserin, gait and cerebellar examination returned to baseline.

The temporal correlation between the use of flibanserin and transient worsening of cerebellar function strongly suggests that this is the causative agent. Since serotonin is essential in cerebellar function, including its action on the cerebellar cortex and deep cerebellar nuclei, it strongly suggests that its action as a serotonin antagonist is the mechanism whereby flibanserin is causing cerebellar symptoms. In those on flibanserin, investigation to detect the presence of cerebellar dysfunction is warranted. Assessment for the presence of cerebellar dysfunction in those who are on anti-serotonin drugs, such as cyproheptadine and methysergide, may be worthwhile.

No Funding