Dimensional effect profiles in treatment-resistant depression: A naturalistic, prospective head-to-head comparison of arTMS, esketamine nasal spray, and oral brexpiprazole.
Giacomo d'Andrea, Clara Cavallotto, Ottavia Susini, Federica Marsico, Giovanna Mammarella, Gianfranco Tamagnini, Antonio Inserra, Gianluca Mancusi, Giorgio Di Lorenzo, Tommaso Barlattani, Francesca Pacitti, Mauro Pettorruso, Giovanni Martinotti
Journal of Affective Disorders July 28, 2026 DOI: 10.1016/j.jad.2026.122333 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Prospective, naturalistic, three-arm observational study Randomized Peer reviewed |
|---|---|
| Sample size | 101 |
| Population | Individuals with treatment-resistant depression |
| Interventions | Esketamine nasal spray accelerated repetitive transcranial magnetic stimulation (arTMS) brexpiprazole augmentation |
| Dose | brexpiprazole 1-2 mg/day |
| Duration | One month |
| Topics | Depression Esketamine |
| Keywords | Accelerated rtms artms Brexpiprazole augmentation Treatment-resistant depression trd |
| Key findings | All three treatments — esketamine nasal spray, accelerated rTMS, and brexpiprazole augmentation — produced significant reductions in overall depressive severity and anhedonia after one month. Rumination showed a significant time-by-treatment interaction, with greater improvement under brexpiprazole. Item-level analyses suggested partially distinct symptom profiles, which the authors describe as exploratory and requiring confirmation in randomized studies with longer follow-up. |
Abstract
Treatment-resistant depression (TRD) is a heterogeneous condition in which symptoms such as anhedonia, rumination, and anxiety contribute to persistent disability. Esketamine nasal spray (ESK-NS), accelerated repetitive transcranial magnetic stimulation (arTMS), and adjunctive brexpiprazole represent novel therapeutic options with distinct mechanisms, though their domain-specific effects in real-world settings remain unclear. To compare short-term changes in depressive severity across ESK-NS, arTMS, and brexpiprazole, and to explore treatment-related effects on anhedonia, rumination, anxiety, and item-level depressive symptoms. One hundred and one individuals with TRD were enrolled in a prospective, naturalistic, three-arm study and treated with ESK-NS, arTMS (accelerated left DLPFC protocol), or brexpiprazole augmentation (1-2 mg/day). Assessments were conducted at baseline and after one month. All treatments produced significant reductions in overall depressive severity and anhedonia. Rumination showed a significant time-by-treatment interaction, with greater improvement under brexpiprazole. Item-level analyses suggested partially distinct profiles, with brexpiprazole preferentially improving pessimistic and ruminative symptoms, ESK-NS enhancing affective responsiveness and cognitive symptoms, and both ESK-NS and arTMS contributing to anxiolysis. In routine clinical practice, ESK-NS, arTMS, and brexpiprazole were associated with short-term improvement in TRD, with exploratory signals of partially distinct symptom-domain profiles. These findings support the value of dimensional assessment in TRD and warrant confirmation in randomized studies with longer follow-up.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cites 21
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- Management of Treatment-Resistant Depression: Challenges and Strategies Neuropsychiatric Disease and Treatment 2020
and 16 more in the library