Clozapine is the standard of care for treatment-resistant schizophrenia. However, up to a third of patients will have a partial or no response to treatment despite an adequate trial of clozapine. There are no accepted guidelines for alternative pharmacological regimens in the treatment of clozapine-resistant schizophrenia (CRS) and electroconvulsive therapy is not always a feasible option. This paper is a scoping review of PubMed literature, reviewing various pharmacological regimens attempted for treating CRS.

A systematic search using the [Title/Abstract] filter was conducted on PubMed to identify articles related to clozapine-resistant schizophrenia (or similar terms). Three researchers reviewed a total of 130 abstracts. The inclusion criteria were limited to observational articles that assessed psychopharmacological modifications with objective measurement tools. After screening 27 full-text articles, only 18 were included in the final analysis.

In this scoping review, the most commonly tested medication was amisulpride, which was explored both as an adjunct and a replacement for clozapine in patients with CRS. The randomized controlled trials and retrospective studies on amisulpride demonstrated significant improvements in symptoms on objective assessments such as the Positive and Negative Symptom Scale (PANSS), The Brief Psychiatric Rating Scale (BPRS), and Scales for the Assessment of Negative Symptoms (SANS). Other assessment tools used by researchers included the SAPS, CGI, RBANS, GAF, and UKU scales, among others.

As adjuncts to clozapine, several medications exhibited significant improvements on the PANSS negative subscale score, such as Amisulpride, Brexipiprazole, Memantine, Ropinirole, and Sodium Nitroprusside. Papers also reported positive outcomes after switching from clozapine to cariprazine or clotiapine, as measured by the SANS and PANSS, respectively. Quetiapine, Loxapine and Fluvoxamine augmentation also showed a significant improvement on the BPRS.

In contrast, one study indicated no significant improvement in outcomes when augmenting clozapine with olanzapine compared to placebo, using the Global Assessment of Functioning (GAF) and Clinical Global Impression Scale (CGIS).

Managing CRS can be challenging, particularly due to the absence of set guidelines on the pharmacological treatment of CRS. Most clinicians choose to add adjunctive medications to clozapine, while others opt to switch to a different medication altogether. Both approaches are viable options with varying results. The findings in this study underscore the potential benefits of various pharmacological regimens in the treatment of CRS. However, it is crucial to consider each patient’s individual needs when making treatment decisions. It is prudent to do further objective analyses on the treatment of CRS.

No Funding

Bipolar disorder (BD) is a lifelong mental disorder with a variable course, comprising one of the primary psychiatric illnesses warranting hospitalization due to its recurrent and chronic nature. Despite the existence of extensive evidence regarding factors influencing psychiatric hospitalization duration, limited scientific evidence establishes the duration of psychiatric hospitalization in patients with BD. The objective of this study is to assess the clinical characteristics and factors influencing the duration of hospital stay in patients with BD.

This is a retrospective observational and descriptive study. The protocol was approved by the ethics and research committee of the Hospital Universitario "Dr. José Eleuterio Gonzalez” in Monterrey, Nuevo León, México under the name "Factores predictores del tiempo de hospitalización psiquiátrica en pacientes con trastorno bipolar". Retrospective investigation was carried out of patients admitted between July 2015 and May 2022. Clinical and sociodemographic characteristics of 276 patients diagnosed with BD type 1 and type 2 were collected. Descriptive analyses were conducted for all variables using frequencies and percentages for categorical variables. Typical dispersion measures were applied to quantitative variables. Mann-Whitney U test was used to compare means between groups for dichotomous variables, and the Kruskal-Wallis test for variables with more than two categories. Spearman’s correlation coefficient was used for quantitative variables. Statistically significant values were considered at p < 0.05.

Factors associated with longer hospital stay included younger age (p < 0.001), being separated or divorced (p = 0.002), unemployment (x=27.94 vs. x=23.77; p=0.12), absence of medical comorbidity (x=27.21 vs. x=20.73; p=0.11), previous hospitalization history (x=28.50 vs. x=23.26; p=0.005), history of substance abuse (x=28.55 vs. 24.68; p=0.26), use of pharmacological restraint (p=0.28), and non-use of mood stabilizers during hospitalization (x=27.54 vs. x=24.11; p=0.27).

Overall, this study highlights the significance of comprehensive and personalized treatment approaches for patients with bipolar disorder. By addressing specific risk factors and optimizing therapeutic strategies, healthcare professionals can potentially reduce the length of hospital stays, leading to improved patient well-being and resource utilization within psychiatric care facilities. However, further research and intervention studies are warranted to validate and implement these findings in clinical practice.

No Funding

Attention-deficit/hyperactivity disorder (ADHD) remains underdiagnosed and undertreated in girls. One important contributor is the predominance of inattentive symptoms in girls relative to boys. Though less “visible,” inattentive symptoms represent a key driver of impairment, often persisting into adulthood. EndeavorRx (AKL-T01) is a game-based, FDA-authorized digital therapeutic directly targeting inattention. This analysis sought to examine potential sex differences in the efficacy of AKL-T01.

We conducted a secondary analysis of clinical outcomes by sex in 326 children and adolescents from two trials of AKL-T01 (n1 = 180 children; 30.6% female, M age = 9.71; n2 = 146 adolescents; 41.1% female, M age = 14.34). All participants had high inattention per a baseline score ≤ -1.8 on the Test of Variables of Attention (TOVA), a computerized, FDA-cleared continuous performance task objectively measuring attention. Participants used AKL-T01 for 25 minutes/day over 4 weeks. Primary outcomes included change in attention on the TOVA Attention Comparison Score (ACS) and sub-metrics, and change in symptoms on clinician-rated ADHD Rating Scale (ADHD-RS). To evaluate study hypotheses, we conducted a series of t-tests of TOVA and ADHD-RS change scores by sex.

Across the pooled sample, girls using AKL-T01 demonstrated significantly greater improvements in attention on the TOVA ACS (MΔ = 2.44) compared to boys (MΔ = 1.32; t[211.77]) = 2.62, d = .31, p = .009), as well as TOVA reaction time standard score (girls’ MΔ = 13.22; boys’ MΔ = 3.54; t[229.12] = 3.93, d = .46, p <.001). We did not observe sex differences in the 2 other TOVA sub-metrics, nor in ADHD-RS (ps >.05). There were sex differences in compliance (t[207.99] = 2.17, d = .26, p = .031), with girls completing more sessions on average (M = 90.22) compared to boys (M = 80.19).

Results suggest that AKL-T01 may be associated with particularly strong improvements to attentional functioning in girls relative to boys. That there were no significant sex differences in ADHD symptom change over the course of treatment in either sex underscores the specificity of these effects to inattention processes rather than broad ADHD symptoms. Limitations include categorization based on binary sex, which may not capture nuances of gender identity.

Akili Interactive

Rates of attention deficit hyperactivity disorder (ADHD) have increased among adults, and barriers to treatment (e.g., medication shortages; inaccessibility of behavioral treatments) underscore need for novel, scalable interventions. There is a particular need for treatments for inattentive symptoms, which are the most frequently endorsed ADHD symptoms in adults. AKL-T01 (EndeavorRx®) is an FDA-authorized digital therapeutic, currently approved for attention in children ages 8-12 with inattentive or combined-type ADHD and a demonstrated attention issue. This study evaluated the efficacy and safety of AKL-T01 in adults.

STARS-ADHD-Adults (NCT05183919) was a multicenter, single-arm trial at 14 US sites. Enrolled patients were 18 or older, had a diagnosis of ADHD (combined or inattentive), and demonstrated attentional impairment with a Test of Variables of Attention (TOVA) Attention Comparison Score (ACS) ≤ -1.8. Treatment involved using AKL-T01 at home 25 minutes/day, 5 days/week, for 6 weeks. The primary endpoint was change in TOVA-ACS. Secondary endpoints were changes in the ADHD Rating Scale-IV (ADHD-RS-IV) inattention subscale and total score, and Adult ADHD Quality of Life (AAQoL) total score. Safety, tolerability, and compliance were assessed.

Of 440 participants screened, 221 were enrolled, and 153 (M age = 39.9, 70% female; 39% current stimulant use) had sufficient data for analysis. TOVA-ACS significantly improved from baseline to study day 42, M change = 6.46, SD = 6.95, t(152) = 11.49, p <.0001. There was significant improvement across all secondary endpoints (ps <.0001). In exploratory responder analyses, 36.6% moved into the normative range on TOVA (ACS>0), and 27.1% had ADHD-RS-IV improvement ≥ 30%. The treatment was well-tolerated (5% reported ADEs; none serious), and compliance was high (M = 81.1%).

Results support the efficacy of AKL-T01 in adults, and the magnitude of TOVA change in adults was nearly 7x the change reported in pediatric trials. Given the increasing rates of ADHD in adults, the barriers to accessing evidence-based treatments, and the centrality of inattentive symptoms as ADHD patients develop into adulthood, AKL-T01 holds promise as a scalable, targeted treatment for attention in adult ADHD with impacts to real-world symptoms.

Akili Interactive

Studies show stimulant medications are effective for different ADHD presentations (predominantly inattentive [IA], predominantly hyperactive-impulsive [HI] or combined [C]); however, few studies have evaluated nonstimulant efficacy in different ADHD presentations. Viloxazine ER [VLX ER] is a nonstimulant, FDA-approved medication for pediatric (≥6 yrs) and adult ADHD. This post-hoc analysis of 4 double-blind (DB), Phase 3, clinical trials (2 in adolescents [NCT03247517 and NCT03247556], 2 in children [NCT03247530 and NCT03247543]), evaluates VLX ER efficacy by ADHD presentation as derived from ADHD Rating Scale, 5th Edition (ADHD-RS-5) assessments at Baseline.

Children and adolescents with ADHD and an ADHD-RS-5 Total score ≥ 28 were eligible for enrollment. ADHD presentation was defined as a rating of ≥2 on at least 6 of 9 ADHD-RS-5 inattention items, or hyperactive-impulsive items or both. For each ADHD presentation, the change from Baseline (CFB) in ADHD-RS-5 Total score (primary outcome in each study) was assessed using mixed models for repeated measures (MMRM). Responder rate (secondary outcome), ≥50% reduction from baseline in ADHD-RS-5 Total score, was analyzed using generalized estimating equations (GEE).

Of 1354 subjects [placebo N = 452, VLX ER N = 902], ADHD presentation was assigned as 288 (21.3%) [IA], 1010 (74.5%) [C], 40 (3.0%) [HI], 16 (1.2%) [none of these]. Due to the small sample size of [HI], only the [IA] and [C] results are presented. At Week 6 (pooled data endpoint), ADHD-RS-5 Total scores were significantly improved for VLX ER relative to placebo for both the [IA] and [C] ADHD presentations. LS mean (SE) treatment differences, p-values were: [IA] -3.1 (1.35), p = 0.0219, and [C] 5.8 (0.97), p < 0.0001. Responder rates were also significantly higher for VLX ER: 43.0% [IA] and 42.7% [C] relative to placebo 29.5% [IA] and 25.5 % [C] (p=.0311 and p<.0001).

Viloxazine ER significantly reduced ADHD symptoms in individuals meeting criteria for ADHD [IA] or [C] presentations at Baseline. Limitations include post-hoc methodology, smaller sample sizes of [IA] and [HI] groups, and the ADHD-RS-5 ≥ 28 eligibility requirement, that may favor enrollment of individuals with ADHD [C] over ADHD [IA] or [HI] presentations. Consistency of response during long-term use should be evaluated.

Supernus Pharmaceuticals, Inc.

Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI). The efficacy, safety, and tolerability of CTN sustained release (SR) for adults with ADHD was demonstrated in 2 pivotal phase 3 trials (Adler LA, et al. J Clin Psychopharmacol. 2022;42:429-39).

Adults (18–55 years) meeting DSM-5 criteria for ADHD enrolled in these double-blind, multicenter, placebo-controlled trials and randomized to treatment if ADHD Investigator Symptom Rating Scale (AISRS) score was ≥28 at screening (if not receiving pharmacologic treatment for ADHD) or ≥22 at screening and ≥28 at baseline (BL) (if receiving treatment). Having had no prior benefit from ≥2 ADHD therapies of 2 different classes, taking prohibited medications, and positive alcohol/drug screen were exclusionary. Trials had 4 periods: (1) screening and washout (≤28 days), (2) single-blind placebo run-in (1 week), (3) double-blind treatment (6 weeks), and (4) follow-up (10 days after last dose). Patients with ≥30% improvement in the Adult ADHD Self-report Scale (ASRS) from start to end of screening were screen failures; those with ≥30% ASRS improvement from start to end of placebo run-in were terminated early. Patients were randomized 1:1:1 to twice-daily CTN SR (200 or 400 mg total daily dose [TDD]) or matching placebo. The 200 mg/d group received CTN SR 200 mg TDD from days 1–42; the 400 mg/d group received 200 mg TDD on days 1–7, and increased to 400 mg TDD on day 8. This analysis assessed CTN SR effects based on median BL AISRS severity score (<38 or ≥38) using a mixed model for repeated measures analysis. Least squares mean (LSM) differences (95% CI) from BL at day 42 were compared between individual CTN SR dose groups and placebo, tested at a 2-sided significance level of 0.05.

In total, 859 patients were randomized (200 mg TDD, n=287; 400 mg TDD, n=287; placebo, n=285). Significant LSM differences on the AISRS were observed vs placebo in the overall population (200 mg TDD and 400 mg TDD, P<0.0001 for each), in the low BL severity (200 mg TDD [P=0.016]; 400 mg TDD [P=0.019]), and in the high BL severity (200 mg TDD [P=0.005]; 400 mg TDD [P=0.003]) populations at day 42. Significant LSM differences vs placebo (P<0.01) began at day 7 (200 mg) and day 14 (400 mg) overall, remaining significant to day 42. Significant LSM differences were observed vs placebo (P<0.05) from day 14 (400 mg TDD) and day 21 (200 mg) in the low severity populations, and from day 21 (400 mg TDD) and day 7 (200 mg TDD) in the high severity population, remaining significant (P<0.05) to day 42.

CTN SR, a potential first-in-class NDSRI, is efficacious for patients with adult ADHD of low or high BL symptom severity, with significant improvements observed vs placebo within the first 3 weeks.

Study Registration: NCT03605680, NCT03605836

Otsuka

Deutetrabenazine is a vesicular monoamine transporter type 2 inhibitor (VMAT2i) for treatment of adults with tardive dyskinesia (TD) and Huntington disease (HD)-related chorea. A 4-week patient titration kit was launched (July 2021) to assist patients in titrating to optimal deutetrabenazine dosages.

START is an ongoing, routine-care, 2-cohort (TD and HD) study evaluating deutetrabenazine dosing patterns, effectiveness, and treatment satisfaction when initiated using a 4-week patient titration kit, with further titration allowed based on effectiveness and tolerability. Patient satisfaction with the kit was assessed via questionnaire at week 8. Results from the first 50 patients enrolled in the TD cohort are presented in this interim analysis.

50 patients in the TD cohort were included (mean age, 58.7 years, 66% female, 74% White, mean baseline Abnormal Involuntary Movement Scale [AIMS] total motor score, 13.8). 39 of 50 (78%) patients successfully completed the titration kit (completed within 5 weeks or reached optimal dose [≥24 mg/day] within 4 weeks; mean [SE] days, 27.5 [0.32]). Mean (SE) time to reach optimal dosage for the 38 (76%) patients who reached it was 46.3 (5.48) days. Mean (SE) deutetrabenazine dosages were 27.7 (0.92) mg/day at week 4, 32.5 (1.00) mg/day at week 8, and 32.8 (1.18) mg/day at week 12. After completion of the kit, mean (SE) dosage was 31.8 (1.24) mg/day, and 95% of patients reaching week 12 had a maintenance dosage ≥24 mg/day. Mean (SE) adherence with the kit was 97.2% (1.39%). 22% of patients had an adverse event (AE); AEs led to dose reduction for 2%, drug interruption for 2%, and study discontinuation for 6% of patients. Serious and treatment-related adverse events were reported for 2% and 6% of patients. 24 of 49 (49%)23 of 49 patients achieved treatment success (“much”/“very much” improved) at week 12 per Clinical Global Impression of Change (GIC); 23 or 49 (47%) per Patient GIC. Total motor AIMS scores were reduced by 4.8 points at week 12. Among the 39 (78%) patients who responded to the questionnaire, 72% found it easy to understand when/which dosage to take, 77% easy to remember to take their medication, 74% easy to change the dose weekly, 69% easy to follow kit instructions, and 77% easy to use the kit overall.

78% of patients with TD successfully completed the 4-week titration kit in approximately 4 weeks, with adherence rates of 97.2%. 95% of patients reaching week 12 had a maintenance dosage ≥24 mg/day. 49% of patients achieved treatment success based on Clinical GIC. Patients reported high levels of satisfaction with the titration kit and 77% found it easy to use. The 4-week patient titration kit enabled patients to titrate DTBZ to an optimal dosage and experience effectiveness similar to the pivotal clinical trials.

Teva Branded Pharmaceutical Products R&D, Inc.

Viloxazine extended-release (ER) is an FDA-approved, nonstimulant medication for pediatric (≥6 years) and adult ADHD. Apart from use as monotherapy, nonstimulants may be combined with stimulants when patients experience inadequate response or difficulties with medication tolerability. This phase IV, open-label trial (NCT04786990) evaluated the safety and tolerability of viloxazine ER administration with psychostimulants in children and adolescents with ADHD. Differences between morning and evening use of viloxazine ER were also assessed.

Children and adolescents (6 – 17 years) experiencing inadequate response (ADHDRS-5 ≥24 and CGI-S ≥3) to psychostimulant treatment (methylphenidate or amphetamine) were enrolled. Subjects maintained stable stimulant use throughout the trial. Following an up to 4-week screening period, subjects continuing to show inadequate response received flexibly dosed viloxazine ER (100-400 mg/day children; 200-600 mg/day adolescents) each morning during Weeks 1-4 and each evening during Weeks 5-8. Safety, tolerability, and efficacy were assessed relative to Baseline, and for change from baseline for morning vs. evening dosing.

56 subjects received viloxazine ER with 85.7% of these completing the study. Adverse events were reported by 55.4% of subjects, most commonly headache (17.9%), decreased appetite (12.5%), and upper respiratory tract infection (10.7%); onset was more common during AM dosing trial weeks [50% of subjects reported AEs during Weeks 1-4 and 36% during Weeks 5-8]. AEs were largely mild (32.1%) or moderate (21.4%) and led to discontinuation for 2 (3.6%) subjects. Baseline mean (SD) Investigator Rated-ADHD-Rating Scale 5th ed. (IR-ADHD-RS-5) score was 37.2 (8.35), n=56. Significant improvement in IR-ADHD-RS-5 was seen by Week 1[ -6.9 (8.16), n=56; P<.0001)] and continued through Weeks 4 and 8 [-13.5 (9.70) p<.0001 and -18.2 (9.99) p<.0001, respectively]. Over 50% of subjects were rated much or very much improved on CGI-I at endpoint. Scores on the sleep disturbance Scale for Children (SDSC) scale also improved at both Weeks 4 and 8 [-8.8 (14.03) P<.0001 and -10.3(17.39) P=.0002, respectively], as did Parent-ratings of morning and evening ADHD symptoms and behavior, suggesting that morning and evening administration of viloxazine ER were both efficacious.

Viloxazine ER showed acceptable safety and tolerability when administered with stimulant medications in this Phase IV open-label trial. Administration of viloxazine ER in the evening instead of the morning did not appear to affect safety, nor the trajectory of drug response or sleep improvement.

Supernus Pharmaceuticals, Inc.

Viloxazine extended-release (ER) is an FDA-approved nonstimulant medication for ADHD in children (≥6 years) and adults. Approval in adults was based on a double-blind (DB) pivotal trial [NCT04016779] showing statistically significant efficacy on the Adult ADHD Investigator Symptom Rating Scale (AISRS; primary outcome). Here we report final results from the long-term, open-label extension (OLE) safety trial [NCT04143217] conducted as a following to the DB trial.

Upon completing DB treatment, consenting subjects who enrolled in the OLE received viloxazine ER 200 mg/day, with flexible titration to an optimal maintenance dose (200-600 mg/day). Addition of a stimulant was permitted, at investigator’s discretion, following Week 12. OLE trial enrollment was temporarily closed at the outset of the COVID pandemic. Subjects completing the DB during this time were allowed delayed entry into the OLE upon requalification. Safety and efficacy measures were assessed relative to DB (or OLE re-entry) Baseline) at OLE Weeks 2, 4, and ~ every 8 weeks thereafter. The trial was planned for 3 years or until commercial availability of viloxazine ER.

Subjects (N= 159; including 133 immediate- and 26 delayed-rollover) received viloxazine ER for 265 ± 254.9 days (mean ± SD). Nine subjects used adjunctive stimulant medication at some point after Week 12. Primary reasons for discontinuation included withdrawal of consent (25.6%), loss to follow up (17.7%), and adverse events (17.6%). Adverse events (experienced by 72.3%) were largely mild (26.4%) or moderate (40.3%) in severity and included (≥10%) insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). Changes in clinical laboratory measures, vital signs, and ECG parameters were consistent with those observed in DB and product labeling. Suicidal ideation (wish to be dead) was reported by 3 subjects at a single visit each; no subject reported suicidal behavior. ADHD symptom (AISRS), executive function (BRIEF-A), global function (CGI), and quality of life (AAQOL) measures showed continued improvement in the OLE relative to that seen in DB. Baseline [mean ± SD)] AISRS Total, CGI-S, BRIEF-A GEC T-score and AAQOL ratings, respectively, were 37.9 ± 6.34), 4.6 ± 0.60, 70.4 ± 10.94 and 54.9 ± 14.96. All showed significant improvement (P<.0001 relative to Baseline) by the first OLE follow-up assessment (Week 2 for AISRS and CGI-S, Week 4 for BRIEF-A and AAQOL). Improvement continued with long-term use. Subjects maintained on viloxazine ER for at least 3 months (≥ Week 12) showed changes at Last OLE Visit of -20.0 ± 11.63 (n=106), -1.8 ± 1.34, -13.6 ± 13.64 (n=104), and 12.7 ± 17.90 (n=87) respectively.

Subjects maintained on viloxazine ER showed continued improvement in ADHD symptoms, global and executive function, and quality of life measures during long-term treatment.

Supernus Pharmaceuticals, Inc.

Parkinsonian symptoms seen with B12 deficiency have been described in five cases where B12 therapy has led to their elimination. Subacute combined degeneration (SCD) presenting with parkinsonian signs of cogwheel rigidity, unresponsive to B12 supplementation, has not heretofore been described.

Case Study: This 62-year-old right-handed woman with a past medical history of hypothyroidism presented with complaints of trouble with memory. Cogwheel rigidity and pernicious anemia with low intrinsic factor and B12 levels (165 pg/ml) were found. SCD was diagnosed and treated with monthly B12 injections over the past three years, providing symptomatic relief, yet the cogwheeling persisted. She described never developing trouble with gait, movement disorders, autonomic abnormalities, olfactory dysfunction, disorders of sleep, visual hallucinations, or other parkinsonian symptoms.

Abnormalities in Neurologic Examination: Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test: 9 (hyposmia). CN III, IV, VI: Bilateral ptosis. Motor Examination: 1+ Cogwheel rigidity both upper extremities. Drift Testing: Right pronator drift with left abductor digiti minimi sign. Reflexes: 3+ throughout other than 4+ ankle jerks. Quadriceps femoris bilaterally pendular. Bilateral Hoffman and Babinski reflexes present. B12 Level: 394 pg/ml (normal).

While predominantly affecting the posterior columns and the lateral corticospinal tract, the demyelination may further extend into adjacent fibers including the reticulospinal tract and the rubrospinal tract, the tracts which, in Parkinson’s Disease, have been cited for their role in maintenance of tone and thus cogwheeling. Additionally, low B12 and elevated homocysteine levels have been noted as potential contributory factors in the pathogenesis of Parkinson’s Disease. It is also possible that this is a violation of Occam’s razor, that this individual has two separate distinct diseases — the prominent subacute combined degeneration as well as a subclinical parkinsonism which was revealed on neurologic examination. The parkinsonian signs may have been present prior to the B12 deficiency, and if not for the examination findings, could have remained undiscovered for decades. In those that present with Subacute Combined Degeneration, evaluation for parkinsonism is warranted.

No Funding

Pseudo-Wellens syndrome (PWS) is a rare but clinically significant condition characterized by electrocardiogram (ECG) abnormalities that mimic acute ST-segment elevation myocardial infarction (STEMI) in the absence of obstructive lesions on coronary angiography. The occurrence of PWS should be on the differential for any patient who visits the Emergency Room (ER) with known and/or suspected drug overdose. This will avoid the potential for inappropriate invasive diagnostic modalities in otherwise cardiac healthy individuals. This literature review aims to explore the ECG changes in patients diagnosed with PWS in the context of drug intoxication presenting to the ER.

Specific keywords such as "Pseudo-Wellens Syndrome," "ECG/EKG,” and "substance abuse," were used to search PubMed, Google Scholar, and PsycInfo. Articles on PWS that were not on patients presenting with substance use or not in English were removed. We extracted substance use history, ECG parameters, and their clinical presentations to the ER for review.

We found cases of PWS in patients presenting with cannabis, PCP, methamphetamine, opioid, and cocaine intoxication, either in combination or singularly. The most common ECG finding across the cases was biphasic T wave inversion in V2 and V3 with involvement in the anterior leads. The authors were unable to find any characteristic ECG changes associated with individual substances. This might be attributed by the small number of patients in the studies and due to the use of multiple drugs by patients at presentation to the ER, especially with drugs known to cause ECG abnormalities such as opioids. While PWS typically resolves spontaneously in most cases, this review revealed a concerning trend. Patients who consumed cocaine were at a higher risk of developing life-threatening cardiac conditions, including myocardial infarction. This finding underscores the importance of considering the pretest probability of acute coronary syndromes and avoiding misinterpretation of PWS as a less severe entity. For those patients presenting with a suspicious diagnosis and high pretest probability indicating an interruption of coronary blood flow, a comprehensive work up should be done to investigate any other possible life-threatening cardiac conditions.

PWS has ST segment and T wave abnormalities, which are ECG abnormalities that are already very common in psychiatric patients seen in-hospital. Recognizing the specific ECG findings in PWS is of utmost importance for clinicians to prevent unnecessary interventions and potential harm to patients. For further understanding, more comprehensive analysis of ECG findings with larger sample sizes while considering comorbid conditions and contributing factors to the patient presentation should be conducted.

No Funding

Ketamine, in theory, as an anesthetic prior to electroconvulsive therapy (ECT) can potentiate anti-depressant effects given that both ketamine and ECT have demonstrated benefit. However, ketamine can cause significant hemodynamic instability, which can limit its use. Propofol can help mitigate these issues, resulting in ketofol, a combination of ketamine and propofol as an anesthetic agent. In this systematic review, we see if this anesthetic cocktail proves to be effective pre-ECT for patients with depression and evaluate the hemodynamic side effects and post-ECT depression outcomes as compared to ketamine or propofol alone.

Search strategies using keywords were created to explore two databases: PubMed and Google Scholar. After removing duplicates, 71 articles were found. All abstracts and full texts were examined by 3 independent reviewers to solve discrepancies in the screening decisions. We included 15 observational articles that are not reviews which had a direct comparison of ketofol with ketamine or propofol only in regards to hemodynamic or depression outcomes.

The review included 12 studies looking at the anesthetic effects of ketofol and 8 studies looking at the depressive effects of ketofol. Based on the GRADE approach, the evidence level of primary and secondary outcomes regarding anesthetic effects ranged from low (1/12 observational study) to moderate-high (11/12 randomized control trials (RCTs)) while the evidence level for depressive effects were moderate to high (8/8 RCTs).

Anesthetic effects were mostly assessed using hemodynamic parameters such as systolic and diastolic blood pressure, mean arterial pressure, and heart rate. Out of the 12 studies, 4 RCTs concluded that ketofol was significantly more hemodynamic favorable compared to propofol, whereas 3 RCTs found the opposite. The remaining 4 RCTs and 1 observational study concluded that there was no statistically significant difference in hemodynamic parameters when administering ketofol.

Depressive effects were assessed using validated psychometric testing. Out of the 8 studies, 2 RCTs concluded that ketofol had a greater reduction in depressive symptoms compared to propofol. The remaining 6 RCTs concluded that there was no statistically significant difference in reduction of depressive symptoms with the use of ketofol.

Ketofol is an anesthetic combination that is being used for a variety of procedures, including ECT. While theorized to assist with the hemodynamic changes that ketamine or propofol alone cause in opposite directions, most studies have demonstrated no significant difference between ketofol and one medication. Furthermore, most studies also show no difference in depression outcomes after ECT between ketofol and ketamine or propofol monotherapy. If a statistically significant change is seen, it is usually attributable to the ketamine portion of ketofol rather than an effect from the combination.

No Funding

Neurology and psychiatry have been linked together for a long period of time. One overlap demonstrated in the literature is the correlation between epilepsy with mood and psychosis. There is a big group of psychoses called the psychosis of epilepsy (POE); however, there is not much evidence about the diagnosis and management. Differentiation between POEs is difficult and is compounded by a lack of evidence-based guidelines on appropriate management. Even if you arrive at the diagnosis, POE can be difficult to manage. Some antiepileptic drugs (AEDs) cause psychiatric side effects and some antipsychotics may be epileptogenic. In this poster, we will discuss ways to diagnose and treat POE, as well as how to optimize certain AEDs in patients with POE.

Articles were chosen from multiple databases, such as MEDLINE, Google Scholar, and PsychInfo, to gather evidence about the diagnosis and management of POE. Specific keywords, such as Psychosis, Epilepsy, Antipsychotic, Antiepileptic, and Electroencephalogram (EEG) were used. Articles talking about recommendations regarding the use of AEDs and antipsychotics in POE were extracted from these databases.

POE includes preictal, ictal, postictal, and interictal psychosis. Preictal psychosis is very rare and tends to present with dissociation and déjà vu. This is correlated with temporal lobe epilepsy and resolves after the seizure. Ictal psychosis will correspond with epileptic activity on EEG and can manifest as aggression, delusions, or hallucinations. Antipsychotics are contraindicated in this POE. Postictal psychosis usually presents as a combination of mood symptoms and grandiose delusions seen with interictal sharp epileptiform discharges on EEG. Interictal psychosis can be subtyped into brief and chronic, with brief occurring during periods of increasing seizure frequency and chronic having no association with seizures. They both present similar to symptoms seen in classic schizophrenia and antipsychotics are often utilized.

Clozapine and chlorpromazine were found to have the highest seizure prevalence from second- and first-generation antipsychotics respectively, and the lowest was found with risperidone. AEDs that are commonly used in psychiatry, such as oxcarbazepine, carbamazepine, valproic acid, and lamotrigine are discussed in detail regarding their optimal dosing strategy for patients presenting with POE.

Diagnosis and management of the various types of POE can be challenging due to the lack of literature. We recommend using the antipsychotic, risperidone, as it has shown to have the lowest seizure prevalence among all antipsychotics. Both neurologists and psychiatrists should keep POE on their differential when dealing with seizure patients with psychosis. It is crucial for psychiatrists to understand how to optimize AEDs in the management of POE as these patients are often seen on the consult service.

No Funding

The incidence of delirium in the ICU occurs upwards of 80% and is associated with increased length of stay in hospitals and mortality. The effects of previously recommended antipsychotics and benzodiazepines for management of ICU delirium have come into question as they have been associated with no change in or even exacerbation of delirium. This has led to unclear pharmacological treatment recommendations and the need to seek explicit treatment of ICU delirium. Dexmedetomidine, an adrenergic alpha 2 receptor agonist, has been shown to reduce the development of delirium and improve the resolution of delirium. The aim of this review is to explore the evidence that supports the use of dexmedetomidine for treatment and prevention of hyperactive delirium in ICU patients.

A literature review using articles from databases such as PubMed and Google Scholar was conducted to gather supporting evidence on the use of dexmedetomidine in ICU delirium. The articles included in this review were randomized controlled trials (RCT), observational studies, systematic reviews and meta-analyses, and literature review articles. The main outcomes measured included a decrease in scales used to measure delirium and agitation, time spent in delirium, duration of mechanical ventilation, and incidence of delirium.

A RCT comparing the use of lorazepam and dexmedetomidine in 106 adult mechanically ventilated ICU patients demonstrated that dexmedetomidine at 0.15- 1.5 μg/kg/h resulted in more days without delirium. Another study done to compare the efficacy and safety of prolonged sedation in 375 mechanically ventilated patients found that individuals receiving dexmedetomidine at a rate of 0.2-1.4 μg/kg/h spent less time on the ventilator, developed delirium 20% less often, and were off mechanical ventilation almost 2 days sooner compared to midazolam. The Dexmedetomidine to Lessen ICU Agitation RCT, which involved 74 adults treated at rate of 0.5-1.5 μg/kg/h in whom extubation was not done due to delirium severity, demonstrated that dexmedetomidine increased ventilator free hours by 17 hours compared to placebo. Another RCT of 100 delirium-free ICU adults demonstrated a greater proportion of patients who remained delirium-free during the ICU stay after administration of nocturnal dexmedetomidine at rate of 0.2-0.7 μg/kg/h. A case series done to explore the use of dexmedetomidine in post-traumatic brain injury (TBI) showed dexmedetomidine at a rate of 0.49 μg/kg/h in 85 patients with severe TBI did not worsen neurological function.

Delirium in ICU patients occur at exceptionally high rates and there is a need for clear pharmacologic treatment. Current literature supports the use of dexmedetomidine for reduction of delirium in ICU patients with potential to eliminate risk associated with previously used antipsychotics and benefits of safe use in TBI, decreased risk of polypharmacy and overall mortality associated with ICU delirium.

No Funding

Delusional parasitosis, yclept Ekbom’s Syndrome, was originally described in 1938 and has an incidence of up to 4.2 per 100,000 people (Olivera, 2017; Orsolini, 2020). While the average duration of this delusion is three years, it can last decades (Al-Imam, 2019). Ekbom’s Syndrome of ultra-short duration, only one hour, has not heretofore been described.

A 36-year-old woman with a past history of schizoaffective disorder, bipolar subtype, generalized anxiety disorder, and alcohol use disorder with a history of seizures and delirium tremens presented with a one- hour duration of the delusion of being infested with bugs. She believed that microscopic bugs flew up her nose, stayed there for one hour, and flew out. This had never happened to her before nor since. She admitted to sadness, crying spells, hopelessness, lack of social interaction, anhedonia, fatigue, irritability, anger, insomnia, anorexia, low interest, amotivation, lack of sexuality, racing thoughts, and anxiety. She denied déjà vu and jamais vu, or any other hallucinations—tactile, visual, or auditory.

Abnormalities in Neurologic Examination: Mental Status Examination: Oriented x2, hyperverbal, anxious mood, blunted affect. Memory Testing: Immediate Recall: 6 digits forwards and 4 backwards. Recent Recall: 2 of 4 objects in three minutes without reinforcement, 4 of 4 objects with reinforcement. Remote Recall: Unable to name the presidents. Able to spell the word “world” forwards, but not backwards.

Oral Calculations: 75%. Written Calculations: 50%. Ideomotor Apraxia: Absent. Ideational Apraxia: 66%. Vocabulary Testing: 19/24. Drawing to Commands: 1/3. Higher Cognitive Function Test: 66%. Proverbs: 60%. Similarities: 80%. Judgement: 40%. Cranial Nerve (CN) Examination abnormalities. Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test: 2 (anosmia). CN III, IV, VI: Bilateral ptosis. Reflexes: 3+ throughout. Other: Blood Alcohol: 0.03.

Delusional Parasitosis, in Diagnostic and Statistical Manual V (DSM V), is categorized as delusional disorder, somatic type, and requires persistence of symptoms for at least one month (American Psychiatric Association, 2013). Ekbom’s Syndrome is generally years in duration, ranging from months to decades, with over 20% of individuals suffering for more than five years (Hinkle,2010). Others have found that mean duration is 2.6 years and suggested that a shorter duration reflected a better prognosis (Boggild, 2010). In a meta-analysis of 1,223 cases, mean duration was found to be three years with no correlation between age of onset and duration of delusions (Trabert, 1995). In a study with 365 patients with delusional parasitosis, 39% had symptoms for less than 1 year, 61% were of greater than a year, and 20% had Ekbom Syndrome for five years or longer (Reilly, 1986). A short duration of 3 months has also been noted but delusional parasitosis is more typically seen to last more than twenty years (Martins, 2016; Colbeaux,2020; Dridi, 2015; Olari, 2011; Alves, 2010; Nicolato, 2006; Mahler, 2008; Bellanger, 2009).The one-hour duration in our patient suggests either that this delusional disorder diagnosis must remain provisional or the criteria should be reduced to substantially less than one-month duration. In those with symptoms of delusional parasitosis, the transient nature of symptoms should not preclude the diagnosis and query as to this disorder in those with acute delusions may be revealing.

No Funding

The efficacy and safety of aripiprazole once-monthly 400 mg (AOM 400) as maintenance monotherapy treatment for bipolar I disorder (BP-I) were demonstrated in a double-blind, placebo-controlled, 52-week randomized withdrawal trial (NCT01567527). This post hoc analysis of data from NCT01567527 evaluated the efficacy of AOM 400 in the earlier BP-I population.

Patients within the first quartile of the dataset according to age (18–32 years: AOM 400, n=36; placebo, n=34) or disease duration (≤4.6 years: AOM 400, n=33; placebo, n=34) were considered to be in the earlier stages of BP-I, and were included. The primary outcome was time from randomization to recurrence of any mood episode, defined as meeting any one of several predetermined criteria, including Young Mania Rating Scale (YMRS) total score ≥15 or clinical worsening.

Time to recurrence of any mood episode was significantly delayed with AOM 400 versus placebo in patients aged 18–32 years (hazard ratio [HR]: 2.462 [95% confidence interval (CI): 1.092, 5.547]; p<0.05) and in patients with a disease duration ≤4.6 years (HR: 3.207 [95% CI: 1.346, 7.645]; p<0.01). Further analysis suggested that the benefit of AOM 400 versus placebo was driven by a significantly lower proportion of patients experiencing a YMRS total score ≥15 (18–32 years: 5.60% versus 44.10%, p<0.001; disease duration ≤4.6 years: 6.10% versus 41.20%, p<0.01) or clinical worsening (18–32 years: 8.30% versus 38.20%, p<0.01; disease duration ≤4.6 years: 6.10% versus 38.20%, p<0.01).

The efficacy of AOM 400 was demonstrated in the earlier BP-I population.

Study registration number: NCT01567527 (ClinicalTrials.gov)

The data in this poster were originally presented at Psych Congress, held on 6–10th September 2023 in Nashville, TN, USA.

Otsuka Pharmaceutical Development & Commercialization Inc. (Princeton, NJ, USA) and Lundbeck LLC (Deerfield, IL, USA).

Depression is a leading cause of disability worldwide affecting over 300 million individuals globally. Despite the abundance of approved antidepressants, the majority of depressed patients do not respond to their first prescribed antidepressant, with over 30% not responding to subsequent drugs. This is largely attributed to individual differences in the underlying pathophysiology of the disease, which make some medications efficacious for some patients while ineffective for others. Multiple studies have been conducted with the aim of identifying patient subgroups associated with drug response, with a large focus on variations in genetic and gene expression levels that may underlie response to specific drugs. However, these studies yielded mostly inconsistent results, with robust genetic effects largely related to drug pharmacokinetics and gene expression level associations poorly reproducible. In this study, we assessed gene expression levels in iPSC-derived neurons from depressed patients with a known response profile to various medications, alongside genetic variations. iPSC-derived neurons have the potential to unravel mechanisms that are neuronal specific and thus not observed in patient whole blood molecular analysis.

Patient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study with known response to Citalopram or Bupropion were reprogrammed and then differentiated to cortical neurons. Analysis of genetic variants and differential gene expression was performed on the derived neurons to identify variants and gene expression levels that are associated with drug response.

Significant differential gene expression was shown between Bupropion responders and non-responders as well as between Citalopram responders and non-responders. Functional enrichment analysis revealed biologically relevant pathways that differ between responders and non-responders in Bupropion and in Citalopram. In addition, we found an interplay between genetics and neuronal gene expression, that is associated with patient drug response. This was specifically observed in genes implicated in drug mechanism of action, including COMT and BDNF.

Patient-derived neurons have utility in mechanistic disease and drug modeling, and can elucidate mechanisms that cannot be read out from systemic whole blood analysis. In addition, combining genetics and target organ gene expression levels has the potential to be used as biomarkers for drug response. Together, these findings support a novel framework for precision medicine in depression.

Genetika+