Spravato as a Therapy for Treatment-Resistant Depression

Author: Pari Dhayagude
Editor: Phoebe Tchoua

Treatment-resistant depression (TRD) is one of the most difficult psychiatric disorders to treat. It  occurs when a patient is unresponsive to two or more antidepressant regimens following adequate dosing, duration, and adherence.1 In 2019, the FDA approved Spravato (esketamine), a nasal spray developed by Janssen Pharmaceuticals, for use alongside oral antidepressants to treat TRD.2 Recently, Spravato has emerged as a potential monotherapy option. Although further research is needed, Spravato provides a new treatment avenue for patients with TRD.3

Overview of Major Depressive Disorder and Treatment-Resistant Depression

Major depressive disorder (MDD) affects over 21 million adults in the United States (US), making it one of the most common mental health disorders.4 According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), MDD is characterized by having at least two weeks of depressed mood or inability to feel joy (anhedonia), accompanied by symptoms, such as changes in sleep, eating, concentration, and feelings of worthlessness.5 Individuals with MDD often experience comorbidities, such as anxiety and substance use disorders, which often exacerbates the severity of symptoms and makes treatment more difficult.6,7 Despite advances in understanding the onset and progression of MDD, traditional treatments are ineffective for 30% of people with depression, highlighting the need for novel treatments that offer rapid, sustained relief for those who do not respond to traditional treatment.1

Patients with MDD who do not respond to standard treatment are often referred to as having TRD. A TRD diagnosis follows after a failure at least two different first-line antidepressants (such as selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs)) fail to significantly alleviate their depressive symptoms.1,8 However, the lack of a clear universal definition of TRD continues to hinder both the development of treatments and patient access to care. Generally, this subpopulation with TRD have similar symptoms, such as a depressed mood and disruptions with sleep, as those with MDD, but the severity is greater. Additionally, individuals with TRD tend to present with increased anhedonia, recurrent MDD episodes, anxiety, suicidal ideation, and physical comorbidities such as metabolic syndrome and type 2 diabetes.9,10,11 Current research on the treatment of TRD focuses on personalized approaches and novel pharmacological interventions over standard medications.

Pathology

The pathophysiology of MDD is not fully understood, but several studies suggest that alterations in monoaminergic neurotransmission of serotonin, norepinephrine, and dopamine significantly contribute to its clinical manifestations.12 Specifically, reduced synaptic availability of these neurotransmitters has been linked to symptoms often seen in individuals with MDD, including lower mood, diminished motivation, and impaired cognitive function. SSRIs and SNRIs focus on correcting the dysregulation in monoaminergic transmission by preventing reuptake of these neurotransmitters. In recent years, there has been growing attention from researchers and agencies, such as the National Institute on Mental Health (NIMH), toward understanding the complex molecular, cellular, and circuit-level imbalances that underlie MDD and TRD. 

Emerging research has identified disruptions in glutamatergic transmission, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and inflammatory signaling as significant contributors to both MDD and TRD.13,14 Chronic stress and elevated cortisol levels can trigger neuroinflammatory cascades, leading to neuronal atrophy and impaired plasticity in the hippocampus and prefrontal cortex.15 In TRD, these underlying disruptions are often more pronounced, limiting the effectiveness of interventions that primarily target monoaminergic pathways. This complex and multifaceted physiology requires newer interventions that target novel molecular mechanisms that can offer relief for patients who do not respond to traditional monoaminergic-based treatments.

Current Available Treatments and Limitations

Pharmacotherapy

Pharmacological treatments for MDD and TRD span several medication classes, each targeting different aspects of monoaminergic dysregulation. First-line treatments generally include SSRIs, such as fluoxetine, sertraline, and escitalopram, due to their efficacy and milder side effects. They act by binding to serotonin transporters on the presynaptic neuron, which prevents the reuptake of serotonin and increases its availability.16 For patients who do not respond to SSRIs, SNRIs such as duloxetine may be used as an alternative. SNRIs prevent the reuptake of both serotonin and norepinephrine, potentially addressing a wider range of depressive symptoms.17 Other pharmacotherapies such as tricyclic antidepressants present alternative mechanisms that may be advantageous in patients who have not responded to first-line treatments, but their anticholinergic activity and risk of overdose may cause adverse side effects.18 A key limitation of antidepressants is that they can take several weeks before a significant therapeutic effect is achieved, and over a third of patients, including those with TRD, do not respond to these treatments.19

Behavioral Therapies

Non-pharmacological therapies can serve as complementary or as alternative treatments for individuals with MDD and TRD. This includes interventions like cognitive behavioral therapy, mindfulness-based therapy, and lifestyle modifications such as incorporating exercise and improving sleep hygiene.20 However, individuals with TRD generally do not respond adequately from standalone behavioral therapies and often require additional interventions to alleviate symptoms. 

Somatic Therapies

Somatic therapies are often used for individuals with TRD when standard pharmacological and behavioral interventions fail to provide sufficient relief. Electroconvulsive therapy (ECT) is a common and effective intervention for severe depression, particularly in individuals presenting with suicidality or psychotic symptoms. The procedure involves administering an electrical current through the scalp to induce a brief seizure and has been shown to be about 60% successful in producing short-term relief.21 However, ECT is associated with several side effects and a $15,000 cost for a full course of treatment.21 Transcranial magnetic stimulation (TMS), a noninvasive procedure that applies magnetic pulses to the prefrontal cortex, may be a more viable alternative to ECT. However, the efficacy of reducing symptoms in people with TRD remains inconclusive, and patients need to receive treatment 5 days per week, increasing patient burden.21 Given the limitations of both ECT and TMS—including side effects, high costs, inconsistent efficacy, and significant time commitments—there remains a critical need for more accessible, effective, and well-tolerated treatment options for individuals with TRD.

Figure 1: Current Available Treatments for Depression. (Figure made by Pari Dhayagude using Canva.)

Spravato (Esketamine) Mechanism of Action

Esketamine, the S-enantiomer of racemic ketamine, provides a different mechanism of action compared to other traditional antidepressant treatments by targeting the glutamatergic system. Instead of blocking monoamine reuptake, esketamine works as a non-selective, non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, an ionotropic glutamate receptor, preferentially targeting those located on GABA interneurons.22 Inhibiting NMDA receptors on GABA interneurons leads to the disinhibition of glutamatergic neuron activity and an acute increase in glutamate release from glutamatergic neurons. In turn, this causes increased stimulation of postsynaptic AMPA receptors, creating a signaling cascade to boost brain-derived neurotrophic factor (BDNF).22 BDNF plays an important role in regulating synaptic formation and maintaining synaptic connections and is critical in synaptic plasticity.23 Unlike traditional antidepressants which can take several weeks to show effects, esketamine can deliver significant clinical improvement within hours to days, making it a vital therapeutic candidate for TRD and urgent interventions in emergency care settings.24

Figure 2: Esketamine mechanism of action. (Figure made by Pari Dhayagude using BioRender).

Clinically, esketamine is available as a 58 or 84 mg intranasal spray (Spravato) designed for self-administration under direct medical supervision. Due to its possible side effects like transient dissociation and sedation, patients must remain at the treatment center for a few hours following administration, during which vital signs and mental assays are regularly taken. Generally, Spravato is administered twice a week for the first four weeks of treatment, followed by weekly maintenance sessions for weeks five through eight, and then on an as-needed basis.25 Until 2025, FDA-approved guidelines required Spravato to be used alongside an oral antidepressant.2 However, Johnson & Johnson recently received approval to use Spravato as a standalone monotherapy for TRD, marking a significant advancement in the pharmacological management of TRD.3 

Clinical Trials

Several clinical trials have investigated esketamine as a treatment for individuals with TRD or severe depression, reaching a consensus on its efficacy and general tolerability.28 One randomized clinical trial conducted by Janssen R&D and academic collaborators evaluated the efficacy of 3 different doses of intranasal esketamine (28, 56, and 84 mg) versus placebo combined with oral antidepressants in 67 participants.29 The results showed a significant ascending dose-response relationship with higher doses correlating to greater reductions in depression scores.29 Most notably, they found a rapid decrease in depressive symptoms with a mean decrease within 8 days of treatment.29 Additionally, sustained improvements continued after reduced dosing frequency, and response and remissions rates favored the esketamine-treated groups, particularly the 84 mg dose group.29 Adverse events in this trial were rare with 5% of esketamine-treated participants discontinuing treatment during the double-blind phase and 2% during the open-label phase.29

Janssen R&D conducted its first Phase 4 clinical trial to evaluate the efficacy and safety of Spravato nasal spray as a monotherapy for TRD.30 This randomized, double-blind, placebo-controlled trial involved 478 participants, of whom 379 met criteria for non-responsiveness to prior treatments and received medication. The findings revealed that the 56 and 84 mg doses of Spravato significantly improved depressive symptoms compared to placebo.30 Results began to show about 24 hours after the first dose, indicating a rapid reduction in depressive symptoms similar to previous trials combining esketamine with an oral antidepressant.29,30 The study suggests that Spravato could be an effective standalone option for patients with TRD, especially when conventional treatments fail and alternate treatments are more invasive. 

Economic Impact

The societal and economic burden of TRD remains high with the most expenses coming from direct expenses (e.g., prescription drug costs, clinician visits, inpatient care) and indirect expenses (e.g., lost productivity and disability).26 One study estimated the national economic burden of TRD to be between $29 to 48 billion annually, assuming that 12-20% of the individuals have TRD.27 On average, individuals with TRD face an annual incremental productivity cost exceeding $6,000 annually compared to individuals without MDD.26 Additionally, unemployment among individuals with TRD results in an estimated $8.7 billion in cost to US taxpayers.26 Emerging alternative treatments like Spravato offer hope for individuals with TRD who have not responded to traditional treatments. By enhancing brain plasticity and providing rapid symptom relief, Spravato not only offers an effective therapeutic option for patients, but it also has the potential to reduce the economic impact associated with TRD.

References

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Figure 2: Created in BioRender. Dhayagude, P. (2025) https://BioRender.com/thiraz6

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