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Tag: major depression

  • Plenty of People Could Quit Therapy Right Now

    Plenty of People Could Quit Therapy Right Now

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    About four years ago, a new patient came to see me for a psychiatric consultation because he felt stuck. He’d been in therapy for 15 years, despite the fact that the depression and anxiety that first drove him to seek help had long ago faded. Instead of working on problems related to his symptoms, he and his therapist chatted about his vacations, house renovations, and office gripes. His therapist had become, in effect, an expensive and especially supportive friend. And yet, when I asked if he was considering quitting treatment, he grew hesitant, even anxious. “It’s just baked into my life,” he told me.

    Among those who can afford it, regular psychotherapy is often viewed as a lifelong project, like working out or going to the dentist. Studies suggest that most therapy clients can measure their treatments in months instead of years, but a solid chunk of current and former patients expect therapy to last indefinitely. Therapists and clients alike, along with celebrities and media outlets, have endorsed the idea of going to therapy for extended stretches, or when you’re feeling fine. I’ve seen this myself with friends who are basically healthy and think of having a therapist as somewhat like having a physical trainer. The problem is, some of the most commonly sought versions of psychotherapy are simply not designed for long-term use.

    Therapy comes in many varieties, but they all share a common goal: to eventually end treatment because you feel and function well enough to thrive on your own. Stopping doesn’t even need to be permanent. If you’ve been going to therapy for a long time, and you’re no longer in acute distress, and you have few symptoms that bother you, consider taking a break. You might be pleasantly surprised by how much you learn about yourself.

    Therapy, in both the short and long term, can be life-altering. Short-term therapy tends to be focused on a particular problem, such as a depressed mood or social anxiety. In cognitive behavioral therapy, usually used for depressive and anxiety disorders, a clinician helps a client relieve negative feelings by correcting the distorted beliefs that he has about himself. In dialectical behavior therapy, commonly used to treat borderline personality disorder, patients learn skills to manage powerful emotions, which helps improve their mood and relationships. Both treatments typically last less than a year. If you start to get rusty or feel especially challenged by life events that come your way, you simply return for another brief stint. Termination is expected and normal.

    Some types of therapy, such as psychodynamic therapy and psychoanalysis, are designed to last for several years—but not forever. The main goal of these therapies is much more ambitious than symptom relief; they aim to uncover the unconscious causes of suffering and to change a client’s fundamental character. At least one well-regarded study found that long-term therapy is both highly effective and superior to briefer treatment for people diagnosed with a clinically significant psychiatric illness; other papers have shown less conclusive evidence for long-term therapy. And few studies compare short and extended treatment for clients with milder symptoms.

    In fact, there’s reason to believe that talk therapy in the absence of acute symptoms may sometimes cause harm. Excessive self-focus—easily facilitated in a setting in which you’re literally paying to talk about your feelings—can increase your anxiety, especially when it substitutes for tangible actions. If your neurotic or depressive symptoms are relatively mild (meaning they don’t really interfere with your daily functioning), you might be better served by spending less time in a therapist’s office and more time connecting with friends, pursuing a hobby, or volunteering. Therapists are trained to use the tools they’ve learned for certain types of problems, and many of the stress-inducing minutiae of daily life are not among them. For example, if you mention to your therapist that you’re having trouble being efficient at work, he might decide to teach you a stress-reduction technique, but your colleagues or boss might provide more specific strategies for improving your performance.

    One of my childhood friends, whose parents were both psychoanalysts, went to weekly therapy appointments while we were growing up. He was a happy, energetic kid, but his parents wanted him and his sister to be better acquainted with their inner lives, to help them deal with whatever adversity came their way. My friend and his sister both grew up to be successful adults, but also highly anxious and neurotic ones. I imagine their parents would say the kids would have been worse without the therapy—after all, mental illness ran in their family. But I can find no substantial clinical evidence supporting this kind of “preventive” psychotherapy.

    Beginning therapy in the first place is, to be clear, a privilege. Therapy is not covered by many insurance plans, and a very large number of people who could benefit from it can’t afford it for any duration. Only 47 percent of Americans with a psychiatric illness received any form of treatment in 2021; in fact, federal estimates suggest that the United States is several thousand mental-health professionals short, a gap that is likely to grow in the coming years. Stopping therapy when you’re ready opens up space for others who might need this scarce service more than you do.

    I do not mean to suggest that a therapy vacation should be considered lightly, or that it’s for everyone. If you have a serious mental-health disorder, such as major depression or bipolar disorder, you should discuss with your mental-health provider whether ending therapy is appropriate for your individual situation. (Keep in mind that your therapist might not be ready to quit when you are. Aside from a financial incentive to continue treatment, parting with a charming, low-maintenance patient is not so easy.) My rule of thumb is that you should have minimal to no symptoms of your illness for six months or so before even considering a pause. Should you and your therapist agree that stopping is reasonable, a temporary break with a clear expiration date is ideal. At any time, if you’re feeling worse, you can always go back.

    Psychiatrists do something similar with psychiatric meds: For example, when I prescribe a depressed patient an antidepressant, and then they remain stable and free of symptoms for several years, I usually consider tapering the medication to determine whether it’s still necessary for the patient’s well-being. I would do this only for patients who are at a low risk of relapse—for example, people who’ve had just one or two episodes, rather than many over a lifetime. Pausing therapy should be even less risky: The beautiful thing about therapy is that, unlike a drug, it equips you with new knowledge and skills, which you carry with you when you leave.

    About a year after my patient and I first talked about ending therapy, I ran into him in a café. He told me that stopping had taken him six months, but now he was thriving. Maybe you, like my patient, are daunted by the idea of quitting cold turkey. If so, consider taking a vacation from treatment instead. It might be the perfect way to see how far you’ve really come.

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    Richard A. Friedman

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  • The Future of Mental-Health Drugs Is Trip-Free Psychedelics

    The Future of Mental-Health Drugs Is Trip-Free Psychedelics

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    One of my chronically depressed patients recently found a psychoactive drug that works for him after decades of searching. He took some psilocybin from a friend and experienced what he deemed a miraculous improvement in his mood. “It was like taking off a dark pair of sunglasses,” he told me in a therapy session. “Everything suddenly seemed brighter.” The trip, he said, gave him new insight into his troubled relationships with his grown children and even made him feel connected to strangers.

    I don’t doubt my patient’s improvement—his anxiety, world-weariness, and self-doubt seemed to have evaporated within hours of taking psilocybin, an effect that has continued for at least three months. But I’m not convinced that his brief, oceanic experience was the source of the magic. In fact, some neuroscientists now believe that the transcendent, reality-warping trip is just a side effect of psychedelics—one that isn’t sufficient or even necessary to produce the mental-health benefits the drugs seem to provide.

    For several years, researchers have understood that the hallucinatory effects of psychedelics can, in theory, be separated from the other ways the drugs affect our mental state and brain structure. But until recently, they have not been able to design a psychedelic that reliably produces only the neurocognitive effects and not the hallucinatory ones. That may soon change. A new generation of nonhallucinogenic psychedelics, at least one of which is currently being tested in humans, aims to provide all of the mental-health benefits of LSD, psilocybin, or Ecstasy without the trip. Trip-free psychedelics would be a great therapeutic boon, dramatically expanding the number of people who can experience the benefits of these drugs. They might also shed new light on how much psychedelics can alleviate psychic distress—and why they do so at all.

    Over the past five years, studies have demonstrated that psilocybin has powerful antidepressant effects, and that MDMA (a.k.a. Ecstasy), in conjunction with psychotherapy, can relieve the symptoms of PTSD. Remarkably, just a few doses of either psilocybin or MDMA can produce a rapid, lasting improvement in depression and anxiety symptoms, meaning symptom relief within minutes or hours that lasts up to 12 weeks. (MDMA is what psychiatrists call an “atypical psychedelic”; it has a mix of psychedelic-like and amphetamine-like effects, producing a feeling of bliss rather than a transcendent or mystical state.) The FDA is widely expected to approve MDMA for supervised use sometime in 2024—an extraordinary turnabout for drugs that have long been stigmatized for their potential (if rare) serious harms.

    From a clinical perspective, this psychedelic revolution is potentially miraculous. An estimated 23 percent of Americans have a mental illness, and a considerable number of them, like my patient, don’t get sufficient relief from therapy or existing medications. Drugs like psilocybin, ayahuasca, and LSD could help many of these patients—but others won’t be able to tolerate the trip. (By “trip,” I mean the variety of altered mental states that psychedelic drugs can cause, such as the transcendence and mystical experience of LSD and psilocybin, and the bliss and social openness of MDMA.) Drug-induced hallucinations are known to give certain people—like those with psychotic disorders or severe personality disorders—extreme anxiety or even lead to a psychotic break. That’s why clinical trials of psychedelics typically exclude those patients.

    I don’t mean to discount the delight and power of a transcendent hallucination. Many people who’ve tripped on psychedelics describe the experience as among the most meaningful of their life. And in several studies of psilocybin for depression, the intensity of the trip correlates with the magnitude of the therapeutic effect. A trip is an extraordinary, consciousness-expanding experience that can offer the tripper new insight into her life and emotions. It also feels pretty damn good. But it’s far from the only effect the drugs have on the human brain.

    During a trip, psychedelics are silently doing something even more remarkable than warping reality: They are rapidly inducing a state of neuroplasticity, in which the brain can more easily reorganize its structure and function. (Microdosing enthusiasts, who take subtherapeutic doses of drugs like psilocybin, claim to experience enhanced creativity. They may be getting neuroplastic effects without a trip, but as yet, little scientific evidence backs up that idea.) Neuroplasticity enhances learning, memory, and our ability to respond and adapt to our environment—and could be central to the therapeutic effects of psychedelics. In depression, for example, the prefrontal cortex (the brain’s reasoner in chief) loses some of its executive control over the limbic system (the brain’s emotional center). Drugs that enhance neuroplasticity allow new connections to be formed between the regions, which can help reset the relationship and put the prefrontal cortex back in control of emotion.

    Like MDMA, ketamine—the animal tranquilizer, surgical anesthetic, and dissociative party drug that was also approved as a rapidly acting antidepressant in 2019—typically doesn’t produce hallucinations. But it does create a dissociative mental state, and it’s known to make neurons sprout new spines within hours of administration, a structural change that’s been linked with a reduction in depression-related behavior in animals. In humans, ketamine has been shown to boost mood—even if it’s administered when patients are unconscious. Several studies show that patients who receive ketamine during surgery wake up happier than they were before the operation. This suggests that you don’t need to consciously experience the dissociative effects in order to get the antidepressant benefits.

    Scientists are on their way to finding out for sure. For the first time, researchers have purposively developed psychedelic drugs that appear to bring about the neuroplastic effects without producing a trip. These drugs stimulate the same serotonin receptor as traditional psychedelics: 5-HT2A, which, when triggered, causes the brain to produce more of a compound called BDNF, a kind of brain fertilizer that promotes neuronal growth and connectivity. But the nonhallucinogenic versions activate 5-HT2A without leading to a trip. (Binding and activating receptors isn’t an all-or-nothing phenomenon; different drugs can bind the same receptor in different ways, producing very different effects.)

    Some of these trip-free psychedelics are new inventions. Last year, for example, scientists synthesized a new nonhallucinogenic psychedelic by imitating lisuride, an analog of LSD. (An analog is a chemical that is structurally very similar to the original compound, but has been modified to have a different function.) It doesn’t have a name yet—just a serial number, IHCH-7113—but it’s being studied in animals.

    Other trip-free psychedelics have been around for decades, if not recognized as such: 2-Br-LSD, another nonhallucinogenic analog of LSD, was first synthesized in 1957 by the same chemist who created LSD. (It was meant to treat migraine.) Recent experiments show that 2-Br-LSD, like LSD, relieves depressive behavior in mice. But unlike LSD, it doesn’t make the mice twitch their heads—a sign that a substance will give humans hallucinations and other psychotic symptoms. More than 60 years after 2-Br-LSD’s invention, the Canadian company BetterLife Pharma is planning to study it as a treatment for major depression and anxiety.

    LSD isn’t the only psychedelic inspiring imitators. Delix Therapeutics, a biotech company based in Boston, is using animal models to study tabernanthalog, which is an analog of the active psychedelic in ibogaine. Tabernanthalog has acute antidepressant and neuroplastic effects in animal models, and, like 2-Br-LSD, it doesn’t cause head twitching. Delix is also testing a drug that it’s calling DLX-1, which David Olson, one of Delix’s co-founders, told me is the first nonhallucinogenic psychedelic to be tested in humans; Phase 1 studies, he said, are nearly completed. Olson, who is also the director of the Institute for Psychedelics and Neurotherapeutics at UC Davis, calls the drugs he works on “psychoplastogens,” for their rapid neuroplasticity-inducing effects. He said that other nonhallucinogenic psychoplastogens that the company is working on are “close to entering clinical trials,” though how soon any of them might reach the market is unclear.

    As of yet, the federal government has provided little funding for nonhallucinogenic-psychedelics research. Delix and other makers of these new psychedelics will have to submit an application to the FDA to get their drug approved, which generally requires that the new drug beats a placebo control in two randomized clinical trials. This can be a slow process, but the FDA can expedite it by designating the drug a “breakthrough therapy,” which is exactly what it did in 2018 with psilocybin.

    In clinical trials, nontrip psychedelics will have at least one major advantage over their trip-inducing analogs: They can more easily be placebo-tested. Classic psychedelic research has been bedeviled by the simple fact that it is virtually impossible not to know that you are taking a classic psychedelic. Indeed, in clinical trials of MDMA and psilocybin, more than 90 percent of subjects who received the treatment correctly guessed that the drug they were given was real. This sort of defeats the purpose of placebo-testing psychedelics at all, because participants who receive the real drugs will expect to feel better. But the new nontrip psychedelics don’t produce the transcendent mental states that tend to “unblind” research subjects. They might produce more typical drug side effects, such as dry mouth or sedation, but that’s a far cry from a mystical experience.

    Nontrip psychedelics may also have it easier with respect to regulation. If they don’t make you high or produce a transcendent state, they’ll likely have little appeal as recreational drugs. The Drug Enforcement Administration classifies LSD and psilocybin as Schedule I drugs, which makes them difficult for researchers to study and doctors to prescribe. Even ketamine is Schedule III and must be administered in a medical setting, which may be inconvenient for patients. Perhaps the DEA will take more kindly to nontrip psychedelics; if so, they’d be easier to access for patients and researchers alike. Plus, nonhallucinogenic psychedelics would not require the time and expense of a guide to monitor the experience. All said, the nontrip psychedelics might end up being a more popular, better-researched choice than traditional ones.

    If the FDA really does approve MDMA next year, psychiatrists will have plenty of reason to celebrate. But I suspect that the future of psychedelic medicine will lean toward the wonder of pure neuroplastic potential and away from transcendence. Psychedelic trips will probably never disappear from society—for one thing, they are viewed as essential to some religious and cultural rituals. But perhaps they’ll come to be seen as less like therapy, and more like good old-fashioned fun.

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    Richard A. Friedman

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  • Advances in Treatment for Major Depressive Disorder

    Advances in Treatment for Major Depressive Disorder

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    Major depressive disorder is the most widespread mood disorder in the world. Also called clinical depression, or just depression, it’s when you have symptoms of low mood or hopelessness for at least 2 weeks. Scientists still don’t know what causes it. But they know that treating it is complex and that people who have it need more ways to feel better faster.

    For about half a century, scientists have put a lot of effort into improving medications that target a small set of neurotransmitters. Those are chemicals in the brain — serotonin, norepinephrine, and dopamine in particular — that affect how your nerve cells talk to each other, which then affects your mood.

    Most people respond to standard antidepressants. But at least 30% of people who try two different kinds of these drugs continue to have symptoms of depression. That’s called treatment-resistant depression.

    So, over the past 2 decades, scientists have changed how they think about treatment for major depressive disorder as their understanding of the brain biology behind depression has changed.

    The biggest change is that medication research has gone past only targeting certain neurotransmitters, says Gerard Sanacora, MD, PhD, director of the Yale Depression Research Program in New Haven, CT. “We’ve opened up a whole new vista of potential targets for new drugs.” 

    New Medications and Faster Results

    There’s a long-held idea that depression takes weeks or months to resolve. But new fast-acting treatments have “changed what we think is possible in the field,” Sanacora says.   

    In 2019, the FDA approved brexanolone (Zulresso). It’s the first drug specifically for postpartum depression, which is a type of major depression. Experts aren’t exactly sure how it works. But it’s a human-made version of a steroid your body makes naturally. It affects your GABA receptors, which help regulate mood.

    Brexanolone isn’t as easy to take as other antidepressants. You get it through a vein in your arm at a health care facility over the course of 60 hours. But it can work quickly. Your depression symptoms might start to lift by the end of your treatment.

    Another breakthrough drug came out that same year.     

    Esketamine is a prescription nasal spray. The low-dose psychedelic drug boosts the activity of glutamate in parts of your brain related to mood. Glutamate’s job is to excite cells in the brain and nervous system. Esketamine can trigger new connections in your brain too. You may start to see improvements in your depression within hours or days of using it, Sanacora says.

    Esketamine offers lifesaving hope for people with suicidal thoughts and relief for people with treatment-resistant depression. But used alone, symptom relief may only last a couple of weeks. That’s why experts agree you should take rapid-onset drugs alongside traditional treatments.

    As for those with mild or moderate depression, Sanacora still first suggests cognitive behavioral therapy, followed by conventional antidepressants also known as selective serotonin reuptake inhibitors (SSRIs). Doctors need more information on the safety and long-term effects of newer treatments for depression.

    “Over the past 20 years, we’ve had a transformative change in the way we treat depression,” Sanacora says. “But we still have to smooth it out to understand for which patients these treatments are best and when.”

    Improvements in Brain Stimulation

    Medications aren’t the only treatment for depression. Electroconvulsive therapy has been around for more than 70 years. It remains one of the most effective ways to manage major depressive disorder, especially if you don’t respond to other treatments. While it isn’t new, scientists have fine-tuned the procedure over the past decades.

    Today, electroconvulsive therapy uses less energy than it did in the past. The goal is to give you the same benefits but with less negative impact on your memory and thinking skills. “That’s been a huge improvement,” says Susan Conroy, MD, PhD, a psychiatrist and neuroscientist at Indiana University School of Medicine.

    Conroy also uses transcranial magnetic stimulation to treat depression, which has fewer side effects than electroconvulsive therapy. It works by sending magnetic pulses around your skull.

    Brain tissue translates these signals into electrical energy, Conroy says, which changes the way areas of your brain talk to each other. “By changing that circuitry, we think that’s how transcranial magnetic stimulation gets people better from depression.”

    These and other forms of brain stimulation aren’t right for everyone. But tell your doctor if other treatments don’t help and your depression keeps you from doing daily activities, you aren’t eating, and you have constant suicidal thoughts.

    “These are all signs your treatment needs to be escalated and pretty quickly,” Conroy says.

    Future Treatment

    Lots of other promising treatments for depression are on the horizon. Deep brain stimulation is one. In this treatment, a surgeon implants electrodes in your brain. These nodes send painless zaps that alter the electrical activity that’s causing your symptoms.

    You can think of this treatment kind of like a pacemaker for your mood. While it’s not approved for the general public, it might be soon. “Technology is advancing really quickly,” Conroy says.

    Researchers are also studying a drug called SAGE-217. Sanacora says there’s interest in how it might help prevent a serious relapse in people with a history of depression. The idea is that you’d take it as soon as your symptoms come back. “But you don’t wait until the symptoms are full-blown,” he says.

    There’s also a lot of buzz around drugs like psilocybin. Studies show these “magic mushrooms” can ease depression about as fast as ketamine — what esketamine is made from — with effects that may last longer. But when it comes to psychedelics, Sanacora says, “We need a lot more research before we can say anything with confidence.”

    In his 25 years in the field, Sanacora says he’s never seen such excitement around treatments for depression. But that doesn’t mean researchers have all the answers or that major depressive disorder has a cure.

    Still, you can take steps now to ease depression or guard against a relapse. That might include medication, different kinds of talk therapy, regular exercise, a good social life, and a healthy sleep routine. You should be doing “all the things we know you can do to protect yourself as much as possible,” Sanacora says.

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