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

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.

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.

MIND-TD is a collaboration of healthcare professionals (HCPs) who are committed to raising awareness of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics and other dopamine receptor blocking agents. The MIND-TD questionnaire was developed to help HCPs screen for TD and facilitate discussion with patients.

In August 2020, an expert panel of 13 HCPs (4 psychiatrists, 6 neurologists/movement disorder specialists [MDSs], and 3 advanced practice providers [APPs]) met virtually to discuss potential screening questions for TD. This work was continued by 4 panelists (1 psychiatrist, 2 neurologists/MDSs, and 1 APP) who tested the questions in clinical practice for revision and refinement. The same group also worked with the sponsor to develop 2 additional sections that could be used to elicit more information from patients. The panel recognized the need for a tool that could facilitate telehealth screening for TD, including audio-only interactions. Therefore, practices from speech-language pathologists (eg, diadochokinetics) were used to refine the questionnaire.

Part 1 of the MIND-TD questionnaire includes a yes-or-no question for each of the 4 following topics: presence of extra or unwanted movements (Movement); feelings of embarrassment or self-consciousness (Impact); if anyone else has noticed the movements (Notice); and if movements interfere with everyday routines (Daily Activities). Part 1 can be administered by any trained medical staff, either in person or via telehealth (with video or audio-only). Routine administration is suggested in all patients who meet any of the following criteria: current or prior use of any first- or second-generation antipsychotic; use of an anticholinergic medication in conjunction with a current or past antipsychotic; or current diagnosis of TD. Part 2 of the MIND-TD questionnaire has 2 sections. The first (Thorough Interview) includes 9 items related to physical/functional difficulties (eg, eating, speaking, walking, and gripping objects) and 3 simple instructions for speech difficulties. The second section (Differentiate) includes checklists of characteristic movements for TD and drug-induced parkinsonism, along with an item related to akathisia and suggestions for observing abnormal or involuntary movements. Part 2 should be administered by the treating HCP in patients who have abnormal movements that may be related to TD. Part 2 requires visual observation of the patient, whether in-person or via video.

MIND-TD is a screening questionnaire that can facilitate a dialogue between HCPs and patients about the risks, symptoms, and impact of TD. The MIND questions can stand alone and be administered during in-person visits or telehealth visits (video or audio-only). The TD section can be used to gather more information about a patient’s abnormal movements.

Neurocrine Biosciences, Inc.

In a phase 3 trial of children with ADHD, DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, improved ADHD symptoms and reduced at-home early morning and late afternoon/evening functional impairments versus placebo, as measured by the validated Parent Rating of Evening andMorning Behaviors-Revised, Morning (PREMB-R AM) and Evening (PREMB-R PM) subscales. This post hoc analysis evaluated the effect of DR/ER-MPH versus placebo onindividual PREMB-R AM/PM item scores.

Data were analyzed from a pivotal, randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) withADHD (NCT02520388). Using the 3-item PREMB-R AM and 8-item PREMB-R PM, both key secondary endpoints, investigators evaluated early morning and lateafternoon/evening functional impairment by scoring each item on a severity scale from 0 (none) to 3 (a lot). For post hoc analyses, treatment comparisons between DR/ER-MPH and placebo at endpoint were determined by using least squares mean changes from baseline on individual PREMB-R AM/PM items score derived from an analysis ofcovariance (ANCOVA) model with treatment as the main effect, and study center and baseline score as covariates.

Of 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose achieved after 3 weeks of treatment was 68.1 mg. Following 3 weeks of treatment, DR/ER-MPH significantly reduced mean individual item scores from baseline versus placebo on all PREMB-R AM items (all P≤0.002; “getting out of bed”, “getting ready”, and “arguing or struggling in the morning”). Additionally, DR/ER-MPH significantly reduced mean individual item scores from baseline on 5 out of 8 PREMB-R PM items (P<0.01 in 2 items [“sitting through dinner” and “playing quietly”] and P<0.05 in 3 items [“inattentive/distractible”, “transitioning between activities”, and “settling down/getting ready for bed”]). There was a trend towards a reduction on 2 other items of the PREMB-R PM (P<0.09). Distributions of the ratings for each item will be presented. No serious TEAEs were reported; TEAEs were consistent withmethylphenidate.

Post hoc analyses revealed that DR/ER-MPH significantly reduced all PREMB-R AM item scores, including “getting out of bed”, and many PREMB-R PM items, including “getting ready for bed” in children with ADHD. These findings are worth further exploration.

Ironshore Pharmaceuticals & Development, Inc.

Eye’ve Seen Enough: Oculogyric Crisis in a 13 year old Male Treated for Comorbid ADHD and Psychosis After Stopping Lisdexamphetamine

Oculogyric crisis is a dystonic movement disorder caused by sustained contractions of ocular muscles that may last minutes to hours. It is known to occur during hypodopaminergic states. Combined use of stimulants and antipsychotics increase the risk for developing a hypodopaminergic state in the brain leading to various dystonic reactions described as a stimulant-antipsychotic syndrome (SAS).

A unique example of SAS occurred in a 13 year-old male with comorbid ADHD and schizoaffective disorder hospitalized for acute psychotic decompensation who had been treated for several months with risperidone and lisdexamphetamine. On admission, the patient had received olanzapine 5mg ODT for acute agitation and lisdexamphetamine was discontinued. He started to cross-taper from risperidone to quetiapine. In this setting he developed dystonia including an oculogyric crisis that resolved with diphenhydramine.

In this case the use of lisdexamphetamine and risperidone may have set up an environment where there was decreased endogenously made dopamine and up-regulation of postsynaptic dopamine receptors. Upon discontinuation of the lisdexamphetamine and acute use of additional atypical antipsychotics (olanzapine and quetiapine), the body experienced a hypodopaminergic state resulting in dystonic reactions that included an oculogyric crisis. This case is unique from previously reported cases by occurring with the use and discontinuation of lisdexamphetamine while most reported cases involved a derivative of methylphenidate as the stimulant. This report adds to the literature showing the importance of monitoring and being aware of potential medication interactions especially when treating for comorbid conditions. This is even more important to recognize after adding or removing either of these medications.

Funding: no funding.

Prior research suggests that religiosity may be associated with healthier levels of mental health in certain domains (eg, higher self-esteem and lower rates of substance use problems). However, very little is known about religiosity and impulsive plus compulsive tendencies. This study examined associations between religiosity and impulsive and compulsive behaviors and traits among university students.

Nine thousand, four hundred and forty-nine students received a 156-item anonymous online survey which assessed religiosity, alcohol and drug use, mental health issues, and impulsive and compulsive traits. Two groups of interest were defined: those with high religiosity, and those with low religiosity, based on z-scores. The two groups were compared on the measures of interest.

Three thousand, five hundred and seventy-two university students (57.1% female) responded to the survey. Those with high levels of organizational religious activity, as well as those with high levels of intrinsic or subjective religiosity, differed from their fellow students in having better self-esteem, being less likely to have alcohol or drug problems, and generally being less impulsive in terms of attention and planning. Compulsivity did not differ between groups. Associations were of small effect size except for the link between religiosity and lower impulsivity, which was of medium effect size.

This study shows a link between higher religiosity and lower impulsivity, as well as higher levels of mental health across several domains. Whether these associations are causal—and if so, the direction of such causality—requires rigorous longitudinal research.

Buprenorphine/Naloxone combination drugs such as Suboxone and Bunavail have not been reported to induce glycolimia. Two such cases are presented.

CASE STUDY: Case 1: A 30-year-old, right-handed, white female with a history of opioid abuse was started on 4.2 mg buprenorphine/0.7 mg naloxone (Bunavail) BID and began sweet cravings and consumption of sweet foods. In a typical day she would eat 16 strawberry pop-tarts and 2 boxes of Little Debbie cookies. This may have provoked the 10 pound weight augmentation in the first two weeks of treatment. She denied any craving for opioids and no evidence of opioid withdrawal was present. Her Clinical Opiate Withdrawal Scale (COWS) score =4 (normal).

Case 2: A 51-year-old, right-handed, male with opiate dependence, four days following the initiation of Suboxone (8 mg buprenorphine/2 mg naloxone) BID, developed strong cravings for sugary foods including donuts and ice cream, of which he was previously never inclined to eat and gained 10 pounds in one month. His COWS score= 7 (mild symptoms).

There are myriad mechanisms that may be acting to induce sugar cravings with buprenorphine/naloxone. Humans and rats acutely withdrawing from opiates, such as heroin, develop strong urges for consumption of sugary substances (Lieblich et al., 1991; Sapira, 1968; Weiss, 1982). Glycolimia in the above cases may reflect early or subclinical withdrawal, which if becoming more severe, would manifest as opioid craving. If the value of the reward system induced by sweets doesn’t meet the threshold invoked by the opioid stimulation, this “withdrawal” may lead to further sugar cravings in an attempt to reach the same reward level. In animals, certain foods and drugs share the same neurological pathway involved in the “reward system” potentially explaining why opioids influence food palatability in humans (Pelchat, 2002).

Alternatively, it is possible that buprenorphine induces hypoglycemia at high doses (Bullingham et al., 1981) such that hypoglycemia may paradoxically act to enhance sugar craving similar to the Somogyi effect in insulin dependent diabetics. Another possible mechanism of action is that since buprenorphine acts to decrease glucose metabolism in the brain (Walsh et al., 1994), this may lead to a neural compensatory response by increasing sugar access to the brain behaviorally via glycolimiaand somatically reducing insulin release, thus explaining the high hemoglobin A1c observed in opioid addicts (Giugliano, 1984). Given the above presentation, complaints of sugar craving may indicate consideration to increase buprenorphine dosing and trial of this in those with glycolimia without opioid dependence may be warranted.

No funding.