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This is the last installment of Debunking the Chemical Imbalance Theory of Depression.
The previous installments can be found here: Part I | Part II | Part III | Part IV


With social media at the forefront of 21st-century communication, there is a tendency for non-experts to argue with one another via evidence-based research. Having an opinion is dangerous when a single Tweet can get you fired, but making a statement that begins, “Studies show that…” cushions whatever belief follows.

scale and text overlay image for pinterest

But research is rigged from the start. It’s an open secret in the academic community, but little known by the rest of us. There are predatory journals that profit off of bad science or outright fiction, but because the journals and websites look official, people confuse them for legitimate science. There’s also the fact that Big Pharma funds its own trials (that are used as the basis for FDA approval) which creates an obvious conflict of interest. And don’t forget about medical ghostwriting, where pharmaceutical reps actually write the content of published articles but slap a (paid) doctor’s name on it. Then there’s the replication crisis, in which the results of research can’t be replicated, which indicates that the results are likely false.

Of course, there’s also all the legitimate, ethical research that does exist but has to survive within the chaos. Can you tell the difference? Are you sure about that? And if you can spot the good from the bad, what about all the research that was never published in the first place? Is a lie by omission still a lie?

This question is at the heart of publication bias, arguably the most troubling aspect of the current state of drug research. Publication bias is what happens when the outcome of a study determines whether or not it gets published or distributed. For example, a researcher could conduct 10 studies claiming that a new drug lowers blood pressure. Let’s say that in four of the trials, blood pressure levels didn’t change. In four other trials, blood pressure levels actually increased. But in two trials, blood pressure levels decreased.

Though 8 of 10 trials did not have the intended outcome, there is nothing in the bylaws that state that the researchers have to publicize that information. Instead, they can focus their publication efforts on the two trials that did show a positive reduction in blood pressure and use those results to get their drug approved by the FDA—even though their own research showed that the drug flopped 80% of the time.

This graveyard of failed or abandoned studies means that doctors don’t have complete information for the drugs they’re prescribing. This is a big reason why I don’t like it when people lump all doctors in a box when it comes to prescribed harm. They can do their research and think that they are acting in an ethical way, but they are being misled just like the rest of us.

How bad is it? Let’s take a look.

In 2015, researcher Erick. H Turner used the Freedom of Information Act to gather all the trials on antidepressants that were approved by the FDA over a 15-year period. Keep in mind that this isn’t all the trials ever conducted, just the ones used to get marketing authorization. Any unsubmitted trials, whether failed or abandoned, are known only to the researchers. Only the results of trials submitted to the FDA are available through the Freedom of Information Act.

There were 74 trials submitted to the FDA; 38 showed that the antidepressants had a positive effect (compared to a placebo and/or a competitor), and 36 showed either no effect or a negative effect. Essentially, it’s a coin toss.

Turner then cross-referenced these studies with peer-reviewed journals to see which ones were actually published for public consumption. Of the 74 original trials, 37 of the positive studies were published whereas only 3 of the negative trials were published.

Rather, from the FDA’s perspective, these drugs had some sort of positive impact 51% of the time. From the public’s perspective, if we’re basing this off of research doctors and patients can access, these drugs are effective 92.5% of the time.

In the words of Ben Goldacre, Senior Clinical Research Fellow at the Centre for Evidence-Based Medicine at the University of Oxford, “If I tossed a coin a hundred times, and I’m allowed to withhold from you the answers half the time, then I can convince you that I have a coin with two heads.”

And that’s why pharmaceutical companies to legally allowed to advertise that antidepressants like Pristiq are “proven to treat depression” and “thought to work by affecting the levels of two chemicals in the brain, serotonin and norepinephrine.” It doesn’t matter that we know it’s not the whole story, because manufacturers aren’t forced to report all their trials.

Unfortunately, there’s no real answer to any of this. Doing your own research is fabulous, but know that the research is incomplete. At some point, you have to reach inside yourself and calibrate your own inner compass.


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Need a little giggle? Order one of my Fuckit Buckets™.

Look, we know that life is a special sort of disaster right now. Your closet is your office, the kids are still at home, and still your mother-law is calling you fat again. Let this little charm be a reminder that sometimes you have to chuck it in the Fuckit Bucket™ and move on!

Get your own Fuckit Bucket™

After 15 years of depression and antidepressants, my mission is to help people find hope in the name of healing. My memoir on the subject, MAY CAUSE SIDE EFFECTS, publishes on May 10, 2022. Pre-order it on Barnes & Nobles, Amazon, or wherever books are sold. For the most up-to-date announcements, subscribe to my newsletter HAPPINESS IS A SKILL.


Coming September 6, 2022

May Cause Side Effects

Brooke’s memoir is now available for preorder wherever books are sold.

This is a heart-rending and tender memoir that will start conversations we urgently need to have. It’s moving and important.

Johann Hari, author of New York Times bestseller Chasing the Scream and international bestseller 
Lost Connections: Uncovering the Real Causes of Depression—and the Unexpected Solutions

More articles from the blog

see all articles

September 23, 2022

The Flowering of Human Consciousness

read the article

September 16, 2022

Three Weeks

read the article

September 9, 2022

Wanting

read the article

September 2, 2022

The Ashton Manual: A guideline for withdrawing from psychiatric drugs

read the article

Part I—The History of Chemical Imbalance Theory
Part II—The Flaws of Chemical Imbalance Theory
Part III—Pharmaceutical Advertising & Chemical Imbalance Theory


At this point in our journey, you’re probably coming around to the idea that the chemical imbalance theory is flawed at best and an outright lie at worst. Although it’s been disproven over and over again and that patients who think a chemical imbalance is the cause of their depression actually have worse treatment outcomes, pharmaceutical advertisements and lifestyle and health websites continue to push the narrative.

Why?

The chemical imbalance theory is unique in that it scratches a specific itch for pharmaceutical companies, doctors, and patients. Pharmaceutical companies need the chemical imbalance theory to peddle their product. They can’t manufacture a pill to erase the lingering, emotional effects of childhood trauma or an unfulfilling life, but they can produce a “biological answer” to a “biological problem.” Someone prone to blood clots takes an anticoagulant. Someone prone to depression takes an antidepressant. The language lends itself to storytelling; the patient a damsel in distress, the drug a regal prince.

This myth wouldn’t survive, however, if people weren’t buying it. It’s easy to understand why people flock to the pharmacy. When people are in pain, they need help. Immediately. Unraveling the emotional ball of knotted yarn is a long and messy process made longer and messier by a bungled healthcare system, a cultural inability to tolerate discomfort, and a social system that doesn’t support people through drastic life changes. A $30 bottle of generic venlafaxine and the assumption that it’s all gone wrong thanks to a chemical imbalance is much easier to swallow.

man shouting into a speaking tube and text overlay

Besides, patients aren’t supposed to be the expert. They aren’t following the words of Dr. Thomas Insel, former Director of the National Institute of Mental Health, who explicitly stated in a 2007 Newsweek article that “a depressed brain is not necessarily underproducing [neurotransmitters.]” Instead, people are influenced by media (advertisements) and experts (doctors.) When both of these institutions are steering them towards a chemical “solution,” why shouldn’t they follow the advice? After all, isn’t “asking your doctor” the right thing to do?

But why are doctors, the experts who are supposed to rely on science, so willing to indulge the chemical imbalance myth when overwhelming, decades-long research does not support it?

The knee-jerk reaction is, of course, money baby! Though the days of outright paying doctors to prescribe specific, brand-name medications are long gone, physicians still receive kickbacks from pharmaceutical companies. It’s even considered public information and can be viewed on OpenPaymentsData.CMS.com. But with the plethora of generic psychiatric drugs available (and that the average per-physician payout, in 2015, was only $201), I don’t think money is the driving factor for psychiatric drug prescription.

A more robust hypothesis is that the chemical imbalance theory has helped destigmatize mental illness, enabling patients to “come out of the closet” with their depression. In theory, if people aren’t afraid to speak up about their private struggles, they are more likely to seek help. This hypothesis is further bolstered by the fact that insurance companies require a diagnosis before they will pay for treatment claims. Treatment for a “bag marriage” or “childhood sexual abuse” is not covered. But treatment for Generalized Anxiety Disorder or Major Depressive Disorder is fair game.

To be labeled with a psychiatric disorder implies that something abnormal has gone wrong in the body and that returning to a state of “normal” is the reasonable thing to do. The chemical imbalance theory fits this narrative and creates a simple way for doctors to explain a complex problem under the time and financial constraints dictated by health insurance. The line between truth and fantasy might be blurred, but if the patient is getting help, does it matter?

Given the 30% rise in suicide rates from 2000 to 20016 despite a 400% increase in antidepressant use and an overall decrease in mental health stigma, I’m going to say that yes, that line between truth and fantasy does matter.

But the blame can’t fall fully on the prescriber’s shoulders. Even the most well-read and researched of the bunch can only operate on the information they’re able to find.

And as it turns out, the game is rigged from the start.

Next week, we’ll dive into publication bias. Or rather, how the pharmaceutical industry legally sells you a two-headed coin.


image of Fuckit Bucket™ products

Need a little giggle? Order one of my Fuckit Buckets™.

Look, we know that life is a special sort of disaster right now. Your closet is your office, the kids are still at home, and still your mother-law is calling you fat again. Let this little charm be a reminder that sometimes you have to chuck it in the Fuckit Bucket™ and move on!

Get your own Fuckit Bucket™

After 15 years of depression and antidepressants, my mission is to help people find hope in the name of healing. My memoir on the subject, MAY CAUSE SIDE EFFECTS, publishes on May 10, 2022. Pre-order it on Barnes & Nobles, Amazon, or wherever books are sold. For the most up-to-date announcements, subscribe to my newsletter HAPPINESS IS A SKILL.


Coming September 6, 2022

May Cause Side Effects

Brooke’s memoir is now available for preorder wherever books are sold.

This is a heart-rending and tender memoir that will start conversations we urgently need to have. It’s moving and important.

Johann Hari, author of New York Times bestseller Chasing the Scream and international bestseller 
Lost Connections: Uncovering the Real Causes of Depression—and the Unexpected Solutions

More articles from the blog

see all articles

September 23, 2022

The Flowering of Human Consciousness

read the article

September 16, 2022

Three Weeks

read the article

September 9, 2022

Wanting

read the article

September 2, 2022

The Ashton Manual: A guideline for withdrawing from psychiatric drugs

read the article

This is the third installment of an ongoing series debunking the chemical imbalance theory of depression. Part I examines the history of the theory while Part II examines its fatal flaws. Part III looks at the history of pharmaceutical advertising.

Antidepressants are a $26.25 billion dollar industry. If the industry as a whole was a person, it would be the 66th wealthiest individual on the planet. Zoloft, Lexapro, Xanax, Wellbutrin, Celexa, Prozac, Klonopin, Effexor, and Cymbalta all crack the top 50 most prescribed drugs in the United States, with Zoloft taking the 14th spot.

Pharmaceutical companies are also publicly traded, which means they’re incentivized to maximize profits for shareholders. And how do companies make more money? By increasing sales. And how do companies increase sales? Through advertising.

Medicine and prescription drugs are no exception. Prescription drugs, in this country, are a business. Full stop. The United States is one of only two countries in the world (New Zealand is the other) that allows direct-to-consumer (DTC) advertisement of pharmaceutical drugs. We simply cannot examine the rise of antidepressant use and the push behind the chemical imbalance theory without considering profit. As the saying goes, if you want the truth, follow the money.

pinterest image with blue pills and text overlay

At the turn of the 20th century, medications were classified either as “ethical drugs” listed by the American Medical Association (AMA) or “patent medications” that were mostly water with a little bit of alcohol, opium, or other mysterious ingredients thrown in. These patent medications were allowed to be advertised without regulation (and were therefore filled with false claims), yet they accounted for nearly half of newspaper revenue in the early 1900s.

In 1914 that The Federal Trade Commission (FTC) was created to crack down on false advertisements. Strangely, drug ads in medical journals were exempt from regulation. It wasn’t until 1938, after 105 people died from a drug that included antifreeze, that the FDA ruled that drugs have to be proven safe before marketing. But they also put the burden of determining whether or not the drug was safe on the drug manufacturer, rather than a third party.

It wasn’t until 1969, a few years after 10,000 babies were born with birth defects as a direct result of thalidomide poisoning from a drug used to treat morning sickness in pregnant women, that the FDA began to require that manufacturers provide information on side effects, contraindications, and effectiveness in drug advertisements. At the time, the majority of drug ads were in medical journals or aimed at physicians. DTC advertising only began in the late 70s and early 80s, when pharmaceutical companies cut out the middle man and began aiming advertisements directly at consumers.

Though there was a brief moratorium on DTC advertising in 1983 after a well-advertised arthritis drug made by Eli Lilly was pulled off the market due to adverse drug effects, the FDA declared in 1985 that drugs could be advertised directly to consumers as long as they met the same criteria as drugs advertised to physicians. All those side effects, contraindications, and risks needed to be included in the DTC ad. This declaration made it difficult to advertise on TV and radio because verbally listing all the side effects simply took up too much air time, so advertising shifted to print media, where disclaimers in small print could flourish.

The 1990s ushered in the advertising era of “lifestyle” drugs for everything from erectile dysfunction to baldness to, you guessed it, depression. In 1997, with pressure from the pharmaceutical industry, the FDA drafted official television-friendly guidelines for drug advertisements (cue the speedy, may-cause-side-effects voiceover.) In the year after these regulations were drafted, DTC drug advertisement spending doubled from $1.1 billion in 1998 to $2.24 billion in 1999. By 2000, every $1 spent in drug advertising resulted in $4.20 in retail drug sales.

In 2015, the American Medical Association called for a complete ban on DTC drug advertisement due to anti-competitive behavior that allowed drug companies to manipulate drug prices for profit and then advertise the benefits of their inflated drugs to consumers. But the push to end DTC advertisements was shot down thanks to powerful drug lobbyists claiming that DTC advertisements provide patients with valuable information about their health and treatment options. By 2017, 72% of commercial breaks during the CBS Evening News contained drug ads.

In the next installment, I’ll examine how the advertising market has enabled pharmaceutical companies to prey on consumers by relying on the chemical imbalance theory as an easy explanation for depression.


image of Fuckit Bucket™ products

Need a little giggle? Order one of my Fuckit Buckets™.

Look, we know that life is a special sort of disaster right now. Your closet is your office, the kids are still at home, and still your mother-law is calling you fat again. Let this little charm be a reminder that sometimes you have to chuck it in the Fuckit Bucket™ and move on!

Get your own Fuckit Bucket™

After 15 years of depression and antidepressants, my mission is to help people find hope in the name of healing. My memoir on the subject, MAY CAUSE SIDE EFFECTS, publishes on May 10, 2022. Pre-order it on Barnes & Nobles, Amazon, or wherever books are sold. For the most up-to-date announcements, subscribe to my newsletter HAPPINESS IS A SKILL.


Coming September 6, 2022

May Cause Side Effects

Brooke’s memoir is now available for preorder wherever books are sold.

This is a heart-rending and tender memoir that will start conversations we urgently need to have. It’s moving and important.

Johann Hari, author of New York Times bestseller Chasing the Scream and international bestseller 
Lost Connections: Uncovering the Real Causes of Depression—and the Unexpected Solutions

More articles from the blog

see all articles

September 23, 2022

The Flowering of Human Consciousness

read the article

September 16, 2022

Three Weeks

read the article

September 9, 2022

Wanting

read the article

September 2, 2022

The Ashton Manual: A guideline for withdrawing from psychiatric drugs

read the article

This is Part II of Debunking the Chemical Imbalance theory. Part I can be found here.

Psychiatry, like most hard sciences, suffers as research trickle down from laboratories to the mainstream. Take our friend from Part I, Harvard neuropsychopharmacologist Joseph Schildkraut, who said in 1965 that the chemical imbalance theory was “at best a reductionistic oversimplification of a very complex biological state.”

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Though Schildkraut explicitly stated that there was no evidence to support or disprove the theory—which led to a generation of research that could not find a statistically notable link between biology and mental disorders—Schildkraut’s research was still cherry-picked by a verywellmind journalist for a January 2021 article entitled, “The Chemistry of Depression: What is the Biochemical Basis of Depression?”

The article gives the reader a general overview of how neurotransmitters work, the three neurotransmitters usually associated with depression (dopamine, norepinephrine, and serotonin), and the all familiar assumption that low levels of these chemicals may be associated with depression.

There are so many problems with this article that it would be impossible for me to unpack it all in one issue, so I’m going to focus on the most egregious statement and go from there: “Restoring the balance of brain chemicals could help alleviate symptoms—which is where the different classes of antidepressant medications may come in.”

For the sake of argument, let’s assume that an imbalance of “brain chemicals” is the cause of depression. How do we measure that imbalance in order to determine the amount and kind of antidepressants needed to restore the balance?

*crickets*

There is not, and never has been, a single test to measure the real-time amount of an individual’s “brain chemicals.” You cannot measure neurotransmitters in a blood test. You cannot measure neurotransmitters in an MRI or CT Scan. You can get an estimate of neurotransmitter levels by measuring something called biogenic amines in urine and spinal fluid. This test operates under the assumption that the results are an accurate depiction of what’s going on in the brain in real-time. This is a shaky assumption given that neurotransmitter levels literally change by the second and that up to 95% of serotonin is produced in the intestines.

There is also some research surrounding measuring neurotransmitter levels through PET scans, but like the biogenic amine test, it is at best, a snapshot in time that will never be relevant for 99.9% of patients.

If we don’t have any way to accurately measure neurotransmitter levels, then it stands to reason that we can’t know what is considered “balanced” in the first place, which is why the administration of psychiatric drugs is more of a guess than a science.

Knowing all this, a slew of questions emerge. If low levels of “brain chemicals” are responsible for depression, why is it that a drug filled with synthetic neurotransmitters can take more than a month to have an effect? And, if chemicals are the primary culprit, why do antidepressants only work for about 60% of patients? (Not to mention the fact that in the long run, talk therapy works as well as drug therapy, without the nasty side effects.)

Some people will argue that from a practical point of view, the validity of the chemical imbalance theory is irrelevant if the drugs help people. This argument would sit better with me if 1) pharmaceutical companies weren’t allowed to manipulate patients with misinformation based on a bunk theory. 2) Mainstream health websites like verywellmind didn’t continue to effectively mansplain the chemical cause of depression in exchange for website traffic. 3) If practitioners enforced short-term use of these drugs and 4) if practitioners actually knew how to take patients off these drugs safely and effectively.

But since none of those things are true, patients end up on a hamster wheel of drug-dependent diagnosis, spending their lives believing that their mental anguish is caused by a chemical imbalance that relieves them of actually addressing the problems and traumas in their lives that lead to depression.

In Part III, I’ll specifically focus on how pharmaceutical companies create billions of dollars in revenue by exploiting the chemical imbalance theory in order to market antidepressants to the general public.


image of Fuckit Bucket™ products

Need a little giggle? Order one of my Fuckit Buckets™.

Look, we know that life is a special sort of disaster right now. Your closet is your office, the kids are still at home, and still your mother-law is calling you fat again. Let this little charm be a reminder that sometimes you have to chuck it in the Fuckit Bucket™ and move on!

Get your own Fuckit Bucket™

After 15 years of depression and antidepressants, my mission is to help people find hope in the name of healing. My memoir on the subject, MAY CAUSE SIDE EFFECTS, publishes on May 10, 2022. Pre-order it on Barnes & Nobles, Amazon, or wherever books are sold. For the most up-to-date announcements, subscribe to my newsletter HAPPINESS IS A SKILL.


Coming September 6, 2022

May Cause Side Effects

Brooke’s memoir is now available for preorder wherever books are sold.

This is a heart-rending and tender memoir that will start conversations we urgently need to have. It’s moving and important.

Johann Hari, author of New York Times bestseller Chasing the Scream and international bestseller 
Lost Connections: Uncovering the Real Causes of Depression—and the Unexpected Solutions

More articles from the blog

see all articles

September 23, 2022

The Flowering of Human Consciousness

read the article

September 16, 2022

Three Weeks

read the article

September 9, 2022

Wanting

read the article

September 2, 2022

The Ashton Manual: A guideline for withdrawing from psychiatric drugs

read the article

I’m going to take the time to dive into the chemical imbalance theory of depression, and why it’s a big ‘o pile of crap. I’m taking the time to do this because 80% of people believe that depression is caused by a chemical imbalance, despite overwhelming evidence otherwise. Today I will focus on the history and discovery of antidepressants and the chemical imbalance theory.

The first antidepressant was discovered by accident.

In 1952, a drug designed to treat tuberculosis, iproniazid, had a surprising side effect: patients in the sanatorium became euphoric when treated with this drug.

Researchers experimented with the mood-altering effects of iproniazid for five years, ultimately discovering that it worked by inhibiting the monoamine oxidase (MAOI) enzyme, which breaks down serotonin and dopamine—two of the neurotransmitters involved in pleasurable emotions. But in 1957, after treating 400,000 depressed patients with the drug, researchers noticed that when patients ate cheese, chocolate, or alcohol, their blood pressure skyrocketed to dangerous levels. As it turns out, iproniazid didn’t just affect serotonin and dopamine, but norepinephrine as well. A release of norepinephrine constricts blood vessels, which leads to elevated blood pressure. Known as “the cheese reaction,” the use of iproniazid was quickly stopped.

But around the same time, researchers were studying a plant known as Rauwolfia serpentina, which had been used medicinally in India for everything from calming babies to insomnia to high blood pressure. Chemists extracted the active compound, called it reserpine, and began testing it on animals.

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Resperine was found to lower serotonin, norepinephrine, and dopamine, all of which lead to a period of near-catatonic inactivity in the animals. It was concluded that low serotonin, norepinephrine, and dopamine levels create a depressed state, and the “chemical imbalance theory” was born.

But there’s a catch: First, resperine was also used as an antipsychotic (rather, a tranquilizer) for schizophrenia and Huntington’s disease. Despite high doses and long-term use, only 6% percent of patients developed clinical depression, and all 6% had a history of depression to begin with. Bafflingly, in 1955, resperine was also the first compound shown to be an effective antidepressant, despite actually reducing levels of serotonin, norepinephrine, and dopamine.

Still, the discovery of iproniazid and resperine gave rise to the theory that different chemicals in the brain create different states of mind. Researchers and patients, it seemed, desperately wanted it to be true. Who wouldn’t want to distill their melancholy into a neat little bow that can be explained by a simple unbalance of a handful of chemicals?

But as early as 1965, the American Journal of Psychiatry put out a paper by Harvard neuropsychopharmacologist Joseph Schildkraut, who said the chemical imbalance theory was “at best a reductionistic oversimplification of a very complex biological state” and that there was no evidence to support or disprove the theory.

Schildkraut’s declaration inspired a generation of researchers to prove him wrong. But over and over again, they failed to find the link between statistically different levels of neurotransmitters between depressed patients and happy ones.

As the Council for Evidence-Based Psychiatry says, “Although scientists have been testing the chemical imbalance theory’s validity for over 40 years–and despite literally thousands of studies–there is still not one piece of direct evidence proving the theory correct. The chemical imbalance theory, in relation to any mental health disorder is thus unsubstantiated, yet a societal belief in chemical imbalances, largely owing to effective pharmaceutical marketing, remains prevalent today.”

In next blog post, I’ll explore the fatal flaws of the chemical imbalance theory, followed by the influence marketing has had on keeping this myth alive. Meanwhile, I’m keeping the links light today. There’s plenty to dig through in the issue itself.

Need a little giggle? Order one of my Fuckit Buckets™.

three images of the fuckit bucket collection

After 15 years of depression and antidepressants, my mission is to help people find hope in the name of healing. My memoir on the subject, MAY CAUSE SIDE EFFECTS, publishes on May 10, 2022. Pre-order it on Barnes & Nobles, Amazon, or wherever books are sold. For the most up-to-date announcements, subscribe to my newsletter HAPPINESS IS A SKILL.

Coming September 6, 2022

May Cause Side Effects

Brooke’s memoir is now available for preorder wherever books are sold.

This is a heart-rending and tender memoir that will start conversations we urgently need to have. It’s moving and important.

Johann Hari, author of New York Times bestseller Chasing the Scream and international bestseller 
Lost Connections: Uncovering the Real Causes of Depression—and the Unexpected Solutions

More articles from the blog

see all articles

September 23, 2022

The Flowering of Human Consciousness

read the article

September 16, 2022

Three Weeks

read the article

September 9, 2022

Wanting

read the article

September 2, 2022

The Ashton Manual: A guideline for withdrawing from psychiatric drugs

read the article