Highlights From the American College of Neuropsychopharmacology Annual Meeting

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Psychiatric Times was invited to attend the American College of Neuropsychopharmacology 2023 Annual Meeting from December 3 to 6, 2023, in Tampa, Florida, where experts from across the field gathered to connect and share groundbreaking data. Complete coverage of this meeting, as well as other conferences, can be found at here.

Targeting of Neuromodulation for Nicotine Use in Schizophrenia

“I have sought to identify specific circuits for nicotine dependence that I can then leverage into schizophrenia-specific treatment for smoking cessation,” said Heather Ward, MD, a psychiatrist at Vanderbilt University Medical Center in Nashville, Tennessee, as part of the panel “Hit Me With Your Best Shot: Personalized Targeting of Neuromodulation for Substance Use Disorders.”

Nicotine dependence is the top preventable cause of early mortality in schizophrenia, with a 20-year decrease in life expectancy due to associated medical consequences such as heart disease, stroke, lung cancer, and more. Additionally, the prevalence of tobacco use in those with schizophrenia is 3 times that of the general population. Compounding this problem are the varied versions of nicotine now available, including vaping, lozenges, and patches, as well as cigarettes. Despite these facts, tobacco cessation treatments are significantly less effective in patients with schizophrenia.

To begin, Ward sought to define which circuit of the brain should be targeted. She and fellow investigators found it in the default mode network (DMN). She then endeavored to engage said circuit using 1 pharmacologic intervention and 1 neuromodulatory intervention, constructing a model that shows decreasing craving decreases DMN connectivity in schizophrenia, and vice versa.

Ward’s exciting preliminary data indicate that neuromodulation, specifically inhibitory DMN-targeted continuous theta burst stimulation (cTBS), could be effective as a schizophrenia-specific intervention for nicotine use. With multiple sessions—5 consecutive days, assessed via scan 2 to 7 days before treatment and 2 to 7 days following treatment—patients with schizophrenia (n = 7) indicated they had fewer cravings for nicotine post neuromodulation session. Furthermore, participants in the nonpsychosis group (n = 14) did not indicate a change in craving, suggesting this treatment exclusively targets those with schizophrenia.

“Some people would suggest that we have actually just identified the area for an agent with pharmacotherapy, that maybe we could be developing small molecules that can modulate DMN connectivity,” said Ward. “But I want to develop TMS [transcranial magnetic stimulation] for smoking cessation. I think it is fabulous that we have evidence that multiple sessions of cTBS can reduce craving.”

The research also indicates different types of modulation could have alternative effects. Ward noted that intermittent TBS had an excitatory effect, actually increasing craving for nicotine. “Maybe it is easier to increase craving than it is to decrease craving,” Ward commented.

Ultimately, Ward’s hope is that TMS can be used to help patients achieve a nicotine-free status. “It is exciting because we are one step closer toward improving smoking cessation treatment in patients with schizophrenia,” said Ward. “I think it is clear we will need more sessions for that.”

While the literature is limited, other research like that published by Corripio et al has sought to understand the effectiveness of neuromodulation—in this case, deep brain stimulation—in treatment- resistant schizophrenia.¹

Reference

1. Corripio I, Roldán A, McKenna P, et al. Target selection for deep brain stimulation in treatment resistant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2022;112:110436.

Novel Therapeutic Navacaprant

Navacaprant—a novel, oral, once-daily, highly selective κ opioid receptor antagonist—is in phase 3 development as a monotherapy for major depressive disorder (MDD). MDD affects 264 million individuals worldwide, shared Sanjay Mathew, MD, professor of psychiatry and behavioral sciences at Baylor College of Medicine, demonstrating the need for novel therapeutics like navacaprant. There is a significant unmet need for patients who do not respond to standard selective serotonin reuptake inhibitors or antidepressants. Furthermore, anhedonia affects 70% of patients and is associated with more severe depressive symptoms and functional impairment.¹

“κ Opioid receptors are novel targets for anhedonia that are abundantly expressed in brain circuits regulating reward, motivation, stress, and anxiety,” said Mathew. “The κ opioid receptor system is a well-characterized pathway that results from several decades of preclinical studies supporting its potential to modulate depression and anxiety.”

κ Opioid receptor antagonists may potentially restore the regulation of multiple neurotransmitters, like dopamine, in reward-processing pathways. Navacaprant has 300-fold selectivity for κ over μ opioid receptors and no agonist activity at κ, μ, or δ opioid receptors.²

Mathew shared data from a phase 2 study that evaluated the impact of navacaprant compared with placebo on MDD and anhedonia symptoms, as well as anxiety, following 8 weeks of double-blind treatment, measured by the Hamilton Rating Scale for Depression 17 (HAM-D-17). The study initially enrolled patients with mild to moderate MDD (baseline HAM-D-17 score of 14-22) but was eventually amended to enroll patients with moderate to severe MDD. The participants’ mean age was 42. Of the participants, 70.5% were female, 61.4% were White, 34.1% were Black, and 4.5% were Asian.

“[In the study,] 645 participants were screened and 441 screen failed. The randomization in the safety population was 102 per arm,” said Mathew.

The efficacy population narrowed down further, consisting of 83 participants in the placebo group and 88 in the navacaprant group. Of the 88 in the navacaprant group, 72 completed the study. The primary end point was change from HAM-D-17 baseline score at week 8; the secondary end point was change from baseline score at week 4. Navacaprant demonstrated benefit in the total population as well as a statistically significant and clinically meaningful improvement in depression symptoms at week 4; however, navacaprant did not achieve statistical significance compared with placebo at week 8. The next step is to pursue a phase 3 development program, which is underway with 3 placebo, large-scale programs for monotherapy.

References

1. Cao B, Zhu J, Zuckerman H, et al. Pharmacological interventions targeting anhedonia in patients with major depressive disorder: a systematic review. Prog Neuropsychopharmacol Biol Psychiatry. 2019;92:109-117.

2. Limoges A, Yarur HE, Tejeda HA. Dynorphin/kappa opioid receptor system regulation on amygdaloid circuitry: implications for neuropsychiatric disorders. Front Syst Neurosci. 2022:16:963691.

Cognitive Impairment in Schizophrenia: Top Takeaways from ACNP 2023

Presenters Kathryn Lewandowski, PhD; Mark Weiser, MD; Sophia Frangou, FRCPsych; and Abraham Reichenberg, PhD, tackled the topic of cognitive impairment in schizophrenia, a major aspect of schizophrenia that can have significant long-term effects. Psychiatric Times listened in to provide a few top takeaways.

Kathryn Lewandowski, PhD, associate professor and director of clinical programming at Harvard Medical School and McLean Hospital, characterized cognitive heterogeneity in psychosis.

“We know that people, even in the first episode of psychosis, also experience at the group level, cognitive impairments,” said Lewandowski.

She and colleagues have attempted to identify meaningful cognitive subgroups within populations via cluster analysis.¹

“We can try to see if approaches like cluster analysis can help us leverage that variability to identify distinct subgroups within that variable of interest that might tell us something meaningful about that particular presentation and that particular person,” said Lewandowski.

To understand what neuroprogression look like across the early course of illness and psychosis, they studied 89 participants, assessed at baseline then 8 and 16 months, using the NIH toolbox to measure cognition and number of different measures of mood, psychosis, and functioning. The 3-cluster solution was the best fit for the data. Cluster 1 was the impaired cluster with 36 participants. Cluster 2 was high performers. Cluster 3 was average.

She identified that:

• Cognitive clusters can be identified early in course of psychosis transdiagnostically
• Clusters are predictive of symptoms and functioning over time, despite few differences at baseline
• Little evidence of deterioration of cognition or symptoms over the course of follow up
• Social and occupational functioning worsened for those in the impaired cluster

Mark Weiser, MD, professor of psychiatry at Tel Aviv University, the associate director for treatment trials at the Stanley Medical Research Center, and chairman of the department of psychiatry at Sheba Medical Center, prerecorded his session from Tel Aviv on the timing of cognitive impairments in psychotic disorders.

Many patients with psychotic disorders have impaired premorbid cognitive functioning, shared Weiser. He wanted to interrogate when cognitive impairment in psychotic disorders occur, and to characterize the pattern of cognitive decline in patients with psychotic disorders.

“The problem is that the vast majority of patients who will later have schizophrenia function in the average or above average level of cognitively, hence making it impossible to use a cognition to predict to later,” said Weiser.

In this ongoing study, he examines adolescent Israeli males who were assessed by the Israeli Military Draft Board at age 17, before the onset of psychosis. To date, the study group includes 32 participants, and the control group includes 26 participants. Participants are assessed at baseline (prediagnosis), then 1 to 12 years after the first test and more than 6 months after their first psychotic break. The test results are then compared with controls.

The standardized draft board cognitive assessment has 4 subtests:

• Instruction comprehension
• Raven, or differentiating figures
• Arithmetic
• Verbal analogies

Results shows that 50% of patients with schizophrenia have a decline in cognitive ability, whereas the majority (55%) of controls have increases in cognitive ability. In terms of ability to understand instruction, the controls did not change much, but patients with schizophrenia declined over the course of study. On the Raven subtest, the controls performed better, and those with schizophrenia performed worse. In arithmetic, controls performed better, and those with schizophrenia again performed worse. Interestingly, in the verbal analogies subtest, the controls improved but those with schizophrenia did not show much change over study course.

The overall results relative to controls showed a mean decrease of 0.5 SD (P = 0.003).

Weiser suggested that future studies should perform structural and functional MRI to characterize patients who decline cognitively.

Brain organization changes with age, but these investigators looked further.

“Patients with schizophrenia have older appearing brains,” shared Sophia Frangou, PhD, professor of psychiatry at Icahn School of Medicine. Frangou shared with ACNP attendees more on the topic of BrainAGE, or the difference between neuroimaging-predicted brain age and actual chronological age.

Higher BrainAGE is associated with adverse physical, cognitive, and mental health phenotypes.

How do you calculate BrainAGE?

• Machine learning algorithms
• Sample size
• Same age range
• Density of data points within any age bin
• Number of neuroimaging features used as input into machine learning models
• Handling of site effects
• Age bias confirmation

Brain aging in schizophrenia shows significant spatial variation and tracks cognitive dysfunction, Frangou shared.

Reference

1. Lewandowski KE, Baker JT, McCarthy JM, et al. Reproducibility of cognitive profiles in psychosis using cluster analysis. J Int Neuropsychol Soc. 2018;24(4):382-390.