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After Prozac: The New and Emerging Treatments (Part II)*

By Walter Donway

September 23, 2025

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Treatments range from novel drugs that act on entirely different brain systems (like glutamate receptors) to device-based brain stimulation and even the controlled use of psychedelic drugs in psychotherapy.

  1. Ketamine

In the lead right now, it seems, is the discovery of ketamine’s antidepressant effect. Ketamine, long used as an anesthetic, is an NMDA receptor antagonist (affecting the brain’s glutamate system). Unlike SSRIs, which take weeks, ketamine can relieve depressive symptoms within hours in some patients. In the 2000s, studies found that a single low-dose intravenous ketamine infusion often produced a rapid reduction in suicidal thoughts and depression severity in patients with TRD. The effect from one dose, of course, is temporary (peaking at 24–48 hours later and lasting about a week), but repeated infusions have shown robust results in clinical trials.

In the lead right now, it seems, is the discovery of ketamine’s antidepressant effect.

A 2023 trial of more than 400 patients (large) with non-psychotic TRD found that 55% of those receiving ketamine infusions achieved at least 50% symptom improvement (versus 41% with ECT) over a 3-week course.

In this head-to-head comparison, ketamine was deemed non-inferior to ECT for TRD–a remarkable finding (or concession) given ECT’s status. What is more, patients treated with ketamine reported fewer adverse effects (no memory loss and only transient dissociative experiences during infusions). Other studies report similar response rates around 50%–70 % for ketamine in TRD, with some patients achieving full remission, at least for a time. And, often important, ketamine works fast, helping patients within days who may have suffered for months or years.

With this evidence, the FDA approved esketamine (Spravato) in 2019, a nasal spray form of ketamine, specifically for treatment-resistant depression. Esketamine is administered in clinics under supervision (typically weekly or biweekly), combined with an oral antidepressant. Trials of this combination suggest that it can roughly double the likelihood of remission compared to placebo in TRD patients. In one long-term study, about 46% of patients were in remission after an optimization/maintenance phase on esketamine, a substantial figure for this difficult population.

Thus, esketamine became the first novel antidepressant mechanism approved in decades and validated the glutamate pathway as a target. Patients who have tried numerous SSRIs with no success have responded to esketamine—again, some within a day or two of the first dose. As with IV ketamine, common side effects include brief dissociation, dizziness, and potential blood pressure spikes, but serious adverse reactions are rare. For now, the chief limitation is that esketamine is expensive, and the regular doses must be administered in a clinic for safety monitoring.

Ketamine/esketamine represents one of the biggest advances since Prozac, addressing a critical unmet need in psychiatry. Optimistically, ketamine-type therapies have been hailed as a new era in depression treatment because of the rapidity of acute relief for suicidal patients and others, who can receive ketamine and often feel markedly better by the next day. Also benefiting are many who don’t do well on monoamine-based antidepressants. Next steps will probably be prolonging ketamine’s effects (through maintenance infusions or combining with therapy) and testing to see if other glutamate modulators can replicate its benefits with fewer logistics (e.g., hospital or clinic visits).

 

  1. Transcranial Magnetic Stimulation (TMS)

Repetitive TMS (rTMS), a noninvasive brain stimulation technique for TRD, came on the scene in the late 1990s, and in 2008 won FDA approval for use with depression. It uses magnetic pulses to the left prefrontal cortex, a region implicated in mood regulation, to stimulate brain circuits. A typical course of treatment is daily sessions for 4–6 weeks. TMS does not require anesthesia; patients remain awake, and aside from mild scalp discomfort or headache, it has few side effects (no systemic effects as medications do).

Its results have not been as dramatic as those achieved with ECT, but it has been efficacious in treating TRD. A 2023 meta-analysis of clinical trials found that active TMS was about 2–3 times more likely to lead to remission than placebo treatment​. Some 36% of patients achieved remission with TMS (vs ~8% with placebo) and ~40% had a significant response (≥50% improvement)​. These outcomes may be viewed as moderate, but they mean that roughly one in three truly resistant patients can get well with TMS even after failing multiple medications–a very meaningful result for those individuals. TMS is also cumulative and durable: some patients who respond maintain their improvement for many months, and periodic maintenance TMS can prolong the benefits.

Research has focused on refining TMS to improve its impact.

One innovation is Theta Burst Stimulation (TBS), a faster treatment (as short as 3 minutes per session) that delivers bursts of stimulation patterned after brain theta rhythms. Intermittent TBS has shown similar efficacy to standard 37-minute TMS sessions, potentially making TMS far more convenient. Another breakthrough is the concept of accelerated TMS: giving multiple TMS sessions per day over a shorter span. A notable study at Stanford used an accelerated TMS protocol combined with MRI-guided targeting (termed SAINT) and achieved 79% remission in 5 days among severely depressed patients—an unprecedented result in a small trial. Even as experiments continue, this suggests that intensifying the dose of TMS could approach ECT-like efficacy without the need for anesthesia or seizures. And it appeals to those hesitant about ECT. One approach to increasing its effectiveness might be combining TMS with psychotherapy for synergistic effects.

 

  1. Psychedelic-Assisted Therapy

Recent years have seen a resurgence of interest in psychedelic-assisted therapy for depression. Classic psychedelics like psilocybin (the active compound in “magic mushrooms”) and LSD were studied for mental health in the mid-20th century, then banned. Now, controlled clinical trials are revisiting their potential when paired with psychotherapy. The premise is that the guided use of psychedelics can induce profound psychological experiences that may open a pathway to changes in mood, perspective, and brain connectivity.

Early reports are promising, especially the use of psilocybin for major depressive disorder. In controlled studies, patients with major depression or TRD received 1–2 supervised sessions with a high dose of psilocybin, embedded within a supportive therapeutic framework (prior preparatory therapy and later integrative therapy). A Johns Hopkins trial reported that two psilocybin sessions led to large decreases in depression severity, with 71% of participants showing a clinically significant response and about half meeting remission criteria at 4 weeks post-treatment. The depression of many participants stayed in remission for six months to a year after the single intervention.

The benefit may be sustained long after the psychedelic experience because therapy helps the patient process insights and solidify changes in outlook.

The hypothesis is that the benefit may be sustained long after the psychedelic experience because therapy helps the patient process insights and solidify changes in outlook. Another major study in 2022 found that a single 25-mg dose of psilocybin led to significantly greater improvement in TRD patients at 3 weeks compared to a placebo dose. But many participants relapsed by 3 months, indicating that more sessions or ongoing therapy may be needed. As of 2025, psilocybin has not been approved by the FDA for depression, but it has attained a “Breakthrough Therapy” designation, and phase 3 trials are underway.

Many will ask how psychedelics can help depression. Research suggests that psilocybin and similar agents boost neural plasticity and temporarily quiet the brain’s rigid habitual patterns (such as the self-critical ruminations in depression), giving people a chance to reconceptualize themselves and their pain. Patients often describe to their therapists a deep sense of connection, emotional release, and new perspective on life experiences that therapy may help to parlay into improved mood and coping. It is a model very different from the daily dose of SSRI to adjust serotonin levels; it seems instead akin to a therapeutic catalyst or one-time “reset” for the brain. Advocates, while conceding that the approach is still experimental, see huge promise for major depression, end-of-life distress, and other conditions. It exemplifies how far depression treatment has moved beyond traditional pharmacology.

 

  1. Other Innovative Approaches in Brief

(1) Implanted devices for deep-brain stimulation (DBS) (already common in treating Parkinson’s disease) are being tried with severely depressed patients. This involves surgically placing electrodes in specific brain regions such as the subcallosal cingulate cortex, sometimes called Brodmann Area 25, a region found to be overactive in deep depression, to modulate neural activity. Early studies had dramatic results in small samples, but a major trial in 2014 failed to show benefit over placebo. New personalized approaches to DBS (tuning the stimulation to individual brain activity patterns) are now being tested, keeping this avenue alive for ultra-resistant depression.

(2) Vagus Nerve Stimulation (VNS) also involves an implant, a pacemaker-like device in the chest, that periodically stimulates the vagus nerve. It was FDA-approved (under specific protocols) for chronic depression that hasn’t responded to at least four treatments. VNS can take months to impact mood and has had mixed results, but some patients do report long-term improvement. The need for surgery and modest evidence of benefit have kept its use limited.

(3) New medications (other than ketamine/esketamine) with novel action have emerged. In 2019, brexanolone (Zulresso), a neurosteroid that modulates GABA receptors, was approved for postpartum depression. It is notable for being a hormone-based approach; it’s an analog of allopregnanolone, levels of which decline after childbirth. Brexanolone is given as a 60-hour infusion and can bring rapid relief in severe postpartum cases. An oral form (zuranolone) for both postpartum and major depression was under development and in 2023 was approved for postpartum depression but not yet for major depression. These drugs raise the possibility of targeting the brain’s stress-hormone systems in depression. There are still other compounds like D-cycloserine and Scopolamine that affect novel targets and show antidepressant effects in research. None is yet mainstream.

(4) Enhanced psychotherapy models are a final field of innovation. Among new therapy frameworks being tried for chronic depression are the Cognitive Behavioral Analysis System of Psychotherapy (CBASP), tailored for persistent depression, and integrative approaches that blend medication, therapy, and rehabilitation in structured programs. Not surprisingly, there is new interest in digital therapeutics (online CBT programs, apps) to extend access and lifestyle interventions (exercise, sleep therapy, diet) that have modest but real effects on depression outcomes. These holistic strategies acknowledge depressive illnesses multifaceted nature.

Recent statistics show that rates of depression have not diminished; if anything, they have risen, especially among young people.

In recent years, the success of ketamine and the magnitude of unmet need, with rising depression rates and a perceived global mental health crisis, have led both industry and public agencies to ramp up efforts again. Small biotech companies are jumping into the field, and NIH initiatives on depression treatment as suicide prevention have increased. Perhaps a consensus has emerged that more than three decades of SSRIs have left millions still suffering, refocusing attention on innovation in the last decade.

Indeed, recent statistics show that rates of depression have not diminished; if anything, they have risen, especially among young people. The National Survey on Drug Use and Health reports that 21 million U.S. adults (8.3%) experienced a major depressive episode in 2021. More than half (5.7%) had a major depression episode classified as severe, causing significant impairment—the kind of debilitating depression that often requires intensive treatment.

 

A Few Demographic Patterns

Depression is disproportionately affecting young Americans. The highest prevalence is in the 18–25-year-old age group, where 18.6% (almost 1 in 5) experienced a depressive episode in 2021. This is more than twice the rate in people over 50 (around 4–5%). Even adolescents have alarmingly high rates. Some 20% of teenagers (ages 12–17) had a depressive episode in 2021, and among girls, the figure was 29%. This is enough to merit the label “youth mental health crisis.” And between 2015 and 2019, depression prevalence also increased fastest among adolescents and young adults, while remaining relatively unchanged in those over 35. For example, among 18–25-year-olds, the recent depression rate climbed from about 10% in 2015 to 15.5% in 2019 and reached 17.2% by 2020 (predating the COVID-19 pandemic, which exacerbated it).

Depression affects women about twice as often as men. In 2021, 10.3% of adult females had a depressive episode versus 6.2% of males. This gender gap seems to begin with teen girls and persists across the lifespan. Potential reasons include biological factors (hormonal fluctuations, etc.), as well as greater social pressures and a higher likelihood of seeking help (hence being counted in the statistics) among women. Men underreport depression or mask it with substance use, so the true gap might be narrower.

Dr. Jean Twenge, professor of psychology at San Diego State University, says, “For the sudden increase in depression—the excess cases after 2012—the changes wrought by technology are a prime culprit. Nothing else changed so much in teens’ lives during that time.” She found that in the United States, 1 in 5 teenage girls is on social media seven hours a day, and comments that “research found that Instagram contributed to body image and mental health issues among teens, especially girls. Social media isn’t just about communicating with friends. The apps use algorithms to serve up content and keep people using them as long as possible, as frequently as possible.”

Rates of reported depression vary by race/ethnicity, though some differences may reflect disparities in diagnosis or willingness to report. The…data show the highest prevalence among individuals who identify with multiple races (13.9%), followed by Native American/Alaska Natives (11.2%). In white adults, the prevalence is around 8.9%, Hispanics 7.9%, Blacks 6.7%, and Asian Americans the lowest at 4.8%. However, other studies note that when adjusted for socioeconomic factors, minority groups have a similar if not greater depression burden, and they often have less access to treatment.

Depression is interactive with economic and social stress. Poverty, unemployment, and low education are risk factors. Surveys have found higher depression prevalence among those with lower income and those who are not currently married​ (and deemed “socially isolated”). The national economic burden of major depressive disorder among US adults was an estimated $236 billion in 2018.

If there is a positive trend, it is in treatment. More people are receiving it than in decades past—in 2021, about 61% of adults with a major depressive episode received some form of treatment (mostly counseling or medication). Among those with severe depression, the treatment rate rose to 75%. This implies, of course, that a substantial minority, especially of those with less severe depression, did not get care. Nor has seeking help kept up with the climbing depression rates; from 2015 to 2019, help-seeking did not increase commensurately. It is called the “treatment gap,” and the human reality is that individuals struggling with depression are not getting help because of stigma, cost, shortages of mental health providers, and a simple lack of awareness.

A trend to ponder is that in the early 1990s, before the Prozac boom, the estimated 12-month prevalence of major depression in the U.S. was 5–6%. Today, the figure is 8–9%. The measure is rough, but it strongly suggests that depression is more common now, not less. Genuinely higher occurrence or better survey methods? Reduced stigma in reporting? Much more measurable are suicide rates, a “lagging indicator” of severe depression, and unfortunately, they have increased in the United States from 2000 until about 2018–2019 before the complex influence of the pandemic kicked in. All this underlines that depression remains an epidemic of its own.

 

Not a “Silver Bullet”—Maybe A Historic Catalyst

Three decades after Prozac, we have no single cure, but we do have a growing arsenal of treatments, tailored to a complex illness. The revolution, perhaps, was not Prozac itself, but that it sparked a wider confrontation with depression’s depth and diversity. There is at least one clear message, and it is that depression is a stubborn illness. Prozac turned out not to be the single “magic bullet” that cures everyone. And so far, there is no sign of one. Progress has been incremental, with each new treatment helping a subset of patients or dealing with a particular need (faster action, fewer side effects). Treating depression has become correspondingly more personalized, combining medication, psychotherapy, lifestyle changes, and possibly neuromodulation.

Three decades after Prozac, we have no single cure, but we do have a growing arsenal of treatments.

Thanks perhaps to new perspectives, economic incentives, and public openness to the subject of depression, mostly since Prozac, someone in 2025 with severe, bedbound depression has multiple options backed by substantial evidence of efficacy. The most important gain, because it has begun to relieve profound human suffering, is the improvement of tools for the hardest cases of TRD. The test a decade from now will be if the incidence of depression, as indicated by suicide rates, work absences, and relative medical costs, has declined.

 

 

*The content of this article is for information or education only and is not medical advice or a substitute for professional medical advice, diagnosis, or treatment. Readers should consult a qualified healthcare provider for personal health questions and never delay professional medical help due to information read online.

 

This is part two of a two-part article.

 

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