Postpartum depression (PPD) is a serious illness where patients (pts) experience depressive symptoms that start during or after pregnancy. Concurrent anxiety symptoms in PPD are common and are associated with poorer outcomes. The Edinburgh Postnatal Depression Scale (EPDS) is a patient-reported instrument used for PPD and may be used concurrently with the clinician-administered Hamilton Rating Scale for Anxiety (HAM-A). Zuranolone (ZRN) is an investigational oral positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid for the treatment of PPD and major depressive disorder in adults. The phase 3, double blind, randomized, placebo (PBO)-controlled SKYLARK study evaluating the efficacy and safety of ZRN 50 mg (ZRN50) in pts with severe PPD met its primary endpoint of change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day (D)15 (−15.6 vs −11.6 for placebo; p<0.001). The percentages of pts achieving HAMD-17 response (≥50% CFB in HAMD-17 total score) and remission (HAMD-17 total score ≤7) were higher in the ZRN group vs PBO. We report a post hoc analysis of the EPDS and HAM-A response and remission rates to assess the effects of ZRN50 on depressive and anxiety symptoms in the SKYLARK study.

Adults aged 18-45 years with severe PPD (baseline HAMD-17 ≥26) were randomized 1:1 to oral once-daily ZRN50 or PBO for 14 days and followed through D45. EPDS and HAM-A response (≥50% CFB in EPDS or HAM-A total score, respectively) and remission (EPDS total score <10 or HAM-A total score ≤7) rates were recorded at D3, D8, D15, D21, D28, and D45. Response and remission rates were modeled using generalized estimating equations for binary responses. Statistical testing was not adjusted for multiplicity; p values and statements of significance are considered nominal. D15 and D45 results are reported.

Among 196 pts randomized and dosed, 170 completed the 45-day study. Significantly greater percentages of pts treated with ZRN achieved EPDS response (52.7% vs 33.7%; p=0.0178) and remission (49.5% vs 33.7%; p=0.0192) at D15 vs PBO and achieved HAM-A response (54.3% vs 37.8%, p=0.0338) and remission (34.8% vs 15.6%; p=0.0050) at D15 vs PBO. Numerically greater percentages of pts achieved EPDS response (57.1% vs 50.6%; p=0.3020) and remission (56.0% vs 47.1%; p=0.0812) at D45 with ZRN vs PBO and achieved HAM-A response (65.5% vs 60.0%; p=0.3066) and remission (44.0% vs 37.6%; p=0.3662) at D45 with ZRN vs PBO.

ZRN50 was associated with improvements in both depressive and anxiety symptoms, which commonly co-occur in individuals with PPD. These results suggest treatment with ZRN may lead to improvements in measures of both depression and anxiety and support the potential role of ZRN as a novel, oral, rapid-acting, 14-day treatment course for PPD.

Sage Therapeutics, Inc. and Biogen Inc. Medical writing and editorial support were provided by Meditech Media, Ltd. and Parexel, and funded by Sage Therapeutics, Inc. and Biogen Inc.

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

Women with schizophrenia frequently discontinue antipsychotic medications during pregnancy. However, evidence on the risk of postpartum relapse associated with antipsychotic use during pregnancy is lacking.

To investigate the within-individual association between antipsychotic continuation during pregnancy and postpartum relapse in women with schizophrenia.

This retrospective cohort study used data of women with schizophrenia who gave live birth between 2007 and 2018 identified from the National Health Information Database of South Korea. Women were classified according to antipsychotic use patterns during the 12 months before delivery as non-users, discontinuers and continuers. Relapse was defined as admission for psychosis (ICD-10, F20–29). The incidence rate ratio (IRR) for admission for psychosis in the 6-month postpartum period was estimated using conditional Poisson regression, with the reference period set between 2 and 1 years before delivery. Additionally, we calculated the relative risk ratios (RRRs) for the IRRs of different antipsychotic use patterns.

Among the 3026 women included in the analysis (median age 34 years, interquartile range 31–37), the within-individual risk of admission for psychosis in the 6-month postpartum period was 0.56 times (RRR, 95% CI 0.36–0.87) lower in continuers (IRR = 1.31, 95% CI 0.89–1.72) than in discontinuers (IRR = 2.34, 95% CI 1.87–2.91). Among discontinuers, the IRRs of admission for psychosis in the 6-month postpartum period did not change significantly with the timing of discontinuation (trend P = 0.946).

Antipsychotic continuation during pregnancy was associated with a reduced risk of postpartum relapse in women with schizophrenia. Continuing antipsychotics during pregnancy would be recommended after a risk–benefit assessment.

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

Prior studies demonstrated the antipsychotic activity of the dual M1/M4 preferring muscarinic receptor agonist xanomeline in people with schizophrenia and Alzheimer’s disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline’s beneficial central nervous system effects while mitigating side effects due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia were demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

The EMERGENT trials randomized people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale (PANSS) total score ≥80, and Clinical Global Impression–Severity (CGI-S) score ≥4. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. In each trial, the primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Other efficacy measures included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scores. Data from the EMERGENT trials were pooled, and efficacy analyses were conducted in the modified intent-to-treat population, defined as all randomized participants who received ≥1 trial drug dose and had a baseline and ≥1 postbaseline PANSS assessment.

The pooled analyses included 640 participants (KarXT, n=314; placebo, n=326). Across trials, KarXT was associated with a significantly greater reduction in PANSS total score at week 5 compared with placebo (KarXT, -19.4; placebo, -9.6 [least squares mean (LSM) difference, -9.9; 95% CI, -12.4 to -7.3; P<0.0001; Cohen’s d, 0.65]). At week 5, KarXT was also associated with a significantly greater reduction than placebo in PANSS positive subscale (KarXT, -6.3; placebo, -3.1 [LSM difference, -3.2; 95% CI, -4.1 to -2.4; P<0.0001; Cohen’s d, 0.67]), PANSS negative subscale (KarXT, -3.0; placebo, -1.3 [LSM difference, -1.7; 95% CI, -2.4 to -1.0; P<0.0001; Cohen’s d, 0.40]), PANSS Marder negative factor (KarXT, -3.8; placebo, -1.8 [LSM difference, -2.0; 95% CI, -2.8 to -1.2; P<0.0001; Cohen’s d, 0.42]), and CGI-S scores (KarXT, -1.1; placebo, -0.5 [LSM difference, -0.6; 95% CI, -0.8 to -0.4; P<0.0001; Cohen’s d, 0.63]).

In pooled analyses from the EMERGENT trials, KarXT demonstrated statistically significant improvements across efficacy measures with consistent and robust effect sizes. These findings support the potential of KarXT to be first in a new class of medications to treat schizophrenia based on muscarinic receptor agonism and without any direct dopamine D2 receptor blocking activity.

Karuna Therapeutics

Although Jackson Pollock is most famous for his drip drawings, these occurred late in his career, starting around 1947. Prior to that he produced some “surrealist inflected” paintings and “gestural abstraction.” Troubled Queen in 1945 is considered Pollock’s masterful transitional work from the regionalist figurative paintings of his early years to the passionate “drip paintings” for which he is best known. As stated by Elliot Bostwick Davis et al (mfashop.com/9020398034), “As Troubled Queen shows, Pollock had begun to work in a very large scale by this time; his paint was dragged over, dripped on, and flung at the canvas. His subject matter was no less highly wrought: emerging from the churning coils and jagged lines of this life-sized canvas are two facelike forms, one a leering mask, the other a one-eyed diamond shape. Their nightmarish presences reflect not only Pollock’s agitated psyche but also the years of violence that had torn the world apart through war.” Thus, Troubled Queen shows that Pollock included images in his painting prior to his “drip paintings,” rendering it feasible that he continued to include images in his “drip paintings” using that new technique. We have coined the term “Polloglyphs TM” to name the images that are encrypted in his “drip paintings” and that tell a story about Pollock’s inner being, camouflaged yet hiding in plain sight.

Here, in order to establish the basis for Polloglyphs in his later “drip paintings,” we have deconstructed the multiple images in Troubled Queen by first showing the image on a white background and then transposing it upon the painting. In this way, the observer can begin to see how images were incorporated into Pollock’s pre-drip paintings. These are not Rorschach ink blots with fractal edges that are fooling the eyes and only in the mind of the viewer, but images purposely put on canvas as the observer can see. Clearly, there is a “troubled queen” in Troubled Queen. Beyond that there are images of war possibly inspired by Picasso’s famous Guernica painted in 1937 and first seen by Pollock in 1939. A character is also seen to her left. Pollock had a trick that can be used to better visualize and uncover his images by rotating this painting 90 degrees counterclockwise. In this case, a small angel of mercy with her sword can be seen in the upper left quadrant. Another character, possibly a soldier with a hatchet and gun with bullet in the barrel can also be seen. Several other images can also be deciphered including a Picasso-like rooster and many others. Together, these images suggest a theme of war during the midst of World War II and may have triggered Pollock’s long standing feelings of inadequacy as his psychiatrist and his draft board found him unfit to serve as a soldier and he was exempted from serving. We encourage the observer to look carefully at Troubled Queen and to develop an opinion on which if any of the images are seen and to ponder as well what they may mean.

No Funding