Tag Archives: Schizophrenia

Cortical Surface Changes Tied to Movement Disorders in Schizophrenia

Patients with schizophrenia and parkinsonism show distinctive patterns of cortical surface markers compared with their counterparts without parkinsonism and with healthy controls, results of a multimodal magnetic resonance imaging study suggest.

Dr Robert Christian Wolf

Sensorimotor abnormalities are common in schizophrenia patients, however, “the neurobiological mechanisms underlying parkinsonism in [schizophrenia], which in treated samples represents the unity of interplay between spontaneous and antipsychotic drug-exacerbated movement disorder, are poorly understood,” wrote Robert Christian Wolf, MD, of Heidelberg (Germany) University, and colleagues.

In a study published in Schizophrenia Research (2021 May;231:54-60), the investigators examined brain imaging findings from 20 healthy controls, 38 schizophrenia patients with parkinsonism (SZ-P), and 35 schizophrenia patients without parkinsonism (SZ-nonP). Wolf and colleagues examined three cortical surface markers: cortical thickness, complexity of cortical folding, and sulcus depth.

Compared with SZ-nonP patients, the SZ-P patients showed significantly increased complexity of cortical folding in the left supplementary motor cortex (SMC) and significantly decreased left postcentral sulcus (PCS) depth. In addition, left SMC activity was higher in both SZ-P and SZ-nonP patient groups, compared with controls.

In a regression analysis, the researchers examined relationships between parkinsonism severity and brain structure. They found that parkinsonism severity was negatively associated with left middle frontal complexity of cortical folding and left anterior cingulate cortex cortical thickness.

“Overall, the data support the notion that cortical features of distinct neurodevelopmental origin, particularly cortical folding indices such as [complexity of cortical folding] and sulcus depth, contribute to the pathogenesis of parkinsonism in SZ,” the researchers wrote.

The study findings were limited by several factors, including the cross-sectional design, the potential limitations of the Simpson-Angus Scale in characterizing parkinsonism, the inability to record lifetime antibiotics exposure in the patient population, and the inability to identify changes in brain stem nuclei, the researchers noted. However, the results were strengthened by the well-matched study groups and use of multimodal MRI, they said.

Consequently, “these data provide novel insights into different trajectories of cortical development in SZ patients evidencing parkinsonism,” and suggest a link between abnormal neurodevelopmental processes and an increased risk for movement disorders in schizophrenia, they concluded.

The study was funded by the German Research Foundation and the German Federal Ministry of Education and Research. Wolf and colleagues disclosed no conflicts.

This story originally appeared on MDedge.com, part of the Medscape Professional Network.

This post originally appeared on Medscape Medical News Headlines

Once-Weekly Oral Antipsychotic for Schizophrenia on the Horizon

A novel, ultra-long-acting oral formulation of the antipsychotic risperidone (Risperdal) only needs to be taken once weekly and appears to be safe and effective, results of a new phase 2 study suggest.

The new formulation, LYN-005 (Lyndra Therapeutics), quickly reached therapeutic levels in patients, provided sustained exposure to risperidone active moiety over 7 days, and reduced peak drug exposure.

Dr David Walling

“This novel formulation has the potential to improve treatment adherence and quality of life in patients with schizophrenia or schizoaffective disorder,” study investigator David Walling, PhD, chief clinical officer for the Collaborative NeuroScience Network, Long Beach, California, told Medscape Medical News.

The findings were presented at the virtual American Society of Clinical Psychopharmacology (ASCP) 2021 Annual Meeting.

Adherence Is Key

About 50% of patients don’t take medications as prescribed, creating a significant relapse risk, Walling noted.

“Here we have the possibility of having a once-weekly oral medication, which means patients don’t have to struggle with the issue of taking the medication daily. Right now, all we have on the market for long-acting medications for schizophrenia are injectables, where the patient has to go get a shot every month or every 2 weeks in order to have the medication in their system for a longer period of time,” he added.

The study included 32 clinically stable patients with a primary diagnosis of schizophrenia or schizoaffective disorder.

Patients received immediate-release (IR) risperidone at 2 mg or 4 mg, based on their current antipsychotic dose, for 13 days. 

They were then randomly assigned 3:1 to receive either IR risperidone-matched placebo and LYN-005 at 14 mg or 28 mg risperidone (12 patients per group), or to LYN-005 matched placebo and IR risperidone, 2 mg or 4 mg, (4 patients per group) for 3 weeks.

LYN-05 was administered once weekly for a total of three doses. IR risperidone was administered once daily.

The study’s primary endpoints were pharmacokinetics after LYN-005 and IR risperidone, and the incidence of adverse events.

Following LYN-005 administration, systemic exposure to risperidone active moiety (risperidone and 9-hydroxyrisperidone combined) increased with the increasing dose. Peak concentration occurred within the first 3 days of dosing and peak exposures from LYN-005 were lower than with IR risperidone.

“Steady state was achieved around day 15. It didn’t take 3 weeks of dosing for patients to achieve steady state. We achieved that around day 15,” Walling said.

LYN-005 was well tolerated in the 85% of study participants who received all three doses.

Adverse events occurred in 18 (75%) patients who received LYN-005. Of these, 10 were with the 14 mg dose, and 8 with the 28 mg dose.

The most common AEs were gastrointestinal, which occurred in 13 (54%) patients receiving LYN-005, with a higher incidence in the 28-mg group than in the 14 mg group.

Additionally, 9 patients had abdominal pain, discomfort, or tenderness, and 5 patients (21%) had nausea.

Overall, the incidence of adverse events was higher for LYN-005 compared with IR risperidone, but they were judged to be mild and transitory, with fewer AEs reported with subsequent LYN-005 dosing. After the first dose, 58% of patients reported an AE; this dropped to 18% after the third dose.

An Important Development

Commenting on the findings for Medscape Medical News, Ira D. Glick, MD, professor emeritus, Stanford University School of Medicine, Stanford, California, said, “The major problem with schizophrenia is getting adherence.”

“The better the adherence, the better the outcome, the worst the adherence, the worse the outcome, so being able to take a preparation less often is a very important advance in the field,” said Glick, who was not involved in the research

Long-acting preparations for chronic mental illness represent a significant advance, he said.

“The future of the treatment of schizophrenia is long-acting injectables. That is the trend,” Glick explained “The oral once-a-week preparation may be useful in a group of patients who are phobic about needles, but with the injections, you can be sure that the patient has received their medication. With the oral, there is more of a chance to be noncompliant.

“That said, having an effective, longer-acting oral for those who refuse injections is helpful. It’s an important development, and it’s part of the advance the whole field is moving toward, to ensure adherence to treatment. We know treatment works, we know it is going to save lives, and that’s what this ultra-long-acting formulation is promoting.”

Walling is chief clinical officer for the Collaborative NeuroScience Network, LLC, Long Beach, California. Glick has disclosed no relevant financial relationships.

American Society of Clinical Psychopharmacology (ASCP) 2021: Abstract 3002873. Presented June 2, 2021.

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This post originally appeared on Medscape Medical News Headlines

Potential First-in-Class Schizophrenia Drug Cuts Negative Symptoms

This post originally appeared on Medscape Medical News Headlines

The novel antipsychotic agent SEP-363856 (Sunovion Pharmaceuticals) has a significant and ongoing effect on negative symptoms in patients with schizophrenia, new research shows.

Results of a phase 2 placebo-controlled trial show SEP-363856 significantly decreased total scores on the Brief Negative Symptom Scale (BNSS), and lowered subscale scores for such symptoms as alogia and asociality, compared with placebo.

The active-treatment group also showed significantly lower scores on the negative subscale of the Positive and Negative Syndrome Scale (PANSS). During an open-label extension of the study, both BNSS total scores and PANSS negative symptom scores continued to decrease.

Overall, the results “provide further confirmation of the effectiveness of SEP-363856 in treating schizophrenia,” study investigator Kenneth Koblan, PhD, Sunovion, told Medscape Medical News.

He added that the compound also showed “a favorable safety and tolerability profile that is differentiated from first and second generation antipsychotics, and which is consistent with the absence of D2-receptor binding.”

The findings were presented at the virtual Congress of the Schizophrenia International Research Society (SIRS) 2021.

FDA Breakthrough Designation

SEP-363856 has a completely different mechanism of action from currently available antipsychotics.

In May 2019, it was granted breakthrough therapy designation by the US Food and Drug Administration (FDA) as a novel treatment for patients with schizophrenia.

Phase 2 data published in the New England Journal of Medicine in 2020 showed it achieved significant and clinically meaningful improvements in PANSS total scores after 4 weeks in patients hospitalized with an acute exacerbation of schizophrenia. It also showed durable effects out to 26 weeks.

In the current analysis, the investigators focused on negative symptoms, both in the initial acute treatment phase and an open-label extension.

They analyzed data from the previous phase 2 trial using a validated Uncorrelated PANSS Score Matrix (UPSM) transformation of the PANSS to isolate the effects of the drug on apathy/avolition and deficit of expression. They also used the BNSS.

Patients aged 18 to 40 years with an acute exacerbation of schizophrenia were randomly assigned to receive either 50 mg or 75 mg of SEP-363856 per day (n = 120) or matching placebo (n = 125) for 4 weeks. Completers were eligible for enrollment in a 26-week phase 2 extension study of 25 mg, 50 mg, or 75 mg of SEP-363856 per day.

The mean age of the participants was 30 years, and 64% were men. The treatment groups were balanced in terms of demographics.

Significant Improvement

The BNSS total score decreased significantly with SEP-363856 over placebo during the 4-week acute treatment period, at a mean reduction of 7.1 vs 2.7, or an effect size of 0.48 (P < .001).

Scores on the PANSS negative subscale also decreased significantly with the active drugs, with an effect size of 0.37 vs placebo (P < .05), as did scores on the UPSM apathy/avolition and deficit of expression subscales (effect size, 0.32; P < .05 for both).

In addition, there were significant reductions with SEP-363856 over placebo for the BNSS alogia, asociality, anhedonia, avolition, and blunted affect subscales (P < .05 for all comparisons) but not for the distress subscale.

During the open-label extension, mean BNSS total scores continued to decrease for the SEP-363856 group, at an average reduction vs extension enrollment across the whole cohort of 11.3.

PANSS negative symptom scores also decreased by an average of 5.2 points, while UPSM apathy/volition scores decreased by 0.4 points on average. UPSM deficit expression scores decreased by 0.5 points.

When the researchers restricted the analysis to those who received SEP-363856 during the acute treatment phase and then continued using the drug during the open-label extension, they found BNSS total scores decreased by an additional 8 points.

Similarly, PANSS negative symptom scores decreased during the open-label extension by an average of 4 points. For UPSM apathy/avolition and deficit of expression, the additional decrease was 0.3 points on average.

In addition, an analysis of the drug’s safety and tolerability showed that, compared with the commonly prescribed antipsychotic lurasidone, it had a significantly lower risk of adverse effects. In addition, the drug was not associated with extrapyramidal symptoms and had no adverse cardiometabolic effects, Koblan reported.

Still in Development

Commenting on the findings for Medscape Medical News, René S Kahn, MD, PhD, chair of the department of psychiatry, Icahn School of Medicine at Mount Sinai, New York City, noted that although the results showed that the drug had a “nice effect” on negative symptoms, it’s still in development.

Kahn, who was not involved in the research, said “we’ve all seen” drugs that were extremely promising in phase 2 trials that have then failed in phase 3 trials. “The proof of the pudding is phase 3, and we have to wait and see,” he added.

“Obviously I hope it’s going to work out, because we are in desperate need of new drugs, especially with a new mechanism of action and not ‘me too’ drugs. And this definitely not a ‘me too’ drug,” Kahn said. However, “we’ll have to wait.”

He noted that psychosis is often the primary focus of schizophrenia management. However, he added, cognitive and negative symptoms are also “very relevant” to the disorder.

“In fact, both of them may be more important in determining the long-term outcome of schizophrenia than psychosis, [and] most of the antipsychotics that we currently have are not very effective against negative symptoms,” he said.

“So it would really be a breakthrough if we have a drug that is really effective not only against positive psychotic symptoms, but also against negative and possibly cognitive, symptoms,” Kahn added.

Commenting on the drug’s safety, Kahn said there is a need for head-to-head studies of active drugs before any firm conclusions can be drawn.

However, he noted the exploratory analysis suggests it has a different side effect profile compared to other medications on the market.

The study was supported by Sunovion Pharmaceuticals Inc. Koblan and his co-investigators are employees of Sunovion Pharmaceuticals.

Congress of the Schizophrenia International Research Society (SIRS) 2021: Abstracts S96 and M1. Presented April 18, 2021.

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