The chemical imbalance theory has fallen in status from bedrock scientific principle to mere marketing device in the minds of many researchers.
A broken heart and a blue, bedevilled brain.
They've been twinned, metaphorically, in poetry and song for millennia.
Over the past 50 years, however, science and medicine have been contemplating the organs and their maladies on a purely biological basis.
In particular, an evolving half-century of medical wisdom came to this conclusion:
Just as coronary diseases - or those of the liver, or kidneys for that matter - were plainly the result of physiological disruptions, so too were the mental illnesses of the brain.
Now, neuroscience would attribute such things as depression and psychosis to "chemical imbalances" - specifically to disruptions in the neurotransmitters that allow the brain's billions upon billions of grey matter cells to speak to one another.
And so mental illnesses became normalized and destigmatized.
And so their treatments, to a huge extent, came off of the couch, out of the asylums and onto pharmacy counters.
And so a $70-billion drug market grew to feed tens of millions worldwide with daily doses of magic bullets - pills that could bring their brain chemistry back into balance.
Trouble is, in the minds of many neuroscientists today, that chemical imbalance theory has turned out to be a myth, with little more scientific or medicinal substance than poetry or song.
And the pills are now largely recognized by a multitude of experts, as well as some of the pharmaceutical companies that make them, as concoctions of magical thinking.
"It's certainly been blown up inside the profession. No insiders believe in these (neurotransmitter imbalance) theories anymore," says Edward Shorter, a medical historian at the University of Toronto.
"That's true of thousands and thousands of researchers. But somehow that news has not filtered through to the public as a whole," says Shorter, who has written numerous books on psychiatric practices.
Some top neuroscientists argue that this is nonsense, that neurotransmitters are a critical and obvious aspect of psychiatric research and therapy.
A key proof of this, they say, is that drugs targeting these brain chemicals have worked wonders - miracles even - in controlling mental and neurological ailments such as schizophrenia and Parkinson's disease.
But if this is so, asks psychotherapist and author Gary Greenberg, why have many drug manufacturers jettisoned the neurotransmitter theory?
Why are they now shuttering or shrinking their massive, psychiatric research labs, where they'd sought new compounds to follow in the blockbuster footsteps of antidepressants like Prozac, Paxil and Zoloft?
"The brain is turning out to be a moving target," says Greenberg, who wrote a controversial article on the subject for The New Yorker last month.
"And consequently drug companies, which are profit-motivated, are not seeing it (neurotransmitter imbalances) as a fruitful avenue," he says.
Neurotransmitters such as dopamine, serotonin and norepinephrine are the brain's chemical ferrymen, allowing electrical impulses to cross from one synapse to another in the mesmerizing cascades of neuronal connections that render thought, emotions, movement initiation and a host of other brain activities.
Imbalances in these communicating chemicals, it was held, were the key cause of the major psychiatric disorders. And targeting these imbalances with drugs became the obvious strategy to treat mental illnesses.
In schizophrenia, for example, it was the dopamine system that was out of whack, while serotonin shortages triggered depression.
But Shorter says the past several years have seen the chemical imbalance theory fall in status from bedrock scientific principle to mere marketing device in the minds of many researchers.
"The view among neuroscientists is that this emphasis on neurotransmitters as the cause of mental illness is more of a (drug sales) concept than a scientific concept," he says.
"It helps drug companies sell drugs."
It does so, Shorter says, by giving physicians an organic medical justification - akin to high cholesterol in cardiovascular diseases or blood sugar levels in diabetes - to prescribe the drugs, while offering patients a comforting rational for taking them.
"But in fact nobody knows what the cause of these mental illnesses (are)," Shorter says. "Almost certainly the cause is situated somewhere in the brain, but what the neurochemistry of psychiatric illness is remains a complete black box."
Not so fast, says Anthony Phillips, director of neuroscience and mental health at the Canadian Institutes of Health Research.
Phillips agrees that the failure of neurotransmitter research to produce new drugs has been a source of consternation in the field.
"There is absolutely concern, there are meetings at the highest levels," says Phillips, who has spent decades studying brain chemistry at the University of British Columbia.
But, he says, most top researchers are still certain that neurotransmitters play a significant role in several psychiatric maladies.
"I think you'd find thousands of neuroscientists who'd think that at one level there is a role for several - maybe not all that many - but certainly several of the major neurotransmitters."
With schizophrenia, for example, there is no question that one of the five neural receptors that welcome dopamine into brain cells is a key player in the disease, Phillips says.
And drugs that block that "D2" receptor work wonders in calming psychotic symptoms in schizophrenic patients, whether a dopamine imbalance is the sole cause of the disease or not, he says.
Even Phillips, however, concedes that those touting the neurotransmitter theory overplayed their hand in depression research.
"Where I think this whole argument got off the track was in the case of the antidepressants, no question," he says. "The idea that depression simply reflects too little serotonin is clearly an overinterpretation of the data."
Phillips, however, says new research shows that disruptions in other neurotransmitters like dopamine are also involved in depressive disorders.
He says as well that current antidepressants may well be acting to stimulate neural stem cells, which could also be the source of their therapeutic effects.
But to understand how the increasingly maligned concept of chemical imbalances came to hold such sway in neuroscience, you have to look at how the drugs that target them were discovered in the first place.
After the Second World War, Greenberg explains in his New Yorker article, scientists rolled out a remarkable string of pharmaceutical successes that would revolutionize the treatment of major psychiatric disorders.
Dating back to 1949, these included the discovery of drugs like Lithium to treat manic depression, Thorazine to combat schizophrenia, the antidepressant Tofranil and the sedatives Librium and Valium.
But these discoveries resulted almost entirely from serendipitous accidents, Greenberg says. And scientists only went searching for the neurological roots of the drugs' workings after the fact.
They hit on neurotransmitters, which were first identified in the 1950s and provided an appealing answer, one that allowed pharmaceutical companies to market the drugs with scientific authority.
Decades of frustrating research chipped away at the neurotransmitter theory, until it was left in rubble, Greenberg says.
It's not uncommon in medicine to look for a drug's mechanisms after its discovery, he said in an interview with the Star.
"What is uncommon is you look and you look and you look for 50 years and you don't find."
Scientists have shown that Prozac and its lucrative antidepressant ilk do indeed act on serotonin.
These drugs, known as SSRIs (selective serotonin reuptake inhibitors), block serotonin-producing cells from reabsorbing a good portion of the neurotransmitter they secrete - as they normally would - leaving more of the chemical available for neural communications.
"But nobody has ever demonstrated that a shortage of serotonin was the cause of depression or any other illness," Shorter says.
And if the drugs do work on some people, as they almost certainly do in an estimated 50 per cent of depressed patients, it's not at all clear they do so because of their serotonin actions.
"They (the drugs) may well have some mechanism that is entirely unknown to us," Shorter says.
"It may be part of the larger causal chain in the brain that is responsible for mental illnesses, but we don't really know where that chain begins or where it ends."
And while it may be better to intervene successfully in the absence of such knowledge, Shorter says, the stringent research focus on neurotransmitters as the key cause of mental illness stopped producing new findings long ago.
"Certainly there haven't been any new drugs on the market in the last (decades) using these (neurotransmitters) as targets," he says.
A main reason for that lack of success, Shorter says, is that the diseases themselves were misunderstood - that the Diagnostic and Statistical Manual of Mental Disorders (DSM) that describes them was often too simplistic.
Take major depression, for example, which has been relentlessly marketed as "the disease of the month," Shorter says.
"In fact it (depression) is a very heterogeneous concept and consists of two very different forms of depression that are just as different as mumps and tuberculosis," Shorter says.
"So trying to develop a single drug for these two very different illness entities is going to be doomed to failure."
Even schizophrenia, which has long and successfully been treated by medications targeting the dopamine system, should be thought of as a variety of ailments, Shorter says.
While antipsychotics targeting dopamine pathways have been hugely successful in treating hallucinations and delusion, they do little to relieve other symptoms, such as the social withdrawal, muddled thinking and lethargy that have been lumped in with the ailment.
Phillips, however, says drug company labs were not looking at the wrong targets and diseases so much as employing bad science.
He says their huge, in-house labs were too insular and secretive and often too focused on small numbers of neurochemical targets.
"Sadly, the (drug company) scientists, while very good, weren't necessarily as good as all the scientists in the world working in an open-sourced way to address these matters."
Phillips says several pharmaceutical companies have switched gears in their search for new drugs, exiting their secretive silos and entering public-private partnerships with university and hospital labs in the more open, sharing strategy that typically makes for successful science.
Even in these broader settings though, he says that neurotransmitters will continue to be the main research focus.
Still, there are other targets emerging in the quest for psychiatric medications, says Dr. James Kennedy, director of neuroscience at Toronto's Centre for Addiction and Mental Health.
For one thing, Kennedy says, neuroplasticity, or the brain's ability to grow new connections, has become a focus of keen interest in mental illness research.
He says the brain, long thought of as a static structure, is instead constantly losing and forming new synaptic connections. And when new connections fail to form, illnesses such as depression can follow.
Unfortunately, current compounds that can encourage the sprouting of new brain connections can also cause cancer, Kennedy says.
"So we've got a long way to go, (though) we're very aware of the (brain growth) mechanism we should target," he says. "But it's a very long, difficult, daunting process."
Today's ubiquitous antidepressants - and schizophrenia medications even more so - should by no means be cast as snake oil, Shorter says.
Antipsychotic drugs are responsible, he says, for emptying the insane asylums over the past four decades, freeing millions from the tortured misery often suffered within their walls.
And SSRIs work well for many people experiencing anxious, obsessive, sleepless forms of depression, though they do little for those suffering from melancholic varieties - a group that is especially at risk of suicide.
"I think the neurotransmitter era served us well in many different ways," says Dr. Sidney Kennedy, head of psychiatry at Toronto's University Health Network.
"And you work with what the technology of the day allows you to work with."
He says, for example, that high-resolution imaging technology that's been developed to peer into working brains allows a better understanding of the organ's circuitry.
And these scans, along with the identification of genetic and protein markers, past trauma and other factors associated with mental disorders will allow for a far more sophisticated diagnosis of patients' individualized psychiatric ailments and the likelihood they will respond to current treatments.
Even among the patients who do respond to the SSRI drugs, however, Shorter says there is no evidence that a great many of them exhibit serotonin shortages.
"They may well have some other mechanism that is entirely unknown to us," he says.
"The neurochemistry of the brain is very complicated. We don't even know how much we don't know."
What is almost certainly known, however, is that there is a large placebo effect in play with modern antidepressants, Shorter says.
He says re-examinations of the research results that won antidepressant drugs their regulatory approval to begin with have shown that they fared little better than sugar pills in several clinical trials.
"In about half of the trials they failed to beat placebos, they just are not very effective drugs (for some forms of depression)," he says.
Certainly the chemical imbalance theory helped to destigmatize psychiatric illnesses, especially depression, and place them on a par in the public's eye with any other physical ailment, Shorter says.
While this is a positive, however, the ready access to psychiatric drugs has caused many physicians to forgo more effective but controversial treatments like electroconvulsive therapies, he says.
Despite ample evidence that they don't work for many - and an obvious uncertainty among pharmaceutical companies about their mechanisms - drugs targeting neurotransmitters are still "given out like candy" to patients around the world, Shorter says.
This is due in large part to a continued belief among many physicians and patients that the issue remains settled scientifically, he says.
But it also reflects an alarming increase in the diagnosis of depression seen after the 1987 entrance of SSRIs into the market - to a massive advertising processional.
"Whether or not these drugs are over-prescribed, that should be a matter for very serious discussion in the medical profession," Phillips says.
"One of the problems that I would see is that anybody is allowed to give these drugs (and) most of them are prescribed by a general physician who has hardly any training whatsoever in psychiatry."
For Shorter, this is the nub of the over-prescribing problem.
"Physicians love to end the consultation with a prescription, it makes them feel like they are doing something useful," Shorter says ( via thestar.com ).
"But the general rule is, if you get better with a cheque for $5,000, or a new boyfriend, you probably don't have a depressive illness."