CGPR: Welcome, Dr. Espí Forcén. Tell us about your work in treatment-resistant depression (TRD).
Dr. Espí Forcén: I work at McLean Hospital’s Depression Residential Treatment Program, where we focus on second-line treatments and second-opinion psychopharmacology. My research interests include psychedelic-assisted psychotherapy and accelerated transcranial magnetic stimulation (TMS) using functional MRI for personalized targeting, similar to the SAINT protocol, which delivers multiple sessions in a few days for faster antidepressant effects.

CGPR: Let’s start with psychedelics. Is there any role for psychedelics like psilocybin in geriatric psychiatry?
Dr. Espí Forcén: Psilocybin is a classical psychedelic, naturally found in certain mushrooms. It’s often described as an entheogen, a substance that can induce mystical states of consciousness. It differs from ketamine, which is classified as a dissociative psychedelic. Psilocybin can produce ego disintegration, altered consciousness, and vivid visuals—which may support psychological healing and insight. Although psilocybin is considered one of the safer substances in pharmacology, older adults have been largely underrepresented in research. A recent systematic review found that of 1,400 study participants, only 19 were identified as 65+ (Bouchet L et al, J Psychopharmacol 2024;38(1):33–48). Despite this, psilocybin has been used safely in cancer patients, including in hospice, with minimal side effects (eg, temporary nausea, headache, elevated blood pressure). Some older adults report using psilocybin in community settings without serious medical issues. Psilocybin is legal or decriminalized in several regions. While its effectiveness for TRD in older adults is uncertain, some argue that older adults may be better equipped to handle the psychological experience. Given its favorable safety profile, a less conservative approach to psilocybin use in older adults may be reasonable.

CGPR: What do you tell patients interested in trying psilocybin? 
Dr. Espí Forcén: I tell patients the safest option is a clinical trial, which is usually free, though some worry about randomization to low doses or placebo. For legal, structured US experiences, Oregon or Colorado retreats offer guided sessions (~$600–$1,000). Travel options include Jamaica retreats with American therapists (~$3,000) or Australia’s psilocybin-assisted psychotherapy (~$20,000). Indigenous ceremonies in Colombia or Peru use ayahuasca or psilocybin, though they lack medical supervision and pose higher risks for older adults. Ayahuasca may be available under religious exemptions in some countries. Some patients consider decriminalized areas where possession isn’t prosecuted, but it is technically illegal without medical oversight, so I can’t recommend this approach.

CGPR: What’s the evidence for TMS in older adults?
Dr. Espí Forcén: Traditional “focal” TMS uses a figure-8 coil to stimulate 1–2 centimeters beneath the skull. It often underperforms, as age-related brain atrophy limits how much stimulation reaches the cortex. Deep TMS with an H-coil reaches 4–5 centimeters into broader mood circuits and is more promising, though it is usually only found in specialized or academic centers (Roth Y et al, J Clin Med 2024;13(3):816). 

CGPR: How about accelerated protocols like SAINT for older adults?
Dr. Espí Forcén: Accelerated protocols deliver multiple sessions over five days instead of the usual four- to six-week course. They haven’t been studied much in older adults; trial participants were in their mid-40s on average. At McLean Hospital’s self-pay program, older adults—including those with comorbidities or mild cognitive changes—responded well. About half improve within five days. Early gains sometimes reflect nonspecific factors (eg, more clinician contact, changes in routine), but real-world response rates approach the 70% seen in younger adults by 30 days. Some patients need maintenance sessions to sustain remission, but overall, accelerated TMS can be a fast, effective option.

CGPR: Assuming finances are not an issue, how do you determine which patients are good candidates for treatments beyond antidepressants?
Dr. Espí Forcén: In practice, most patients with depression can be considered. Insurance usually requires failure of two to four antidepressant trials before covering TMS, but clinically I see it as an excellent first-line treatment. If I became depressed and could pay out of pocket, I’d choose TMS due to its favorable side effect profile. I’m also comfortable recommending it for patients who haven’t tried medications if they can self-pay. Side effects are minimal, usually mild headache, and seizures are extremely rare, only occurring in 1 in 30,000 treatments (McClintock SM et al, J Clin Psychiatry 2018;79(1):16cs10905). TMS promotes neuroplasticity without withdrawal or dependence. Ketamine is another option. It works rapidly and can be psychologically engaging, especially when combined with psychotherapy to help patients process the experience. But it may not be appropriate for patients with serious medical comorbidities or a history of substance use. For severe depression, ECT remains the most effective, but it requires anesthesia and multiple treatments over several weeks (Steffens DC, N Engl J Med 2024;390(7):630–639). 

CGPR: How does ketamine compare to ECT, and can it be added during ECT? 
Dr. Espí Forcén: It might seem logical to use ketamine for anesthesia during ECT, but the anesthetic dose differs from the 0.5 mg/kg used for depression, and older adults often tolerate it poorly. There’s no strong evidence that combining ECT with ketamine improves outcomes. One study suggested ketamine is non-inferior to ECT, but meta-analyses show ECT is more effective overall (Anand A et al, N Engl J Med 2023;388(25):2315–2325; Menon V et al, JAMA Psychiatry 2023;80(6):639–642). 

“In our clinic, over half of those who started esketamine needed ongoing doses monthly or every other month. This pattern is similar to what we see with SSRIs: Patients improve, try to stop, and then relapse or experience discontinuation symptoms. That raises questions—is it relapse, dependence, or tachyphylaxis? Is the brain adapting to the drug? With esketamine, I see this chronic pattern more often than with TMS or psilocybin.”

Fernando Espí Forcén, MD

CGPR: What about combining TMS with ketamine or using accelerated TMS instead of ECT?
Dr. Espí Forcén: Data on combining TMS and ketamine are limited to case reports and a few open-label studies. A recent pilot study found that adding ketamine to TMS didn’t meaningfully improve outcomes over TMS alone (Shanok NA et al, Psychopharmacology (Ber) 2024;241(7):1427–1433). No randomized trials have compared TMS plus ketamine to TMS alone. Researchers are now exploring N-methyl-D-aspartate receptor agonists like D-cycloserine, which may enhance TMS response. Accelerated TMS hasn’t been compared head-to-head with ECT, but it offers a faster, less invasive option for many patients.

CGPR: How long do the benefits of TMS usually last?
Dr. Espí Forcén: After accelerated TMS, improvement continues for about a month, then stabilizes. Officially, the benefit can last six months, but we’re starting to see some patients decline after three months, so we say the range is three to six months. I explain it to patients like charging a battery: We can jump-start it, but if you leave the car parked in the garage, it’ll die again. Patients can keep the engine running by staying active, engaging in psychotherapy, and returning to activities that were difficult during depression. Even with good follow-through, depression can still relapse, but these steps help reduce the risk. Regular TMS works similarly, but the course is spread over two months. Sometimes we apply a second round or deliver maintenance sessions twice a week if insurance allows.

CGPR: Can you speak about using esketamine in older adults?
Dr. Espí Forcén: Esketamine is an intranasal formulation of one of the enantiomers of ketamine and is FDA approved for TRD. Data in older adults are mixed. A post-hoc analysis of a retrospective study found that 53% of older adults with TRD treated with esketamine responded, and 33% achieved remission after 3 months (d’Andrea G et al, Am J Geriatr Psychiatry 2023;31(12):1032–1041). But the TRANSFORM-3 RCT found no statistically significant benefit of adding esketamine to an antidepressant in those 65+, though adults aged 65–74 fared somewhat better than those 75+ (Ochs-Ross R et al, Am J Geriatr Psychiatry 2020;28(2):121–141). The large difference in efficacy outcomes likely reflects several factors: inclusion criteria, sample size, and the first study’s retrospective design, which can overestimate effects compared with an RCT.

CGPR: Given those results, when might esketamine make sense for geriatric patients?
Dr. Espí Forcén: It may be reasonable to extrapolate the data for younger-older adults, but I’m more cautious in those over 75. I review the limited evidence with patients and families, especially if there are medical comorbidities. I’d hesitate to use esketamine in patients with respiratory, cardiovascular, or urinary issues, or in those with psychosis, delirium, confusion, or cognitive impairment.

CGPR: How about ketamine for older adults with trauma or PTSD?
Dr. Espí Forcén: In patients with trauma history, ketamine is controversial. The traditional medical model sees it strictly as a pharmacologic agent, with benefits attributed to glutamate modulation. From this perspective, ketamine isn’t recommended for PTSD. There’s limited evidence, and if trauma surfaces during treatment, clinicians may feel unprepared to respond. In contrast, the ketamine-assisted psychotherapy model takes a different view. Here, ketamine can have entheogenic effects, capable of causing mystical experiences or altered states of consciousness. For trauma survivors, these experiences can unmask repressed material. Rather than avoiding this, the psychotherapy model embraces it. The assumption is that depression often coexists with trauma, and for many people, they’re inseparable. If traumatic content emerges, trained therapists use the experience as an opportunity for healing and integration. Research on ketamine-assisted psychotherapy is still early. The traditional medical model has a stronger evidence base, especially regarding symptom reduction in depression. But patients often present with both depression and trauma. For some, combining ketamine with psychotherapy offers a meaningful path forward if the clinical team is prepared.

CGPR: How does the relapse risk with esketamine compare to TMS or psilocybin?
Dr. Espí Forcén: We don’t have robust long-term data for esketamine, but what we see clinically is fast response as well as fast relapse. Many patients end up on chronic treatment. In our clinic, over half of those who started esketamine needed ongoing doses monthly or every other month. We see this with selective serotonin reuptake inhibitors too: Patients improve, try to stop, then relapse or experience discontinuation symptoms. So is it relapse, dependence, or tachyphylaxis? Is the brain adapting to the drug? With esketamine, I see this chronic pattern more often than with TMS or psilocybin. I view it more as a psychopharmacologic agent, and it behaves like one: high relapse risk and ongoing use for many.

CGPR: Why wouldn’t you see much relapse after using psilocybin?
Dr. Espí Forcén: With psilocybin, most people have one or two sessions and feel they don’t need more. Psilocybin seems to trigger neuroplastic changes that support a lasting shift, and many people report they’ve gotten what they needed after just a few experiences.

CGPR: Looking ahead, what excites you most about interventional psychiatry for older adults?
Dr. Espí Forcén: I’m really excited about portable, noninvasive tools like transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS). These use very low electrical currents to modulate brain activity and could one day be delivered in any clinic, or even at home. Accelerated TMS is also advancing fast: Using fMRI, we can target brain regions opposite the anterior cingulate cortex to fine-tune mood circuits and personalize targets for anxiety, OCD, and even Alzheimer’s disease. TMS itself is becoming more flexible and affordable for depression, migraines, and beyond. Deep brain stimulation might eventually offer longer-lasting effects, but for now, it’s still too invasive for routine psychiatric care.

CGPR: Thank you for your time, Dr. Espí Forcén.