Why don’t your psychiatric drugs work better?

Tomorrow is World Mental Health Day, and in many ways, it seems like the world has made great strides in mental health care. In 2023 alone, the US National Institutes of Health (NIH) poured $1.25 billion into research studying how mental illness manifests in the brain. People are prescribed more psychiatric drugs now than ever, while talking openly about depression, anxiety, and ADHD isn’t just becoming less stigmatized — online at least, it’s almost cool. Despite having more access to medication in the US than ever, over 50,000 Americans died by suicide last year — the highest number ever recorded. The US Surgeon General describes mental health as “the defining public health crisis of our time,” but we’re barely any closer to understanding the neuroscience of mental health than we were 50 years ago. --- This story was first featured in the Future Perfect newsletter. Sign up here to explore the big, complicated problems the world faces and the most efficient ways to solve them. Sent twice a week. --- Despite the popular framing of mental illnesses as being fundamentally caused by electrochemical imbalances in the brain, a pile of evidence decades in the making suggests the truth is much more complicated. It’s the biggest open secret in neuroscience — psychiatric medications often don’t work. If drugs that alter chemical signaling in the brain are capable of silencing auditory hallucinations and suicidal thoughts, then brain chemistry must somehow explain mental illness, at least in part. But while medications like antidepressants and antipsychotics make many people feel a lot better, they make just as many — or more — feel the same or even worse. (Prescribing the right meds for the right condition is mostly a guess, and the wrong match can accidentally shoot someone into a manic episode, for example.) The brain is one of the most complex machines in the universe, made up of 86 billion cells connected by 100 trillion synapses. To give you a sense of just how complicated that is, it took over four years for neuroscientists to build a map of a single fruit fly’s brain, which only contains about 0.00003% of the neurons in a human brain — and as much of a scientific achievement as that was, it doesn’t even come close to fully explaining a fly’s behavior. Try scaling that project up by several orders of magnitude, and the prospect of fully understanding human brain chemistry looks downright impossible. It could be that neuroscience simply hasn’t had enough time to develop truly effective mental health therapies for most conditions. It’s a relatively young field, and scientists have only been able to get a good look at living brain activity for a few decades. The breakthrough psychiatry needs could be right around the corner. But it’s also possible that some of the best mental health care lies outside Western psychiatry altogether. Maybe two things can be true at once. Psychiatrists no longer think chemical imbalances cause mental illness. Why do we? For thousands of years, mental illness could only be explained by supernatural forces or moral deviance. In Enlightenment-era Europe and its colonized territories, people with psychiatric disorders were largely confined to asylums — later rebranded as “psychiatric hospitals” — up until the 1950s. In the early 20th century, Sigmund Freud and his peers popularized psychotherapy, which helped (and continues to help) people navigate disorders like depression and anxiety. But physicians at asylums were initially hesitant to adopt it, preferring a “somatic” approach to mental health care that involved stimulating the body and the nervous system to alter the mind. Leading doctors once believed that disorders like schizophrenia were caused by an underactive “vegetative” nervous system, an old term for the parts of the brain that control basic life-sustaining functions like digestion and breathing. Early psychiatric treatments were designed to send a big enough shock to the brain — whether with electricity, an intentional malaria infection, or coma-inducing drugs — to kickstart these supposedly underactive processes. Psychiatrists who invented malaria treatment — using the malaria virus to induce a high fever, hopefully killing neurosyphilis-causing bacteria — and the prefrontal lobotomy both won the Nobel Prize in Medicine while asylums were still the norm in Europe. Over time, however, physicians began to acknowledge that their somatic treatments weren’t working very well. That, combined with the observation that mentally ill brains didn’t seem to have anything visibly wrong with them when autopsied, began to drive physical treatments out of fashion. Everything changed in 1952, when Parisian surgeon Henri Laborit accidentally discovered that chlorpromazine, an antihistamine he used to make anesthesia less dangerous for his patients, was also a powerful antipsychotic. When chlorpromazine entered the market in 1954, it changed psychiatry like the discovery of insulin changed diabetes. Suddenly, people who had been chronically restrained in mental hospitals could have calm conversations with their psychiatrists. Within a year, public psychiatric hospitals in the US began closing as policymakers hoped that new drugs would render institutionalization obsolete. For years, no one knew how drugs like chlorpromazine worked, only that they did, albeit with unpleasant side effects like drowsiness, weight gain, and uncontrollable muscle spasms. Neuroscientists later figured out that antipsychotics like chlorpromazine bind to a certain type of dopamine receptor in the brain, flagging the neurochemical dopamine — specifically, having too much of it — as the biological root of schizophrenia. The idea that a chemical imbalance could change someone’s thoughts, feelings, and behaviors quickly spread throughout psychiatry. Selective serotonin reuptake inhibitors (SSRIs) like Prozac, widely used antidepressants introduced in the 1980s, block neurons from reabsorbing leftover serotonin after a chemical signal is sent. Theoretically, if a lack of serotonin contributes to depression, keeping more serotonin molecules available should make people happier. About half of people who take SSRIs feel better after a couple of months. However, antidepressant researcher Alan Frazer told NPR, “I don’t think there’s any convincing body of data that anybody has ever found that depression is associated to a significant extent with a loss of serotonin.” Pinning schizophrenia simply on dopamine is similarly oversimplified and old-fashioned. Today, researchers believe that many neurotransmitters — on top of other genetic, social, and environmental factors — affect the likelihood that someone experiences mental illness. Even though dopamine- and serotonin-related self-help videos keep making the rounds on TikTok, neuroscientists and psychiatrists have been vocally skeptical of the “chemical imbalance” trope for decades. Electrochemical interactions, to the extent that scientists are capable of understanding them, can’t fully explain — or more importantly, treat — mental illness. The future of mental health doesn’t belong only to neuroscience Thinking of mental illness as something that medication can solve provides people “a way to establish their suffering as both tangible and unfeigned, and it offers a simple account and positive prognosis for their struggles,” sociology professor Joseph Davis wrote for Psyche. If a person claims their mental illness as a disease beyond their control, like cancer, then others may be more likely to view them as humans worthy of respect and opportunities. Two weeks ago, the US Food and Drug Administration approved a new antipsychotic drug that doesn’t target dopamine receptors — the first since chlorpromazine was first introduced. The new medicine, called Cobenfy, targets acetylcholine instead, a neurotransmitter that notably isn’t dopamine, but can affects dopamine levels indirectly. The fact that Cobenfy is the first new option presented in 70 years was enough to make headlines. But whether it actually works better than existing options remains to be seen: None of the drug’s three clinical trials ran long enough to tell whether Cobenfy will cause the same long-term side effects — dramatic weight gain, repetitive body movements — as its predecessors. The introduction of Cobenfy captures a lot of what’s troubling — and what’s hopeful — about the role of neuroscience in treating mental illness. Sure, a new pharmaceutical treatment may relieve the worst symptoms of schizophrenia with fewer side effects than before. But introducing a new drug can’t eliminate the condition altogether or fundamentally shift how people navigate psychosis. The latter strategy — radically reconsidering how communities care for people with even the most severe mental illnesses — is recommended by the World Health Organization. In many cultures, mental health problems are not considered biomedical problems, so people generally don’t seek things like medication. Community-based mental health care, where lightly-trained laypeople facilitate therapy sessions in their own neighborhoods, can work as well as formal psychiatric care in many settings, with or without medication. While community-based models are often discussed in the context of non-psychotic mental illnesses like depression, options beyond psychiatry can help people experiencing more severe psychosis, too. Anti-carceral care strategist and crisis responder Stefanie Kaufman-Mthimkhulu believes that whether the root cause of psychosis is ultimately ancestral spirits, childhood trauma, post-viral inflammation, or a delicate shift in neurochemistry, “it is critical to offer people multiple ways to define and make sense of our experiences.” Neuroscience can only take us so far. At some point, our willingness to find value in mental states beyond our own has to take over.

What really matters

Why don’t your psychiatric drugs work better?