Effect of SPRAVATO on Brain Volume and Structure

SUMMARY

• Lorente et al (2025)¹ conducted a 6-month, open-label, proof-of-concept study to evaluate clinical and molecular effects of SPRAVATO on brain volume in 7 adults with treatment-resistant depression (TRD) receiving SPRAVATO adjunctive to oral antidepressants. Neuroimaging showed significant increases in volume within frontal, limbic, and hippocampal regions, along with improved microstructural integrity. Serum neurofilament light chain (sNfL) levels, a potential biomarker of neuronal damage, decreased from 14.67±1.64 to 12.14±1.51 pg/mL (P=0.0781).
• Dworak et al (2025)² conducted a randomized, double‑blind, placebo‑controlled, cross‑over neuroimaging study to evaluate the acute effects of intranasal SPRAVATO on brain volume, with a focus on thalamic structures, in healthy adults. Participants received a single intranasal dose of SPRAVATO 56 mg or placebo prior to magnetic resonance imaging (MRI). Across the entire study population, no significant differences in thalamic volumes were observed between SPRAVATO and placebo treatment. However, a significant increase in the right thalamic volume was observed in a subgroup (n=12) of patients administered placebo during the first scan followed by SPRAVATO during the second scan (P_corr=0.048; F=7.279).

EFFECT ON BRAIN VOLUME AND STRUCTURE

Neuroimaging Proof-of-Concept Study in Patients with TRD

Lorente et al (2025)¹ conducted a 6-month, prospective, open-label study (depTesk) in adults with TRD receiving SPRAVATO adjunctive to oral antidepressants and other psychotropic medications (N=7; mean age, 48.2 years; female, 71%). Patients received SPRAVATO twice weekly for 4 weeks, followed by weekly administration for 20 weeks. At baseline and 6 months, structural MRI imaging was performed to measure brain changes and at baseline and 6 months, and blood samples were taken to measure sNfL levels.  Depressive symptoms (eg, MADRS and PHQ-9) were also assessed.

Baseline brain volume, particularly in the nucleus accumbens, putamen, thalamus, basal forebrain, hippocampus, and cortical regions, including insula and frontal lobe, were significantly lower in TRD patients compared with 21 matched healthy controls.

At 6 months, both MADRS (from 31.7 to 11.9) and PHQ-9 (from 20.1 to 9.1) improved from baseline. Brain volume changes and tractography changes after 6 months of treatment are presented in Table: Comparative Brain Volumes Before and After SPRAVATO Treatment and in Table: Tractography Analysis After SPRAVATO Treatment.

Decreased sNfL were observed after 6 months of treatment (mean±SEM) from 14.67±1.64 pg/mL to 12.14±1.51 pg/mL (P=0.0781).

Neuroimaging CrossOver Study in Healthy Patients

Dworak et al (2025)² evaluated the acute effects of SPRAVATO on brain volume using a randomized, double‑blind, placebo‑controlled, cross‑over neuroimaging study in 26 healthy participants (female, 54%; mean age, 24.3±3 years). Participants underwent two MRI sessions conducted 7 and 28 days apart, receiving either SPRAVATO 56 mg or placebo (0.9% saline) immediately prior to each scan. Structural MRI was performed immediately after dosing to assess volumetric changes in the whole thalamus and thalamic subnuclei.

Across the entire study population, no significant differences in thalamic volumes were observed between SPRAVATO and placebo treatment. In a subgroup of participants who received placebo during the first MRI session and SPRAVATO during the second session (n=12), a significant increase in the right thalamic volume was observed following SPRAVATO administration compared with placebo (P_corr=0.048; F=7.279).

In exploratory analyses within the same subgroup, significant volume increases were observed in the right pulvinar anterior nucleus (P=0.048; F=5.409) and the right mediodorsal lateral parvocellular nucleus (P=0.034; F=6.527). Post‑hoc exploratory analyses of visual cortical regions (left and right lateral occipital cortex) did not show significant volumetric changes following SPRAVATO administration. It is important to note that these P-values are nominal and should be interpreted as descriptive only.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 10 December 2025.