The Drugs That Changed Our Minds

by Lauren Slater

  As psychopharmacology gains a tighter and tighter grip on psychiatry, with drug companies luring psychiatrists to ghostwrite papers or represent medications in a positive light in exchange for handsome fees, psychiatry seems to grow more and more unstable, less and less likely, or able, to address the questions, controversies and contradictions at its core. These questions are moral as well as neurological or biochemical. On the one hand, is it right to put patients on a drug that may be making their brain behave in an abnormal fashion, especially when there is no definitive evidence of chemical imbalance in the first place? On the other hand, is it right to do nothing in the face of severe suffering?

  Does Depression Damage the Brain?

  Helen Mayberg, a neurologist and leading depression researcher at Emory University in Atlanta, reported in 2013 that psychotherapy, specifically cognitive behavioural therapy, is just as effective, statistically, as antidepressants are in reversing depression. But what about those patients who are too sick to tolerate the rigours of reflection? Beyond that, just because we have not found a chemical imbalance in the brains of mental patients does not mean there isn’t something terribly askew in those brains, something that antidepressants could be treating, albeit in indirect or not entirely detectable ways. Perhaps, for those with a depressive disorder, raising the amount of serotonin available in the synaptic cleft triggers the DNA to make a new protein, and this altered gene expression allows a patient to recover.

  Suppose we do nothing for the depressive except watch and wait for him to recover? The trouble is that myriad researchers and practitioners have suggested that depression is at least as toxic to the brain as the drugs we use to treat it. Untreated depression bathes the brain in the stress hormone cortisol, and long-term exposure to cortisol can cause the brain’s prefrontal cortex to waste. Thomas Frodl, a neurobiology researcher at Trinity College in Dublin, found that depressive episodes may result in neuroplastic changes to the brain. Frodl looked at inpatients with major depression alongside controls recruited from the community, studying their brains with fMRI technology both at baseline and three years later. ‘Compared with controls,’ he observed, ‘patients showed significantly more decline in grey matter density.’ In other words, contra Whitaker, untreated depression may cause brain damage too. Furthermore, other research shows that the more episodes of depression a person has, the more vulnerable he or she is to future relapse. Each episode, if left untreated, damages our grey matter, quite literally shrinking our hippocampus (a ridge in the brain responsible for memory), torquing our amygdala (an almond-shaped mass in the temporal lobe that handles the emotions) and sending our neurons into chaos.

  But if it is not about correcting a chemical imbalance, how else might psychotropic drugs help our brains? There is some research which posits that the reason why antidepressants take weeks to work, even though they almost immediately raise neurotransmitter levels, is that the medications, far from being toxic, are actually neurotrophic, meaning they spawn the cranial conditions that allow fresh neurons and new neuronal connections to be born. Drugs like fluoxetine, this research suggests, might increase branching of the dendrites in the neuron, a process that is the substrate of how we learn and feel and play. So it could be that the way antidepressants make us feel better is by helping the brain grow a richer, thicker forest of connections, which enable us to think faster and with more acuity. This line of reasoning stands in absolute contrast to what Whitaker and Glenmullen have found in their analyses of many outcome studies which all seem to show antidepressants burning the brain. That there can be two such utterly opposing views points to the fledgling science that psychiatry is shows we have a long way to go before even beginning to understand the interplay of people and their medicines.

  Diagnostic Drift

  In addition to the lowering of stigma associated with mental illness, the move towards a more individualistic and less communal society, and the possibility that antidepressants are irrevocably altering the interplay of our neurotransmitters, another possible reason for the sharp rise in depression in our time could be the phenomenon called ‘diagnostic drift’. This term refers to a particular diagnosis coming untethered from its initial conceptual moorings, so that a category of illness once tightly tied to very specific behaviours is suddenly relevant to everyone and his aunt, with the result that the disorder in question – in this case depression – becomes so watered down, so deeply diluted, that it almost ceases to have any medical meaning at all.

  Psychiatry as a profession has been through several cases of diagnostic drift. Post-traumatic stress disorder, now as common as crisps, was once reserved for war-ravaged veterans trying to reintegrate back into a society hardened against them. Then, as a result of cultural shifts and the rise of feminism, ‘trauma’ became a household word, and it wasn’t long before patients were suddenly releasing repressed ‘memories’ of heinous acts perpetrated by people dressed as devils. Memories, for a time, got so out of hand, so deviously fictive, that patients began claiming they had multiple personalities, split-off selves they said were the result of their severe traumas. The acme of this cultural and therapeutic frenzy was the construction of a whole new diagnostic category: multiple personality disorder, a diagnosis that, in the 1980s, was fairly easy to obtain if you came to see your therapist with complaints of forgetfulness or strange feelings of detachment, both of which were supposed signs of other personalities lurking around the patient like invisible ghosts.

  Eventually the fad died down, in part because psychologist Elizabeth Loftus definitively showed that it was eerily, easily possible to induce false memories in a substantial number of people by simple suggestion. Her work, perhaps more than anything else, signalled the end of the trauma party that had left its thumbprints all over the excessive 1980s. Now multiple personality disorder does not even exist as a diagnostic category any more. It has been replaced by a diagnosis called dissociative identity disorder, which shares some features with its precursor but is rarely used. While we can be thankful for that fact, this history also reveals how uncomfortably unstable and suggestible psychiatry’s diagnoses really are, how they sometimes arise in large part out of cultural constructions and committee consensus and not out of what we would most want them to stem from: blood, bile, torn tissue or altered neurotransmitter levels.

  Diazepam, the vaunted tranquilliser for the relief of anxiety and tension, was another instigator of diagnostic drift. By 1969, six years after it was approved and marketed under the brand name Valium, diazepam had become the top-selling pharmaceutical in the US, a status it retained for the next fourteen years, peaking in 1978, with more than 2 billion tablets sold. Once that drug came on to the market, suddenly hundreds of thousands, and then millions of women were suffering from a bad case of nerves. It’s not that anxiety didn’t exist before diazepam but rather that diazepam, once it was born, gave vast numbers of people who were tense by nature a chance to turn their character trait into an illness. Once that trait had been named a sickness, and the person with that trait a patient, the new medication became necessary.

  But for all the popularity of diazepam and the other benzodiazepines, the birth of fluoxetine caused a cultural shift in the US more seismic than anything in psychiatry that had preceded it. Yes, chlorpromazine forever changed the face and fate of madness, but its relevance was restricted only to those with a truly rare disorder, pushed to the sidelines of society. The drug never became a household word. Likewise, the tricyclics and the MAOIs never penetrated deeply into popular culture. For the most part, these drugs were reserved for the severe mental pain that accompanies the rare event of a major depressive episode. More common is a condition called dysthymia, a milder form of depression, the equivalent of a persistent low-grade fever. Individuals with dysthymia, glass-half-empty characters, usually function fine but possess little capacity for joy.

  When fluoxetine came on to the market, in early 1988, people experiencing dysthymia were ultimately the ones who made the drug
a runaway success. It was as though everyone with any kind of depressive streak came forward with palm held out. Researchers began to discover, serendipitously, that the drug was not tied tightly to major depression after all. In fact, much like chlorpromazine and its off-label uses a generation earlier, fluoxetine could successfully treat not only a nation of dysthymics but also those with conditions not even in the DSM. Time reported, for instance, on a patient named Susan, a self-described workaholic who got irritable around her periods and who had once thrown her wedding ring at her husband. On fluoxetine, the jagged edges of her personality were planed into something smooth, and functioning was so much easier that life became a joy. Eventually the concept of depression ballooned to embrace the irritable Susans, the workaholics, the pessimists, the panicky and the malcontents, to the point where the diagnosis included personality types as much as any specific psychiatric syndrome. Practitioners in the field now prescribe fluoxetine for a wide range of conditions from panic attacks to cataplexy, suggesting that perhaps all of these disorders share a common neural substrate with depression.

  Of course, these developments were all to the benefit of Eli Lilly, and the drug company promoted the diagnostic drift, encouraging GPs and psychiatrists to treat even mild complaints with their new concoction. Lilly instituted a ‘Depression Awareness Day’, when anybody could call an 800 number to see whether he or she was depressed, punching in numbers on the phone’s keypad to answer yes or no on a ten-item ‘exam’ featuring statements such as ‘I get tired for no reason’.

  The publication of influential psychiatrist Peter Kramer’s Listening to Prozac, a bestseller that by and large painted a glowing picture of a drug able to remove the thorns in anyone’s character, did nothing to dispel the building enthusiasm. The book not only helped raise the popularity of the drug but also caused the definition of depression to dilate. After all, if fluoxetine was an antidepressant, then daily disappointments and quotidian difficulties – misfortunes big and small – had to be subsumed within the concept of depression in order to justify the large numbers of people taking the medicine. University of Toronto historian Edward Shorter, in his History of Psychiatry, considered by many the standard text in the field, draws a distinction between the solid science involved in the discovery of fluoxetine and the mere scientism beneath its promotion to the masses. ‘Good science lay behind the discovery of fluoxetine as a much safer and quicker second-generation antidepressant than imipramine and the other tricyclics,’ he wrote. In contrast, ‘scientism lay behind converting a whole host of human difficulties into the depression scale, and making all treatable with a wonder drug. This conversion was possible only because clinical psychiatry had enmeshed itself so massively in the corporate culture of the drug industry. The result was that a scientific discipline such as psychiatry nurtured a popular culture of pharmacological hedonism, as millions of people who otherwise did not have a psychiatric disorder craved the new compound because it lightened the burden of self-consciousness.’

  It is a serious problem to which psychiatry seems to be particularly vulnerable. There is not, for instance, an epidemic of pulmonary specialists touting drugs for profit. One naturally wonders what it is about the profession of psychiatry that makes it so susceptible to compromise, both financially and diagnostically. Psychiatrists themselves are responsible for the oil spill of depression diagnoses, and contrary to what Robert Whitaker has written, it may be that this diagnostic proliferation is all the explanation we need for why depression is on the rise. In truth, one hopes that diagnostic drift is the answer to the mysterious increase in depression, since, while it is a troubling phenomenon, it is reversible, at least in theory, which makes it less troubling than the thought of brain-damaged patients gobbling their psychotropics because they really have no other choice, their neurons so perturbed that their descent into depression happens faster and faster, with shorter intervals of time in between, until relapse is inevitable and addiction all but guaranteed.

  All-Purpose Fluoxetine

  Fluoxetine and other serotonin boosters were heralded as psychiatry’s second big pharmacological breakthrough in the treatment of depression. The drugs were supposedly more advanced, more effective and above all cleaner than the tricyclics and the MAOIs discovered in the 1950s. On closer examination, however, the SSRIs, while in some ways an improvement on the previous class of antidepressants, were not quite the breakthrough the field claims. Because the serotonin system is so widespread, the drugs cannot, by definition, be clean, meaning they cannot actually target a specific site in the brain. The problem when it comes to truly understanding depression, then, is not just the particular negative side effects, such as sexual dysfunction, that SSRIs cause by disabling disparate neural systems. It’s also, oddly enough, their ‘positive’ effects. When serotonin boosters are given to non-depressed subjects, for instance, the subjects become peppier, chattier, more social and in general more upbeat. ‘What’s wrong with that?’ you might ask. Nothing in general, except that although this outcome might seem desirable on the one hand, it’s also, on the other, an obvious indication that these purportedly superior drugs are essentially blanketing the entire brain, much like ibuprofen for a headache. But while fluoxetine might act as a buffer to reduce pain, it does not treat the cause of depression, which remains unknown, and therefore the drug has little to teach us about the origins of the disease.

  Similarly, studies with animals have shown that when fluoxetine is given to baby rats removed from their mother, it reduces the frequency of their ultrasonic cries, again suggesting that the drug is more like morphine or cocaine. It is able to assuage general distress, in other words, but unable to tell us as much about depression as the earlier drugs like imipramine did. The tricyclics, in sharp contrast, do nothing for already non-depressed subjects except give them nasty side effects. But because tricyclics work only on depressed subjects and relieve only depression, they may be a superior torchlight into the mechanisms of pathological despair.

  The final time I talked with her, Ann Bolo, having recently celebrated her daughter’s first birthday, was finally off fluoxetine, unable to tolerate any longer its sexual side effects. While the drug is touted as non-addictive, Bolo found that to be utterly untrue. ‘Getting off Prozac was one of the hardest things I ever had to do,’ she claimed, and described enduring withdrawal effects that stunned her: electrical zapping sensations in her head, dizzying migraines, all-consuming nausea and a deep despair that she rode out with exceptional strength and commitment. ‘There were so many times in those first weeks,’ Bolo said, ‘when I was like, All right, I give up, put me back on the drug. But my marriage was at stake, and prior to having the baby I hadn’t been depressed, so I hung on to the belief that I’d get my old self back.’ And she did. Others, however, are not so lucky. Many, many patients are sustained on SSRIs for years, for decades, and when they try to go off, they cannot tolerate the withdrawal. Others, as Whitaker has written, have relapses while on the drugs, causing them to increase their doses and only further perturb a brain already tilted by the onslaught of synthetic chemicals.

  Still, psychiatry continues to tout the SSRIs as one of its biggest innovations to date, and takes it one step further by claiming that at long last it is practising medicine in truly scientific ways. Jeffrey A. Lieberman has gone so far as to assert that in the first decade of the 21st century, ‘the once stagnant field of psychiatry showed all the signs of a profession undergoing intellectual rejuvenation.’ It’s an opinion that stands in direct opposition to what Cornell University psychiatrist Richard Friedman, director of the Psychopharmacology Clinic at New York–Presbyterian Hospital, has bluntly stated, ‘It is hard to think of a single truly novel psychotropic drug that has emerged in the last thirty years.’

  Rising Doses

  I’d like to think psychiatrists such as Lieberman are correct. After all, I have a vested interest in a vibrant and intellectually honest psychiatry, seeing as I daily swallow a number of its drugs.
On the one hand, I have been on a serotonin booster since I was twenty-five years old, and on a tricyclic for six years before that; I am currently fifty-four. For thirty-five years, then, I have been trying to soothe my brain with psychiatry’s medicines, but I cannot confidently claim that I am better because of it. The picture is mixed. Prior to the SSRIs, I swallowed imipramine. I did not get well and seemed to have no real future prospects of getting well. On SSRIs, however, I have been able to stay out of mental hospitals, to write nine books, to bear two babies who are now adolescents with their own keen interests and proclivities, to manage a marriage and then a divorce, and, just as importantly, to nurture a circle of friends. If that isn’t an advertisement for psychiatry, then I don’t know what is.

  On the other hand (and there is always another hand when it comes to the slippery subject of psychopharmacology), the 10 milligrams of fluoxetine I first took twenty-nine years ago, and which so magically removed the dead-weight symptoms so that my whole world became a gorgeous glimmer, worked for only a little while, and it wasn’t too long before I needed 20, then 30, then 60, then 80, then 100 milligrams of fluoxetine in order to get the relief that the initial tiny 10 milligrams had provided. What the rising doses and the relapses that preceded them suggested, of course, was that my brain was adapting to the drug and that my illness, far from being quelled, was raging right along beneath the blanket fluoxetine provided.

  Yet even though I was terrified of having to raise the dose continually, fluoxetine had exerted such a powerful effect against my obsessive-compulsive behaviour, and my bipolar depressions, that I became completely dependent on it psychologically and perhaps physically. The idea that one day it might not work for me any more horrified me, and I spent more than my fair share of nights fretting about a future that would turn into a rerun of my past, which had been full of the window grills set into the mortar of the mental hospitals that housed me. The thought of backsliding petrified me. More than anything else, I needed my medication to work, but the signs increasingly suggested that I could not count on fluoxetine, that it was at best a temporary fix and that eventually I’d have to dose myself so severely that I’d do real damage to my liver, which metabolises the drug, or to my kidneys or, God knows, to my brain.