K

atie first spoke with a demon when she was 14. He perched on the edge of her bed, and would persistently urge her to do bad things — like blow up her Arkansas high school.

She spoke to God, too.

Her parents, Pentecostal Christians, believed her visions made her special. So she received no therapy, and no medications, and no diagnosis as her schizoaffective disorder began to take root.

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Katie, who is now 35, has been homeless and hospitalized several times. She tried “just about every drug there is,” she said, before she found a medication — the antipsychotic risperidone — that works well for her. She’s got a happy and stable life these days, living with her husband in Texas. But she knows it’s tenuous.

“The thing is: A lot of times, a drug will work for you for several years, and then it’ll just stop,” said Katie, who asked that only her first name be used to protect her privacy. “At some point, I know I’ll have to find another drug.”

It’s a common, and well justified, fear for people with psychiatric disorders. While scientists have made tremendous advances in decoding the genetics of physical illnesses, such as cancer, and developing precision therapies, treatments for mental health remain blunt tools.

They work by blasting entire mechanisms in the brain, without addressing the specific chemical pathways that have gone awry. As a result, the side effects can be quite substantial — and the efficacy is often low. Some people develop resistance to a drug years into treatment, and then have to go through a long period of trial and error to find another.

While demand for mental health drugs has surged, big pharmaceutical companies have largely backed away from investing in the field; the number of psychopharmacological drug research programs has shrunk 70 percent in the last decade, according to NeuroPerspective.

In part, that’s because generic versions of popular drugs like Prozac dominate the market, leaving little incentive for companies to sink tens of millions into developing alternatives. But it’s also because the biological causes of mental illness are so complex. There hasn’t been much innovation in psychiatric medications in more than two decades.

To advance the field, researchers say they need to find biomarkers — tangible biological clues that can help diagnose mental illness, just the way high blood glucose levels can signal diabetes. The hope is that those biomarkers could help pinpoint what’s gone wrong in the circuitry of a particular patient’s brain and offer clues for drug development — and, perhaps one day, even precision psychiatric therapies. But that’s far easier said than done.

Some biomarkers might not be physical: Research suggests that voice analysis could give clues as to a patient’s  mental illness, as certain sentence structures and cadences can objectively be linked to psychiatric disease.

There may be hints in the blood, too, suggests an intriguing small study published in Analytic Chemistry. It’s based on research from the University of Maryland that found that testing for oxidative stress — that is, the imbalance of free radicals in the bloodstream — might help doctors diagnose schizophrenia more quickly.

As more genes are linked to various mental illnesses, the number of psychiatric biomarkers should increase, said Dr. Stephen Strakowski, chair of psychiatry at Dell Medical School at the University of Texas Austin.

Yet drug development veterans are careful to add a note of caution: Even when the mechanism of a brain disease is better understood, it’ll still be a very long road to better treatments. The physical characteristics of brains disordered by Alzheimer’s are well known, for instance, yet drug companies have failed for decades to come up with effective drugs, despite pouring hundreds of millions into research.

When it comes to mental health, one big help would be developing better animal models on which to test potential psychiatric drugs.

Researchers studying cancer and many other illnesses can use mice, primates, and other lab animals to understand how the disease behaves and whether a treatment looks promising.

But the human brain and mind are extraordinarily difficult to replicate. Mice simply don’t have the same thought processes as humans, and therefore the misfirings in a rodent brain can’t compare to a person’s, said Robert Desimone, director of the McGovern Institute for Brain Research at MIT. So the brain mechanisms that lead to PTSD, or anxiety, or schizophrenia — while all biological — are harder to understand.

“It took literally decades of work in the cancer field before we got to a level of mechanistic understanding,” Desimone said. That’s vital to achieve in psychiatry, he added: “That’s what the field has been missing all this time.”

That’s why much of the institute’s focus these days is to engineer better animal models for mental illness. Using tools like CRISPR gene editing and optogenetics, scientists hope to create animals whose brain misfirings can more closely mimic what’s going on in mental illness.

A new center for autism research at MIT, meanwhile — launched this month with a $20 million donation — will focus on unraveling the genetic and biological basis of that disease.

“When it comes to pharmaceutical development, we’re not necessarily looking for a new treatment that totally cures a psychiatric disease,” Desimone said. “But we’d like to make a substantial impact: If we could improve the intellectual disability in autism by 50 percent, for example, that’d be huge.”

“It took literally decades of work in the cancer field before we got to a level of mechanistic understanding. That’s what the field has been missing all this time.”

Robert Desimone, brain researcher

The global pharma company Novartis is also pumping resources into studying the genetics of psychiatric diseases, focused on the relatively small populations of people who have a clearly inherited predisposition to mental illness.

Big pharma used to test its therapies on broad swaths of people with mental illness — say, anyone with a diagnosis of bipolar disorder. Novartis plans a much more targeted approach, looking for subgroups of patients with similar genetic traits or biomarkers,  according to Ricardo Dolmetsch, a former Stanford researcher who now heads up neuropsychiatric drug discovery at the company.

Novartis is also exploring the idea of conducting clinical trials that couple medication with a digital therapy tool — creating an app, for instance, that helps strengthen neural circuitry in tandem with a drug.

That’s part of a broader push among doctors to test out video games, for instance, as “electronic medicine” to help treat mental illness such as depression. “The brain is very plastic, and with the combination of a drug with a sort of digital therapy as well, you could create a better clinical trial,” Dolmetsch said.

Researchers are also testing out transcranial magnetic stimulation of nerves in the brain to quickly improve symptoms of depression. Doctors have long used electroconvulsive therapy, which deploys electric shocks to jar a patient’s nervous system out of treatment-resistant depression. Now, scientists are looking at updated devices that might cause fewer side effects.

The lowest-hanging fruit, according to Dolmetsch, is the potential of so-called street drugs like ketamine, psilocybin, and ecstasy in treating mental illness. Ketamine, long used as an anesthetic, is showing remarkable promise in treating depression. Psilocybin, the active chemical in hallucinogenic mushrooms, is being studied as a way to ease anxiety and depression in terminally ill cancer patients. And MDMA, or ecstasy, is being studied as a psychotherapy tool to treat PTSD.

“Perhaps the right combination of a hallucinogen with a psychiatric or a behavioral therapy might help these drugs make an impact,” Dolmetsch said.

Not everyone agrees that science has advanced far enough to start thinking about precision treatments for mental illnesses.

Jeff Jonas, for instance, has spent his career working on psychiatric drugs, such as the antidepressant Lexapro, the anxiety medication Xanax, and ADHD drug Vyvanse. He’s now the CEO of a small biopharma company, Sage Therapeutics, working in the field of mental health.

Jonas said he thinks the treatment of mental illness is “not amenable to a target-based approach” — at least not yet.

Instead, he’s focused on looking for compounds that might act in a novel way to modulate brain activity for most patients with a specific condition. His experimental postpartum depression drug, for instance, aims to tinker with a neurotransmitter that’s known to soothe anxiety. It is showing early efficacy in helping to ward off serious symptoms like panic attacks, inconsolable sadness, and feelings of inadequacy.

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Improvements can’t come quickly enough for patients.

Psychiatric drug prescription rates have increased substantially in the past two decades, with the rate of antidepressant use alone quadrupling. One in six Americans now takes a psychiatric drug, such as an antidepressant or a sedative, according to a recent report.

Yet finding the right drug can be a painful process of trial and error. And waiting.

Most psychiatric medications take weeks or months to work, so patients and their doctors must wait to see if a drug is effective, wait to tinker with the dose, and wait to see if another medication works better.

It took Katie’s doctors 15 years to properly diagnose her condition, and even longer to find the right drug. Each medication she tried had its own spate of side effects: Celexa, for instance, made her gain more than 100 pounds, and she developed diabetes.

On Risperdal, the diabetes has gone away — but she still has high blood pressure and high cholesterol, and must take additional drugs to keep them in check. “With Risperdal, the voices don’t go away — but they get really quiet,” Katie said. “They hardly bother me anymore.”

She isn’t holding her breath for a miracle drug that will cure her disease. But she is holding on.

“I find that bravery is highly relative: If you have no other option, it’s easy to be brave,” Katie said. “But my biggest takeaway: For all those who are suffering, there is hope.”

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  • This article addresses the poor track record of psychiatric drugs. But instead of concluding that the drugs or a flawed diagnostic system is the problem, the article focuses on the brain as the possible culprit in why the drugs don’t work.

    It starts out with the story of Katie, who has been struggling for 20 years with visions and voices. My heart goes out to Katie in her life of struggle. But the article inhumanely and sterilely portrays her as merely a difficult patient. It notes that she has been homeless and hospitalized several times. But it never addresses the likely reason she was homeless: she’s been hospitalized and drugged several times. This would make her a shell of a human being without connection to her emotional world, which is where we find value, motivation, meaning, and the willingness to have faith in ourselves and others.

    She is said to have finally found the right psychiatric drug after trying “just about every drug there is”. She is now taking Risperdal, one of the most dangerous of the psychiatric chemicals. It is said to “work well” for her. But this just means it put her into such a stupor that she isn’t concerned by the visions and voices anymore. But also, she is unlikely to be able to do anything else in an independent and functional way – thus the times of homelessness. Later in the article, she says, “With Risperdal, the voices don’t go away – but they get really quiet. They hardly bother me anymore.”

    The author points out that it took Katie’s doctors 15 years to properly diagnose her condition, and even longer to find the right drug. Now why would it take 15 years to find a correct diagnosis? The DSM has been touted as a remarkable breakthrough as an objective and accurate psychiatric diagnostic tool. How could this be? The answer: The DSM is not, in fact, a valid diagnostic tool of real brain disease diagnoses. It is a catalogue of human problems in living, with fuzzy boundaries, similar to horoscope categories.

    The article claims that while “scientists have made tremendous advances in decoding the genetics of physical illnesses, such as cancer, and developing precision therapies, treatments for mental health remain blunt tools.” The first part of this is true, but the reason mental health treatment tools are blunt is because “mental illness” (I’ll now dispense with the quotes but remember the term is figurative) is not an illness of the body that can be targeted for treatment. It is a metaphor that refers to personal, economic, political, spiritual, and existential dilemmas common to all people. If they keep looking for it in the body they will never find it. It would be like looking for evidence of heartbreak by examining the heart.

    Nonetheless, psychiatry continues in blaming the brain. Psychiatric drugs are said to “work by blasting entire mechanisms in the brain, without addressing the specific chemical pathways that have gone awry.” In truth, medical science has never demonstrated mechanisms of the brain or chemical pathways to have “gone awry”. Again, they are looking in the wrong place. As another analogy, it would be like looking for the reason a driver is speeding by examining the engine.

    With continued focus on the brain, the poor track record of psychiatric drugs and a 70% decline in drug company research is ostensibly “because the biological causes of mental illness are so complex. There hasn’t been much innovation in psychiatric medications in more than two decades.” This demonstrates the error. They keep looking and looking a the heart in order to find the causes of heartbreak, and they come up empty handed. True, the causes of mental illness are complex, but not complex bodily systems. The causes are complex human experiences.

    So the search for biomarkers in the brain continues in order to help diagnose mental illness and to find treatments, with the often used comparison to the biomarker of increased blood glucose to diagnose diabetes. They hope such biomarkers will tell them “what’s gone wrong in the circuitry of a particular patient’s brain and offer clues for drug development — and, perhaps one day, even precision psychiatric therapies. But that’s far easier said than done.” Actually, that’s impossible. It’s impossible because they keep looking in the brain for defective circuits when decades of research has failed to give even a scintilla of evidence that the brain is what’s wrong. In most other areas of real scientific research the preponderance of evidence gathered dictates the direction of future research. In psychiatry, the research continues looking for proof the earth is flat, after years of evidence showing that it is spherical.

    Then comes an absurdity. This article suggests that some biomarkers might not be physical. This is an oxymoron: biomarker by definition is about biology, which is physical. Voice analysis is an example given, but wouldn’t this just demonstrate not a biomarker, but one’s experience of emotional distress? The medically-scientifically-sounding quote, “Research suggests that voice analysis could give clues as to a patient’s mental illness, as certain sentence structures and cadences can objectively be linked to psychiatric disease” just means voice tone and structure are linked to distress. But more problematic about this, why not just listen to the meaning of what the person has to say? They are looking right past the issue.

    But returning to biomarkers, a study is used to suggest an imbalance of free radicals could help diagnose schizophrenia. This is another absurdity. Free radicals increase when someone is under chronic stress. These aren’t biomarkers of schizophrenia, they are biomarkers of chronic distress. But would we really need to find biomarkers in order to conclude someone is distressed?

    So the article turns to genes. One chair of psychiatry says, “As more genes are linked to various mental illnesses, the number of psychiatric biomarkers should increase.” Another misleading comment because no gene has ever been linked to mental illness.

    In another frequently used tactic, the story of Alzheimer’s is presented to assuage those who are frustrated with the failure to find treatments for mental illness. It is said that the “physical characteristics of brains disordered by Alzheimer’s are well known, for instance, yet drug companies have failed for decades to come up with effective drugs, despite pouring hundreds of millions into research.” Throwing Alzheimer’s in here is a ploy, again to give a medical impression about mental illness. Alzheimer’s is a condition caused by real brain defects. There are no brain defects of mental illness.

    The article then turns to illicit street drugs and their use as “treatment”. Aside from the fact that current illicit street drugs like cocaine and heroin were once prescribed as “medicines”, this line of research is silly. It is said that Ketamine is showing remarkable promise in treating depression. Psilocybin for anxiety and depression in terminally ill cancer patients. And MDMA, or ecstasy, for PTSD. Sure. And I use rum and coke to treat my workaholism. These drugs just like prescribed legal psychiatric drugs do no more treating than does alcohol.

    Throughout this article, the language used and the allusions made give the impression that mental illness is about brain defects, when there is no evidence of that. It is repeated that brain mechanisms, circuits, and pathways are misfiring, awry, jarred, and strengthened. This is incredible as there is no evidence of any of it.

    In closing out the article, the author notes that psychiatric drug prescription rates have increased substantially in the past two decades, with the rate of antidepressant use alone quadrupling, and with one in six Americans on some type of psychiatric drug. This should tell us something. Is the huge increase in drug prescription rates a sign of increasing prevalence of mental illness? Or that despite the use of these drugs, they don’t work? Or perhaps an even more parsimonious explanation: there is no illness to treat.

    Chuck Ruby, Ph.D.
    Executive Director
    International Society for Ethical Psychology and Psychiatry
    http://www.psychintegrity.org

    • Chuck: I enjoyed reading your comment, and I fully agree with what you say. Loved your analogies as well – examining the car engine to find out why a driver is speeding, examining the heart to find out causes of heartbreak and how DSM categories can be compared to horoscope categories!

    • Very well written I was sort of screaming the same thing, metaphorically speaking as I was reading the article. The author piles one unfounded assumption upon another without qualification building a house of cards of pure speculation masquerading as science.

    • Thanks Dr. Ruby. Refreshing and essential points. I have found that much of what are Alzhiemer’s treatments are currently, esp. in regards to later confounded stages, in fact treating the treatments or not treating the initial presentations. Those treatments are for dementias [sic] commonly, historically and popularly misunderstood and mistreated, esp. then misapplied to misdiagnosed therefore mistreated Alzheimer’s “presentations” when those people need to be paid attention to more humanly rather than exclusively pharmacologically. Treatments and the flawed definitions and diagnostics of dementia and conceptual applications, need extreme revision, not the victims (blame, castigation, shunning of etc.) of those with organically regressive diseases, wrongfully treated as mental illness. People need people (more) to hang on to humanity. I often teach, demented is not necessarily dementia. Medical ignorance paired with social shunning can provide terrible re-victimizations of our most needy. Please forgive my long-winded emphasis. I shared your organization with my students and will emphasize it in my curriculum. Critically, humanly and progressively, of course.

  • This article covers a wide span severity of mental illness from anxiety to schizophrenia to depression to autism. I have been part of the pharmaceutical community since 1972 and I can assure your readers – research into mental illness has been constant since the 1950’s. In the field of schizophrenia for instance – Thorazine developed by SKF was the first of 18 different phenothiazines used extensively in the 1950’s to 1980’s. Different classes using a more targeted approach focusing (like Haldol) on dopamine D1 sites heralded several new introductions. The product with unparalleled efficacy in 1990 was Clozaril (clozapine) (yes- Sandoz then -now Novartis) which had blood monitoring issues feared more by psychiatrists than patients & family’s but has been drastically underutilized. It is a messy drug focusing on a wide array of dopamine sites from D1 to D5 – so much for the specificity. To date, it is the ONLY drug of any kind approved by FDA for suicide reduction and yet it is not used much. Excitement followed in other areas like glutamate receptor theory- but not much yield. In the US, we have been fortunate to have top scientists like Ross Baldessarini,MD of McLean’s internationally heralded Brain Bank do basic brain specific research. So, dear reader, it hasn’t been for lack of effort or investment by pharmaceutical companies – it is due to the fact the brain is this incredibly complex organ far surpassing all other illnesses. To the patients and families- I sympathize with you greatly. Stay strong!

    • As I see it, when it comes to mental health, giving medicines is not a solution. In various organs of our body (such as the heart, liver, spleen, etc.), it is extremely rare for biological abnormalities to suddenly develop out of nowhere. But as soon as someone displays a mental issue, a biological/physiological abnormality in the organ brain is presumed to cause it, and an assumption is made that a drug should somehow be administered. What bothers me the most is that these drugs are given in the absence of any structural or other biological/physiological differences between brains of people with and without mental health conditions. Despite decades of research, scientists have not been able to find any such differences, and this is the reason diagnosis of mental health issues happens through the use of checklists – there are no objective tests (and diagnosis made this way also fails to meet the Virchowian standard of disease). Correct me if I am wrong, but this situation draws me to the conclusion that pharmaceutical companies develop psychiatric drugs with only profits in mind. Additionally, studies have shown that psychiatric drugs work only due to their placebo effect: people show the same changes in brain scans when they respond to a placebo as they do when they take an actual psychiatric drug.

  • We need to remember that science does not understand consciousness. What is happening right now is just because the activity of the brain and the mind are correlated, an incorrect assumption is made that the brain has to be somehow “treated” for mental problems. What has been observed in numerous of studies however, is that the organization of brain circuitry is constantly changing as a result of MIND-RELATED ACTIVITIES (brain changes as a result of experience, learning, rumination, worry, calming, etc). This happens through epigenetic and NEUROPLASTIC mechanisms.
    In other words, studies have shown that when you treat the ‘mind’ of a patient (e.g. provide support for issues they are facing, help patients to have hope, teach patients practices that calm the mind such as mindfulness meditation that prevent ruminating, worrying, reduce stress, etc.), healthy structural and functional changes in the brain happen. We need to remember that it is the mental states themselves that give rise to biochemical abnormalities, and it is the mental states themselves that make things normal again. Administering drugs (in a hit or miss fashion, which is what pharmaceutical companies do) create chaos in the brain further exacerbating these psychiatric issues.

  • I spent my career using broad, nonspecific classes of meds to treat psychiatric illness, witnessing routinely the substantial side effects they can cause. I am heartened that this article mentions TWO pharmaceutical companies doing basic research. Most companies leave basic research to the government, and invest instead in researching different, patentable formulations of older medications. Cheers to the two you’ve cited!

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