History & evidence: where these treatments came from

Words first: “cleared” is not “approved”

Most TMS devices reached the U.S. market by FDA clearance (the 510(k) or De Novo pathways, which judge a device against safety and performance standards). Spravato, a drug, went through FDA approval. Marketing often blurs the two; this library does not.

TMS — from a twitching thumb to a depression treatment

• The physics: Michael Faraday described electromagnetic induction in 1831 — a changing magnetic field creates an electric current. That principle is the whole engine of TMS.
• 1959–1980: Kolin and colleagues stimulated nerves magnetically; Merton and Morton stimulated the human cortex electrically in 1980 — effective, but painful.
• 1985 — the founding paper: Anthony Barker, Reza Jalinous, and Ian Freeston at Sheffield published non-invasive magnetic stimulation of the human motor cortex in The Lancet. A coil on the scalp made a thumb twitch, without electrodes or pain. Modern TMS starts here.
• 1995–1996 — into psychiatry: Mark George and colleagues reported daily left-prefrontal repetitive TMS for depression (1995); Alvaro Pascual-Leone and colleagues followed with controlled work in The Lancet (1996). Wassermann's 1998 safety guidelines, from a 1996 NIH workshop, set the field's safety frame.
• 2005 — theta burst: Ying-Zu Huang and colleagues described theta-burst stimulation. The THREE-D trial (Blumberger et al., The Lancet, 2018) later showed intermittent theta-burst (iTBS) was non-inferior to standard 10 Hz treatment — in about 3 minutes a session instead of about 37.
• Deep TMS: Abraham Zangen, Yiftach Roth, and Mark Hallett developed the H-coil, which reaches deeper structures. Levkovitz et al. (2015, n=212) was the pivotal depression trial; Carmi et al. (2019) the OCD trial; Zangen et al. (2021) the smoking trial.
• 2007–2010 — the trials behind clearance: O'Reardon et al. (2007, n=301) was the NeuroStar registration trial. The NIMH-funded OPT-TMS trial (George et al., 2010) — independent of any manufacturer — found remission in 14.1% on active treatment versus 5.1% on sham. Honest numbers, and worth knowing: TMS helps a meaningful share of people whose depression resisted medicine; it does not help everyone.
• SAINT / SNT: Nolan Williams's Stanford group (Cole et al., 2020 and 2022) built an accelerated, MRI-targeted protocol — many sessions a day over 5 days — cleared for treatment-resistant depression.

FDA timeline — TMS

Spravato — from a 1962 anesthetic to a nasal spray

• There is no single inventor of Spravato. Anyone who names one person is selling a story. Here is the true shape of it:
• 1962: Calvin Stevens at Parke-Davis synthesized ketamine. First human studies followed in 1964 (Domino and Corssen), showing dissociative anesthesia; it was patented in 1966 as Ketalar.
• 2000: Robert Berman and colleagues at Yale published the first randomized trial of ketamine for depression (n=7) — improvement within 72 hours, at a time when every antidepressant took weeks.
• 2006: Carlos Zarate and colleagues at NIMH (n=18, treatment-resistant depression) found improvement within 110 minutes, with 71% response and 29% remission at 24 hours.
• The Janssen program: esketamine — the S-enantiomer of ketamine, with stronger NMDA-receptor potency — was developed as an intranasal spray by a Janssen R&D team including Ella Daly, Jaskaran Singh, Husseini Manji, Wayne Drevets, Maggie Fedgchin, Carla Canuso, and David Hough. Singh et al. (2016) showed IV esketamine worked in TRD; Daly et al. (2018) showed the intranasal dose-response.

The pivotal trials — including the one that missed

• TRANSFORM-1 (Fedgchin et al., 2019, n=346): a fixed-dose pivotal trial that did not reach statistical significance at week 4. It belongs in any honest account.
• TRANSFORM-2 (Popova et al., 2019): flexible-dose, positive — about a 4-point greater MADRS improvement than placebo spray at day 28.
• TRANSFORM-3 (Ochs-Ross et al., 2020): in older adults, no significant difference. Also part of the record.
• SUSTAIN-1 (Daly et al., 2019): relapse prevention — patients who had responded stayed well longer on continued Spravato than on placebo spray.
• ASPIRE I & II (2020–2021): rapid reduction of depressive symptoms at 24 hours in patients with acute suicidal ideation or behavior. The FDA did not find suicide prevention demonstrated — that limitation is on the label to this day.
• ESCAPE-TRD (Reif et al., NEJM, 2023) and independent reviews, including the critical counterweight by Gastaldon et al. (2020), continue the argument in the open literature — which is how medicine is supposed to work.

FDA timeline — Spravato

Read the full dossiers — every paper, with citations — on the Videos & FAQ page.