Inventing Brain Imbalance In Service of Pharmaceuticals

"You want to know why it took so long for the truth to come out?"

"I am afraid this has something to do with the toxic relationship between industry and academia. [Drug companies encourage MDs to prescribe often, and heavily and have] paid many academic psychiatrists to promote their products."

Dr. Joel Paris, Montreal psychiatrist

"But the main thing that has got people riled up is that we have dared to draw conclusions about anti-depressants."

"It seems the main criticism is that antidepressants work. It doesn't mater how they work. It doesn't matter that the original idea, the original theory for how they work is unproven. They work, and that's all that matters."

"[To me, it matters] Because whether they work or not depends on how we understand what they are doing. We have to consider other possible ways that they may be 'working' ... which include the fact they are drugs that change normal brain chemistry."

"[When the first SSRI, Prozac was launched in the 1980s] the pharmaceutical industry knew it couldn't market them in the same way as [benzos], so, it had to convince people that they had an underlying disease and needed o take the drugs for an underlying disease."

:If you think something is wrong with your brain and a drug is going to put it right, of course you're going to take it."

Dr.Joanna Moncrieff, consultant psychiatrist, professor of critical and social psychiatry, University College, London

Chip Somodevilla/Getty Images; J. Scott Applewhite-Pool/Getty Images; Yulia Reznikov/Getty Images

 

Dr.Moncieff is the co-founder of the Critical Psychiatry Network and agrees that sedatives like benzodiazepines can be useful short term in a crisis: "But I think that drugs that affect the brain, we should be cautious about". No evidence exists that such drugs reverse an underlying abnormality of the brain, but "they are doing something to the brain. And by doing that they change our normal mental states."

Dr. Moncrieff points out that specific drugs known as SSRIs (selective serotonin reuptake inhibiters that are believed to work by correcting abnormally low serotonin, a neurotransmitter helping to move messages between brain cells thought to play a role in how brains process emotions) represent a drug formulation whose efficacy is taken on trust as a tried-and-true medication for clinical depression, but that in actual fact they are not at all effective.

An international media frenzy broke out with news headlines such as "How were so many duped?" when it became all too evident that the "serotonin theory" of depression, the belief in too little of the brain chemical leading to depression was debunked. The hypothesis weathered well for decades becoming deeply entrenched throughout the psychiatric medical community, a huge assist in promoting a class of antidepressants taken by millions worldwide. 

Several months ago a major review concluded there was no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations, for basically, no convincing evidence of a "chemical imbalance" exists. The paper's authors have been ridiculed and attacked, accused of succumbing to urban myths that link antidepressants to mass shootings. 

The suggestion and subsequent acceptance that a "chemical imbalance" in the serotonin theory first introduced 60 years ago seemed promising. However, said Dr. Allen Frances, professor emeritus of psychiatry at Duke University, involved in creating the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders in 1994, the association was weak and failed to replicate. "Depressions are so remarkably heterogeneous, there can't possibly be any unitary cause", stated Professor Frances; further study "revealed just how ridiculously complicated is brain structure and function".

For their "umbrella" review published in Nature's Molecular Psychiatry, Dr. Moncrieff and her co-authors reviewed high-level studies in six major areas of research which spanned 56 years, involving tens of thousands of people. The studies involved indirect measures of serotonin activity in the knowledge that no "normal level" of serotonin exists. The investigators reviewed studies indicating indirect measures of serotonin activity; serotonin and its breakdown products in people's blood or cerebral spinal fluid comparing levels between people diagnosed with depression and those not diagnosed with depression, as healthy "controls".

 

No overall difference in levels of serotonin was found by the researchers between the two groups. Serotonin comes from tryptophan, an amino acid extracted from the diet. Healthy people on diets lacking tryptophan did not become depressed. Looking at studies of genes involved in the brain's serotonin system, researchers again found no consistent difference between depressed and healthy volunteers.

 

"I think people need to think carefully about why they are taking [SSRIs] and what they think the drug is doing for them."

"If they are taking the drug because they think it's correcting an imbalance in their brain,I would suggest that they could re-evaluate whether they need to take it", said Dr. Moncrieff.

 

According to Dr. Frances, what is often lost in the controversial conversation over chemical imbalance and depression, is that mild depressions are usually caused by life stressors which do not require medications. "Instead, they improve with time, support, reduced stress and/or psychotherapy", while severe depressions do require medication, rarely responding to anything else.

 

It is not just for depression that SSRIs are prescribed, but for social anxiety disorder, panic disorder, OCD (obsessive-cmpulsive disorder), phobias and an even longer list of complaints. Like all drugs, these carry side effects which include agitated feelings, low alcohol tolerance and loss of libido and sexual dysfunction. 

A recent analysis paints a compelling picture that depression isn't caused by a chemical imbalance in the brain. But experts say this is already widely accepted and it's also true that antidepressants can be extremely beneficial to some patients — even if we don't know exactly why. (Shutterstock / Chanintorn.v)

Depression Distraction

"I couldn't stop crying. The thought that consumed me the entire way on that road was just driving my car into the marshland so I can drown."

"Within a few weeks, the suicidal thoughts just disappeared."

"[I am now] seeing things that are beautiful in the world, and when I was in the depths of depresions, all I saw was what was ugly."

Sarah, 38, (last name withheld), California

 

"One person's depression might look very different from another person's depression."

Dr.Katherine Scangos, assistant professor of psychiatry, U.C.S.F.

Dr. Katherine Scangos of UCSF sits with Sarah, the first patient to receive a new type of brain stimulation treatment for depression. (Image credit: Maurice Ramirez; UCSF 2021)

Sarah was put through the wringer in a sense in a desperate attempt to find a therapy or a drug that would help manage her bouts of deep depression; treatments, medications, hospital day program, electroconvulsive therapy, transcranial magnetic stimulation. Nothing worked for her. But it's not just her experience in actual fact; close to a third of the 230 million people living with depression worldwide echo her experience of persistent symptoms despite searching out a working solution. 

And then something new came her way through researchers at the University of California, San Francisco when a battery-powered matchbook-sized device was implanted in Sarah's brain, and calibrated to detect neural activity patterns occurring when she is becoming depressed. Her "pacemaker for the brain" responds by delivering pulses of electrical stimulation meant to pause the depression.

What Sarah and the UCSF researchers have embarked on is a personalized technique with a treatment known as deep brain stimulation; its purpose, to treat depression. The researchers make it clear that additional research is required before it is fully understood how effective this approach may be and to be able to gauge which patients would benefit from it. Parkinson's disease along with several other disorders use deep brain stimulation as a treatment.

The U.S. regulators have not approved the treatment for depression since results have been inconsistent, including two trials brought to a halt when it was realized that the technique appeared to have no benefits to patients making it superior to a placebo. What is different about the technique personalized for this test subject is the individualized locations targeted leading to patterns of electrical activity in people's brains. 

The "one size fits all" application -- as Dr.Darin Dougherty, director of neurotherapeutics at Massachusetts General Hospital -- was unsuccessful, he pointed out from his perspective of having been involved in one of the cancelled trials. Typically, deep brain stimulation is delivered continuously, while the device planted in Sarah's brain supplies a six-second burst when depression-linked brain activity becomes assertive. Dr.Dougherty explained that the stimulation is meant to disrupt or shift the neural activity, producing a healthier pattern easing symptoms of depression.

Along with the implant, continuation of psychiatric medications has not entirely succeeded in eliminating depression-causing activity, but in the same token Sarah now can manage her illness in an improved atmosphere; asserting her personal agency for routine decision-making where previously uncertainty assailed her. 

Standard treatments for depression sees some 30 percent of those afflicted unresponsive, or the side effects are intolerable to them. Deep brain stimulation, although promising, has a  high cost attached to it, making it unavailable to many depression sufferers since it comes with a cost of thousands of dollars and the surgical implantation can carry infection risks,

 

"Our job now is really o figure out what it is that identifies who needs this kind of involvement", explained Dr. Helen Mayberg of the Icahn School of Medicine, New York City. The number of times a day over a period of a year that Sarah's device detects depression-linked activity, delivering stimulation, has decreased somewhat. Sarah is unable to feel the finely tuned stimulation but believes she can detect its occurrence since she develops "emotional distance" that keeps negative feelings "compartmentalized". 

A small device implanted in the brain of a patient with severe, treatment-resistant depression was trained to issue electrical pulses to areas of the brain linked to the condition. The effects of the neurostimulation kicked in almost immediately, according to a new study from UCSF Health. (Getty Images/Chinnapong)