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Anywhere Clinic

The Science

Evidence-based care,

Every treatment we offer at Anywhere Clinic is grounded in peer-reviewed research, and we say plainly which treatments are FDA-approved or cleared and which are off-label. Below is a clinician-level look at the science behind ketamine therapy, TMS, Spravato®, and our integrative psychiatry model, including the trials, mechanisms, and response rates that inform how we treat depression, anxiety, PTSD, and OCD, with a link to every source.

Ketamine Therapy

Off-label · studied mainly as IV infusions

Rapid-acting glutamate modulation for treatment-resistant depression

Ketamine blocks NMDA glutamate receptors. In animal studies this sets off a cascade, including BDNF (brain-derived neurotrophic factor) signaling, that leads to new synapses in the prefrontal cortex (Li 2010). Standard antidepressants usually take 4–8 weeks to work (NIMH); in trials of IV ketamine, mood improved within hours to a day.

Clinical evidence

In an 18-person NIMH crossover trial in treatment-resistant depression, 71% of the 17 people given ketamine met response criteria the day after a single IV infusion, and 35% kept that response for at least a week (Zarate 2006). In a larger two-site randomized trial (73 people), 64% responded at 24 hours, compared with 28% given an active placebo, midazolam (Murrough 2013). Both studies used single IV infusions, and their authors called for more data on how long the benefit lasts. Evidence for at-home oral or sublingual dosing is more limited. Ketamine is prescribed off-label and is not FDA-approved for any psychiatric condition.

TMS (Transcranial Magnetic Stimulation)

FDA-cleared 2008 (depression), 2018 (OCD)

Non-invasive cortical stimulation, FDA-cleared since 2008

TMS delivers focused magnetic pulses to the left dorsolateral prefrontal cortex (DLPFC), a region involved in mood regulation. The magnetic field is about as strong as an MRI scanner's and is switched on and off rapidly to stimulate nerve cells in the targeted area (NIMH). Repeated sessions are thought to strengthen connections in mood-regulating networks. Patients sit awake in a chair, with no anesthesia and no sedation.

Clinical evidence

In the NIMH-funded OPT-TMS trial (199 people who weren't taking antidepressants), 14.1% remitted with active TMS versus 5.1% with sham, and almost 30% remitted in the open-label phase that followed (George 2010). In a study of 307 people treated at 42 U.S. clinical practices, 58% responded and 37% remitted on a clinician rating (Carpenter 2012). The FDA has since cleared TMS for OCD (2018) and as an add-on treatment for depression in adolescents 15 and older (2024) (NIMH). In a 29-person sham-controlled trial of an accelerated 5-day protocol (SNT, formerly SAINT), depression scores fell 52.5% with active treatment versus 11.1% with sham four weeks later (Cole 2022).

Spravato® (Esketamine)

FDA-approved 2019 · new indications 2020, 2025

FDA-approved nasal esketamine for treatment-resistant depression

Spravato® is the S-enantiomer of ketamine, formulated as a nasal spray and given under direct medical observation in a healthcare setting certified under the FDA's REMS program. It binds NMDA receptors with greater affinity than racemic ketamine. Patients are monitored for at least 2 hours after every dose (FDA label).

Clinical evidence

In the TRANSFORM-2 trial behind its 2019 approval, Spravato® plus a new oral antidepressant lowered MADRS depression scores more than placebo spray plus an antidepressant at day 28 (Popova 2019); the label notes most of the difference was already seen at 24 hours. In the SUSTAIN-1 relapse-prevention trial, people in stable remission who kept taking Spravato® had a 51% lower risk of relapse than those switched to placebo spray (Daly 2019). In 2020 the FDA added depressive symptoms in adults with major depression and acute suicidal thoughts or behavior, and in 2025 approved use on its own for treatment-resistant depression (Drugs@FDA). The label notes it hasn't been shown to prevent suicide or reduce suicidal thoughts.

Integrative Psychiatry

Therapy + medication beats medication alone

Whole-person care: pharmacotherapy + psychotherapy + lifestyle

Our model layers evidence-based pharmacotherapy (SSRIs, SNRIs, atypical antipsychotics, stimulants, mood stabilizers) with structured psychotherapy modalities, Cognitive Behavioral Therapy (CBT), Dialectical Behavior Therapy (DBT), Eye Movement Desensitization and Reprocessing (EMDR), and Acceptance and Commitment Therapy (ACT), and lifestyle medicine including sleep hygiene, exercise prescription, and nutritional psychiatry.

Clinical evidence

A meta-analysis of 52 randomized trials (3,623 patients) found that adding psychotherapy to antidepressant medication worked better than medication alone, with the clearest evidence for major depression, panic disorder and OCD (Cuijpers 2014). For adult depression, a network meta-analysis of 101 trials found combined treatment more effective than either psychotherapy or medication alone (Cuijpers 2020). We use stepped care: when first-line treatment hasn't worked, we discuss interventional options like TMS, ketamine, or Spravato®.

Ketamine, in depth

How ketamine acts on the brain

Ketamine works on the NMDA-glutamate system rather than the serotonergic pathway targeted by SSRIs. Research describes downstream effects on synaptic plasticity. Ketamine is prescribed off-label and is not FDA-approved for psychiatric conditions; suitability is determined individually by a licensed clinician. Learn more about our at-home ketamine program or read the full step-by-step program.

NMDA receptor antagonism

A leading theory: ketamine blocks NMDA glutamate receptors on inhibitory interneurons, which leads to a burst of glutamate signaling at AMPA receptors in the prefrontal cortex.

BDNF & synaptogenesis

In mouse and rat studies, ketamine's rapid antidepressant-like effects depended on fast production of brain-derived neurotrophic factor (BDNF) (Autry 2011) and came with new synapses in the prefrontal cortex (Li 2010).

Restored neuroplasticity

In animal studies, chronic stress shrinks synapses in prefrontal circuits, and ketamine's effects run opposite to those losses (Li 2010). Some programs pair dosing with integration therapy for this reason; that pairing is still being studied.

A long clinical history

Ketamine has been FDA-approved as an anesthetic since 1970. It's a Schedule III controlled substance with misuse potential, and it can raise blood pressure and cause dissociation, so screening and monitoring matter (Ketalar label).

Why patients choose at-home ketamine

  • Mechanism of action differs from SSRIs, NMDA receptor modulation rather than serotonergic reuptake inhibition
  • Studied in peer-reviewed trials for several psychiatric indications; ketamine is prescribed off-label and is not FDA-approved for psychiatric conditions
  • Sublingual at-home protocol avoids the cost and burden of in-clinic IV infusions for appropriate patients
  • Pairs with integration therapy as part of a structured psychiatric care plan
  • Psychiatry visits can be billed to insurance where we're in network; compounded medication, when prescribed, is paid to the pharmacy

Ketamine: An Evidence-Based Overview

Every study, FDA label and NIMH page cited on this page is listed in the sources below, with a link to the original. The ketamine trials above used IV infusions in research settings; ketamine is prescribed off-label and is not FDA-approved for any psychiatric condition.

See the sources

How we practice

Principles behind every treatment plan

"Evidence-based" isn't a marketing phrase for us, it's the operating system for our clinic. Here's how we translate research into the care you actually receive.

Peer-reviewed evidence

Our protocols draw on randomized controlled trials, meta-analyses, clinical guidelines from the APA and WFSBP, and FDA labeling. At-home ketamine is off-label, and the evidence for at-home dosing is more limited than for IV infusions.

Measurement-based care

We use validated rating scales (PHQ-9, GAD-7, MADRS, YBOCS) at baseline and follow-ups to track symptom change objectively, not just by impression.

Continuous education

Our providers attend conferences (APA Annual Meeting, Wonderland, MAPS) and complete CME on emerging treatments, including ketamine therapy, neuromodulation, and digital therapeutics.

Personalized stepped care

Treatment escalates based on response. Most patients start with first-line therapy and medication; we add interventional options like TMS, ketamine, or Spravato® only when clinically warranted.

Common questions about the science

Plain-language answers to the technical questions patients ask most often.

Clinically, treatment-resistant depression (TRD) usually means a major depressive episode that hasn't responded to at least two different antidepressants, each taken at an adequate dose for an adequate length of time (often 6 weeks or more). A U.S. estimate built from insurance claims found that about 31% of adults treated with medication for major depression had TRD (Zhdanava 2021). People with TRD may be candidates for interventional treatments like ketamine, Spravato®, or TMS.

Both work on the same NMDA receptor system, but Spravato® is the FDA-approved esketamine nasal spray, given in a REMS-certified healthcare setting with monitoring for at least 2 hours after each dose. Ketamine (an at-home lozenge in our program) is prescribed off-label and is not FDA-approved for any psychiatric condition; it's typically self-pay, and at-home dosing is offered only in some states. The choice depends on your history, medical screening, coverage and logistics.

TMS has been FDA-cleared for depression since 2008, and NIMH describes it as safe and well tolerated overall. Side effects include scalp discomfort, mild headaches and brief lightheadedness; seizures are possible, but the risk is low, and long-term side effects haven't been fully studied. Ketamine and Spravato® both carry real risks, which is why screening matters (Spravato is given in-clinic under REMS supervision); the main risks (dissociation, blood pressure increases, bladder problems with long-term misuse or high-dose use) are reduced through careful dosing, screening, and monitoring. Long-term data are still limited.

Meta-analyses of dozens of studies have found that mental health treatment and assessments by video produce results largely equivalent to in-person care (Batastini 2021; Fernandez 2021), while making care easier to reach for rural patients, working parents, and people with mobility or anxiety barriers. Interventional treatments (TMS and Spravato®) still require an in-person visit.

Sources

  1. Zarate CA Jr, et al. A randomized trial of an NMDA antagonist in treatment-resistant major depression. Arch Gen Psychiatry, 2006 (NIMH)
  2. Murrough JW, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry, 2013
  3. Li N, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists (rat study). Science, 2010
  4. Autry AE, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses (mouse study). Nature, 2011
  5. Ketalar (ketamine hydrochloride) prescribing information, DailyMed: anesthetic indications, Schedule III, initial U.S. approval 1970
  6. NIMH: Mental Health Medications (antidepressants usually take 4 to 8 weeks to work)
  7. NIMH: Brain Stimulation Therapies (rTMS clearances, side effects)
  8. George MS, et al. Daily left prefrontal TMS for major depressive disorder: a sham-controlled randomized trial (OPT-TMS). Arch Gen Psychiatry, 2010
  9. Carpenter LL, et al. TMS for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety, 2012
  10. Cole EJ, et al. Stanford Neuromodulation Therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry, 2022
  11. Spravato (esketamine) prescribing information, DailyMed: indications, REMS, monitoring for at least 2 hours, clinical studies
  12. Drugs@FDA: Spravato (NDA 211243) approval history (2019 approval; new indications 2020 and 2025)
  13. Popova V, et al. Flexibly dosed esketamine nasal spray plus a new oral antidepressant in treatment-resistant depression (TRANSFORM-2). Am J Psychiatry, 2019
  14. Daly EJ, et al. Esketamine nasal spray plus oral antidepressant for relapse prevention in treatment-resistant depression (SUSTAIN-1). JAMA Psychiatry, 2019
  15. Cuijpers P, et al. Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis. World Psychiatry, 2014
  16. Cuijpers P, et al. A network meta-analysis of psychotherapies, pharmacotherapies and their combination in adult depression. World Psychiatry, 2020
  17. Zhdanava M, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry, 2021
  18. Batastini AB, et al. Are videoconferenced mental and behavioral health services just as good as in-person? A meta-analysis. Clin Psychol Rev, 2021
  19. Fernandez E, et al. Live psychotherapy by video versus in-person: a meta-analysis of efficacy. Clin Psychol Psychother, 2021

Want to talk through the science with a provider?

Our psychiatric providers are happy to walk you through the research behind your treatment options during a free 15-minute consultation, no obligation, no pressure.