Listening to Prozac by Peter D. Kramer is such an interesting read regarding the introduction of what we call the “grandmother antidepressant”. This book discusses many theories, various other medications used in the past, and the introduction of Prozac in the US in the 1980’s.

If you would like to get this book, click here. 

 

My favorite excerpts are below:

Prozac was released in December 1987. Prozac enjoyed the fastest acceptance of any psychotherapeutic medicine ever- 650,000 prescriptions per month by the time the Newsweek cover appeared, just over 2 years after Prozac was introduced. 

 

Prozac’s enormous popularity of how it went beyond treating illness to changing/ altering personality. We have found a medication that can affect personality, perhaps even in the absence of illness.

 

Often it will be the most competent child in a chaotic family who will come for help. In the field it is known as the “parental children”. 

 

Depressed mother’s children, since they have to spend their formative years gauging mood states, develop a special sensitivity to small cues for emotion. In adult life, some maintain a compulsive need to please. 

 

Some people might prefer pharmacologic to psychologic self-actualization. Psychic steroids for mental gymnastics, medicinal attacks on the humors, anti-wallflower compound- these might be hard to resist. 

 

Hyperthymics are merely optimistic, decisive, quick of thought, charismatic, energetic, and confident. 

 

I found it astonishing that a pill could do in a matter of days what psychiatrists hope, and often fail, to accomplish by other means over a course of years: to restore to a person robbed of it in childhood the capacity to play. 

 

She (a social worker)  believed that medication-induced change, unaccompanied by growth in self-understanding, was inferior to what psychotherapy has to offer. 

 

“Mothers little helper”- Miltown, amphetamine, barbituates, Librium, and Valium were the most popular and widely available in the 50’s and early 60’s- that were used to keep women in their place, to make them comfortable in a setting that should have been uncomfortable, to encourage them to focus on tasks that did not matter. 

There is a sense in which antidepressants are feminist drugs, liberating and empowering. 

 

The story of Lithium has the quality of legend. Lithium is an element of the periodic table, where it sits just below sodium. Like sodium, lithium readily forms salts. Early in the century, lithium bromide had been used as a sedating tranquilizer but lithium fell out of favor in the 1940’s when it was used in an uncontrolled way as a sodium substitute for cardiac patients, some of whom died. At just this inauspicious time, in 1949, the Austrailian John F. J. Cade, “an unknown psychiatrist, working alone in a small chronic hospital with no research training, primitive techniques and negligible equipment”, discovered that lithium salts were a remarkable specific treatment for manic depression. 

Cade’s discovery is often characterized as serendipitous. Cade had found that the urine of manic patients was especially toxic to guinea pigs, and he was looking for the responsible substances. He thought one might be uric acid, and he began experimenting with lithium urate, not because of any psychiatric properties of lithium, but because lithium urate was the most soluble salt of uric acid. To Cade’s surprise, far from being toxic, the salt protected guinea pigs against the urine of manics, and it also sedated the animals, effects Cade found were due to the lithium. He immediately tried other lithium salts on himself and, when they proved safe, on ten hospitalized manic patients, all of whom recovered, some almost miraculously. The discovery of lithium as an antimanic agent resulted from one man’s curiosity and powers of observation and deduction. 

Because of the cardiac deaths, as well as Cade’s lack of renown in the profession, the use of lithium for mania spread slowly. But by the late 1960’s, doctors once more considered lithium to be a reasonably safe drug. It was also understood that lithium can treat and prevent recurrences of manic-depressive illness but is only rarely effective for schizophrenia. 

 

The success of lithium set off an explosion of precise psychiatric diagnosis. In a few decades, American Psychiatrists went from using only 2 diagnoses, neurosis and schizophrenia, to using hundreds. Lithium and the one-drug/one-disease model had an enormous influence on the minds of physicians. Lithium made it look as if medications would be splitters- definers of illness. But, sadly, there has never been another lithium. Most subsequent medications have been lumpers, and none more so than Prozac. Within a couple of years of its introduction, Prozac was shown to be useful in depression, OCD, panic anxiety, eating disorders, premenstrual syndrome, substance abuse, attention-deficit disorder, and a number of other conditions. 

 

Lithium is now being used to treat other forms of disturbance. 

 

The first modern antidepressant, iproniazid, enjoyed its own meteoric career. Iproniazid was developed as an antitubular drug in the early 1950s and at first it appeared successful. Not only did it decrease the number of tubercule bacilli in the sputum, it also stimulated patients appetites, gave them energy, and restored to them a general sense of well-being. 

Iproniazid did suppress the replication of bacteria. It was discovered to be a “psychic energizer” to use the phrase of Nathan Kline, the psychiatrist who investigated the drug’s effects on the mind. Kline hoped an increase in a patient’s vital energy would reverse depression. Using the language of psychoanalysis, then the dominant theory of mind, Kline wrote: “The plethora of id energy would make large amounts of energy easily available to the ego so that there would be more than enough energy available for all tasks. Such a situation would result in a sense of joyousness and optimism. 

Approximately four hundred thousand depressed patients were treated in the first year. Unfortunately, 127 of these patients developed jaundice. Given the prevalence of viral hepatitis, this was probably a small number of cases for the population involved, but the manufacturer thought (wrongly) that it had a more potent antidepressant coming to market, so, rather than fight the bad publicity, it withdrew iponiazid. Iproniazid’s reputation had been fatally tainted by the report of side effects, and it was never heard from again. 

 

Leading researcher in Switzerland, Ronald Kuhn, was pursuing a different line of reasoning. The most effective drug treatment for depression was opium. Opium was recognized as an odd substance. It caused some of the symptoms melancholy in healthy subjects and alleviated symptoms in the depressed. Kuhn thought opium presented the proper model for a true antidepressant. 

The hallmark of opium was that it restored energy in the depressed without being inherently energizing. 

 

Chlorpromazine (Thorazine) was introduced in 1952 and it constituted a breakthrough in the treatment of schizophrenia- it is known as the drug that emptied the state mental hospitals.

 

 In September 1957, less than half a year after the reports regarding Iproniazid’s initial success, Kuhn announced that he had found a substance that sedated normal people but relieved depression. His new drug was called imipramine (tofranil). The theoretical importance of imipramine was that it was the first nonstimulating antidepressant. Despite the enthusiasm of isolated researchers, the announcement of the efficacy of imipramine was mostly met with skepticism. An entirely new medicine with no other indication than the treatment of depression, imipramine took some years to catch on. 

 

The great result, in terms of our theoretical understanding of mental functioning, has been the biogenic-amine theory of depression. Stated simply- the theory holds that mood is determined in the brain by biogenic amines– complex chemicals a part of whose structure resembles that of ammonia. 

Shortly after the drugs were introduced, it was shown that both iproniazid and imipramine influence the way nerve cells terminate messages. Nerves communicate by releasing “transmitter” substances- in this case amines- into the space, or synapse, between cells. The message is then ended by a two-stage process in which the amines are taken back up into the transmitting cell and inactivated by “janitorial” enzymes. 

 

The amine hypothesis is perhaps false and at least incomplete. Like the evidence supporting the amine hypothesis of depression the evidence against it came from drug effects. For one thing, researchers identified antidepressants (not in use in this country) that have no direct effect on the amines. For another, there is a curious time lag in the onset of action of antidepressants. Imipramine can block the reuptake of neurotransmitters in a matter of minutes or hours. But it takes about 4 weeks for patients on imipramine to begin to feel less depressed. Why should a patient with effective levels of the relevant neurotransmitters not experience an immediate change in mood? Why do some depressed patients not respond at all? The amine hypothesis cannot answer these questions. A particular line of evidence made it clear early on that the biogenic-amine hypothesis was imperfect. 

 

Depletion of amines is not enough in itself to cause depression. 

 

Only 5% of neurotransmitters in the brain occur via amines, but amines are the lighted streetlamps under which the secret of depression is most often searched for. 

 

Monoamine Oxidase is the janitorial enzyme that oxidizes (burns, or inactivates) certain amines. By inhibiting monoamine oxidase, MAOIs prolong the effective life of those amines in the brain.  

 

In the 1960’s, a rash of deaths from brain hemorrhage was reported among patients taking MAOIs; other patients, thought they did not die, experienced severe headache on the basis of extremely high blood pressure, an odd occurrence because the MAOIs were used to lower blood pressure in people with hypertension. 

That means by which MAOIs make blood pressure skyrocket was elucidated in an interesting way. A British pharmacist who read a description of patients’ headaches wrote a seemingly naive letter noting that they resembled those his wife suffered when she consumed cheese, but not butter or milk. He asked whether the reaction might not be related to an interaction between MAOIs and substance in cheese. Barry Blackwell, the doctor to whom the pharmacist had written, at first dismissed the suggestion- no drugs were known to interact with food substances in this way. But then he began to observe a series of patients on MAOIs who suffered headache and even extremely high blood pressure upon eating cheese. Convinced that the “cheese reaction” was real, Blackwell set out to identify the offending ingredient. It turned out to be a chemical, ordinarily broken down by MAO, that causes nerve cells to release complex amines. Aged cheeses contain large amounts of this substance- so much that, when the janitorial enzyme is poisoned, a cheese eater on MAOIs will be flooded with biologically active amines, including ones that raise blood pressure. Once the problem had been explained, it was a simple matter to advise patients to avoid foods that interact dangerously with MAOIs. 

 

From the time antidepressants were developed, two different amines were understood to influence mood: norepinephrine, a substance that was familiar to pharmacologists because of its close relationship to adrenaline, and serotonin, another substance that is active throughout the body but about which less was known. 

 

The new grail, pursued throughout the 1960s and 1970s and well into the 1980s, was a drug that would be like imipramine but that would selectively influence serotonin. 

In its search for a clean analogue of imipramine and for an analogue that would be strongly alter serotonin levels, psychopharmacology treaded water for over 30 years. 

 

Hopes that a more specific agent would make a difference were dampened by the advent of Desyrel (trazodone) in the early 1980s. Desyrel was so sedating that it had been marketed first in Europe as an antianxiety drug, but patients would tend to become tired or dizzy before you could get them on doses that radically changed the functioning of nerves that use serotonin. 

 

By 1970 most research in America was focused on norepinephrine as the key chemical in mood regulation, this book summarized findings, better appreciated in Europe, that pointed to a role for serotonin. 

 

Psychiatrists were aware that Anafranil (clomipramine) was about to be introduced in the US. Though as dirty a drug as any, it also affects norepinephrine, histamine, and acetylcholine pathways. 

 

Xanax is an unusual compound. Although part of the xanax molecule looks like an antidepressant. It was first released as an extraordinary treatment for panic anxiety and it was believed to have very few side effects. 

 

L-tryptophan is an essential amino acid, and it is the substance from which the body makes serotonin. 

 

Late adolescence is a time in which it is normal for rapidly changing moods to accompany an unstable sense of self. Identity, which includes sensitivity to approval and rejection, is a central development issue. 

 

Emil Kraepelin, the contemporary of Freud who differentiated manic depression from schizophrenia, had noted that a severe mood disorder typically began with trauma, was later reactivated, and finally took an “independent course”. 

 

Robert Post, a psychiatrist who has devoted his professional life to the elucidation of manic-depressive illness, decided to try these patients on Tegretol, a medicine heretofore used mainly to control seizures in outright epilepsy but bearing a chemical resemblance to the antidepressants. 

Tegretol seemed a promising drug because of a sort of “experiment of nature”: epileptics on Tegretol were observed to experience improvements in mood. Psychiatrists were wary of Tegretol, because it has a rare, severe side effect. Tegretol can cause an irreversible drop in the production of white blood cells, which are needed to fight infection. Tegretol turned out to be a better medication for rapid cycling than lithium and useful in other types of manic depression that do not respond to lithium. 

 

If rapid cycling and epilepsy are connected, beyond analogy and their responsiveness to Tegretol, it is in a complex, still-undiscovered way. Both do often occur in the same part of the brain, and both probably involve a disorder in the transmission of signals, but there was still a good degree of serendipity involved in the discovery that two possibly “kindled” illnesses respond to the same medicine. 

Kindled rats suffer physical trauma, whereas the histories of most depressed people reveal psychological trauma. But the similarity in pattern of illness between depressed patients as they progress to rapid cycling and kindled rats as they progress to epilepsy allows researchers to speculate that, for certain brain cells, physical and psychological trauma may be quite similar in their effects. 

 

A biological image of “functional autonomy”: trauma is translated into anatomical changes in the brain, even before any major illness becomes evident. Under the kindling model, rats become sensitive to ever more subtle stimuli. This model reflects some of what we see in certain rejection-sensitive patients: symptoms become “unmoored” from their historical antecedents, and people who have suffered serious trauma later find themselves vulnerable to what for others would be minor losses or threats of loss. 

The kindled-epilepsy model also resembles models of how animals learn to see. At first, animals have to scan a visual field painstakingly; in time, they presumably make hard neural connections that allow certain complex shapes to be processed simply and rapidly. In both cases, kindled epilepsy and perceptual learning, a repeated stimulus results in an anatomical change in the brain. Kindling appears to be a kind of learning, but a learning that can occur independent of cognition. 

 

Lithium tends to be most effective when a patient has had 3 or fewer episodes of mania. Thereafter, antiepileptic drugs, such a Tegretol, are more likely to work. 

 

The kindling model has led researchers to fear that, in progressive manic depression, drugs appropriate to the early stages of illness become ineffective as the illness worsens, because of structural changes in the sufferer’s brain. The goal is to prevent the hard-to-reverse deterioration that occurs as the illness progresses. 

 

Psychiatric researchers have been interested in another hormone produced by the adrenal gland, cortisol. Cortisol is the hormone that is abnormal in Addison’s disease and Cushing’s disease. It has effects on healing and inflammation. The body’s own cortisol, when released into the bloodstream, affects mood, food intake, the sleep-wake cycle, and level of locomotor activity- all factors altered in depression. It is sometimes called the stress hormone. 

 

Cortisol levels are high in many acutely depressed adults. Autopsies often show the adrenal gland to be enlarged in adults who have died by suicide. The gland is also enlarged, according to imaging studies, in about a third of depressed patients. 

 

Most of what interests researchers is not so much cortisol produced by the adrenals as the substances in the brain that stimulate the adrenals. At the top of the cascade is a substance produced in the brain called corticotropin-releasing factor (CRF). 

 

Chronically stressed rats have enlarged adrenal glands. Moreover, stressed rats produce excess CRF in regions of the brain that parallel those known to affect mood in humans. Repeated stress “sensitizes” rats to produce even higher levels of CRF. Medications (antidepressants) can prevent neural damage in stressed rats.

 

One psychological stress that has been looked at in humans is sexual abuse. It points to a marked effect of childhood sexual abuse on the stress-hormone system. The National Institute of Mental Health has been following 160 girls, aged 6-15yo when the research began, who had in the prior 6 months been subjected to legally documented sexual abuse by a family member. OVer a 4-5 year follow up period, these girls (as opposed to a group of girls matched for age, social class, presence of one or two parents in the home, and other factors)  were found to have consistently higher-than-normal cortisol levels, disruption of the normal daily pattern of the rise and fall of cortisol levels, and exaggerated cortisol responses to stimulation. These disruptions of the stress-hormone system were correlated with high levels of depression in the abused girls, generally some years after the episodes of abuse. 

 

The rhesus monkey (a type of macaque) shares over 90% (perhaps as high as 94%) of its unique segments of DNA with humans. 

 

It is clear that severe stress in infancy and childhood can produce major changes in monkeys’ adult social behavior. 

A brief separation from the mother early in life- 1 or 2 six day periods at 30 to 32 weeks of age- followed by a reunion and normal parenting predisposes young monkeys to an enhanced response to separation 2 to 3 years later, even in the absence of intervening abnormal stressors. 

 

Pain has its price.

 

In the mid-1960s, it was thought that low epinephrine levels cause depression. By the mid-1970s, the prevailing theory held that there are two kinds of depression: one related to abnormalities in norepinephrine, the other to abnormalities in serotonin. 

 

Serotonin is known to affect sleep, appetite, and the like. But, most dramatically, raising the level of serotonin seems to enhance security, courage, assertiveness, self-worth, calm, flexibility, resilience. Serotonin sets tone. Serotonin may not have much to do with depression at all, even though in its absence depression is more likely, and in its presence depression can disappear.  

 

Late onset depression is a distinctive mood disorder of those who first experience depression after age 60. People who have been healthy all their lives, if they fall prey to depression in old age, tend to be more anxious, hypochondriacal, apathetic, self-reproachful, and suicidal than elderly patients who first episode of depression occurred early. Like other elderly people who became depressed, late-onset depressives are likely to be more severely depressed, and more often psychotic, than younger adults with depression. 

 

Melan-cholia is simply Greek for “black bile”. 

 

Depressed patients tend very early in the sleep cycle to enter the sort of dream sleep characterized by inactivity of the body except for rapid eye movements (REM). So characteristic is this pattern that “short REM latency” is considered a biological marker of depression. 

 

Studies for a variety of perspectives- child development, animal ethology, descriptive psychiatry, and sociobiology- point to temperament as a crucial factor influencing personality and overall psychological well-being in a large and recognizable slice of humanity: the inhibited, the vulnerable, the highly reactive, the mildly depressed. What the different models have in common is an understanding that not only depression but also temperament rests on and is sustained by levels of neurotransmitters and stress hormones. One conclusion we might draw from this understanding is that medications that alter levels of, or transmission by, these substances ought to affect temperament. 

 

If you alter serotonin and norepinephrine, you should be able, merely by virtue of that change in the biological interior milieu, to produce a more socially comfortable individual. 

 

Perhaps preferable is the old word, “thymoleptic”. A thymoleptic is a substance that acts on the “thymus”- Greek for the soul or spirit or seat of the emotions. Thymoleptic comes close to expressing our understanding that medications act on the neurohumors, and that the medications’ effects on anxiety, depression, and personality are particular manifestations of the deeper alteration. 

 

What was called a “character disorder”- later “personality disorder” – was for many years a contraindication for treatment with medication. 

     

So strong is the influence of medication on the way we think about personality that a number of the psychiatrists charged with updating the standard diagnostic manual have suggested doing away altogether with the distinction between mental illness and personality disorder. Their assumption is that personality disorder and discrete mental illness are thoroughly intermixed- that much of what has been called personality disorder is the final, behavioral expression of a variant state of the biogenic amines. 

 

The effect of medication on personality makes research on biological temperament look more interesting, and that research in turn makes plausible the idea that “antidepressants” are really “thymoleptics”. 

 

High reward dependence (posited to be a function of the norepinephrine system) corresponds loosely to sensitivity; high harm avoidance (serotonin), to inhibition; and low novelty seeking (dopamine), to fastidiousness or inflexibility.

 

In Cloninger’s terms, Prozac decreases rewards dependence, increases novelty seeking, and decreases harm avoidance. In summary, it takes a passive-dependent person (nHR) and makes her more of a sociopath (Nhr). 

 

The article says genes “are estimated to account for… 30% of personality differences”. A geneticist would deem this statement meaningless: the degree to which a trait is heritable varies according to the range of environments over which it is studied. 

 

One reason amphetamine is popular as a drug of abuse is that people feel good about themselves on it. Uppers enhance users’ sense of of their place in the world. They feel big, important, worthy of attention. The classic experience of college students writing papers while on amphetamines is to overvalue the composition while the drug is active-even to imagine they are great writers and have dashed off a masterpiece- and then, as the drug wears off and they “crash”, to undervalue their work and themselves. The problem with amphetamine as a treatment for disorders in self-image is precisely that it exposes the user to dramatic ups and downs. But its ability temporarily to alter self-valuation might have told us something about the physiological nature of self-esteem. 

 

Constantly critical parents do often destroy the confidence of their children. Much research attests to the role of parenting in the formation of self-esteem. For instance, an often cited study of children in Connecticut concludes that self-esteem in 10 to 12 year olds correlates with measures of “parental warmth, acceptance, respect, and clearly defined limit setting”. 

 

Paul recalled going to bed every night in tears. To Paul, childhood was a series of overwhelming family fights punctuated by teasing directed especially at him. He emerged into adulthood feeling inferior, unmanly, misunderstood, and cheated of love. 

 

Anhedonia, the illness, is a quaint Victorian variant of neurasthenia in which a person cannot experience pleasure. Freud redefined the inhibition of pleasure as psychological. 

 

Klein had worked with drug addicts, and he noticed that addicts had distinct preferences. Those who favored morphine could generally be distinguished from those who favored cocaine or amphetamine. And though both types of drugs give a rush of pleasure, the eventual effects are different. Opiates satiate an addict, at least while they remain effective. Cocaine and amphetamine do not satiate but, rather, excite further desire; stimulant addicts will tend to “go on a run” and rapidly use all the drug at their disposal. 

 

Prozac does not provide pleasure; it restores the capacity for pleasure. 

 

According to the “self-medication hypothesis of addictive disorders”, a formulation of the Harvard psychiatrist Edward Khantzian, addicts use cocaine to treat affective states very similar to those I have discussed in relation to dysthymia; opiates, in contrast, may be used to mute the disorganizing effects of rage. In other words, drug abuse, particularly stimulant abuse, is not merely the pursuit of pleasure or, as was once thought, an attempt at regression, but, rather, a complex behavior aimed at coping with intolerable feelings in a person who, without medication, may experience little enjoyment. 

 

But amphetamines are addictive and cause paranoia- they are drugs of abuse- and for these reasons we allow them to be prescribed only for very narrow medical indications, chiefly ADHD. 

 

When depressed patients respond well to Prozac, they often report that their mental processes run faster and more smoothly than they did before the onset of the depression. 

 

The standard with that of rural Greece, where formal grieving, of a mother for a child or a wife for a deceased husband, lasts 5 years. Here in this culture, it is a culture with impressive affect tolerance. 

 

Aranow and his colleagues return to Schwartz’s concerns that, mood brighteners might decrease true autonomy by distancing man from an aspect of his humanity- his legitimate despair- and by reinforcing dehumanizing cultural expectations, such as the requirement always to be happy and productive, even in the face of a world that deserves a more complex emotional response. 

 

Not only does Prozac increase resilience, in some people it increases the profundity of emotion available to them as well. 

 

Richard Schwartz anticipates a question when he writes of psychotherapy, “…a person grows by taking something human from another person, a process that I find more appealing than taking a pill…” Schwartz’s argument has the flavor of what has been called pharmacological Calvinism, the sense that there is something bad per se about taking pills. Cure by pill is seen as dehumanizing when compared with psychotherapy, even the parts of psychotherapy that provide support rather than insight. The problem is not that the medicine fails to confer affect tolerance or fails to move people toward an adaptive interaction with reality, but, rather, that it succeeds. In doing just what psychotherapy aims to do, Prozac performs chemically what has heretofore been an intimate interpersonal function. 

 

Prozac lends, or creates, confidence. The impact of such a medicine remains unclear: perhaps the apparent liberation it offers is merely the freedom to be hyperthymic. 

 

Prozac, like psychotherapy, emboldens the inhibited and the injured. 

 

In my experience, many patients, including some who may never have had a diagnosable mental illness, are better able to explore both their past and their current circumstances while they are taking prozac. For these people, to whom medication constitutes help in recovery from childhood trauma or protections from the threat of terrible decompensation, the drug seems to aid rather than inhibit the struggle to locate the self. 

 

Psychotherapy remains the single most helpful technology for the treatment of minor depression and anxiety. 

 

Biochemically, suicide looks a good deal like aggression. A variety of postmortem studies have compared the brains of otherwise physically healthy people who died from suicide with those who died as accident victims. What distinguishes the suicides is low levels of brain serotonin. 

 

Under 5% and probably closer to 1%, experience a paradoxical worsening of suicidal thoughts on any antidepressant. 

 

The impression given the public was that Prozac can turn average Joes into homicidal maniacs. 

 

It continues to stimulate a discussion about perspectives on the self. A new philosophy course at Notre Dame is built around the imaginary dialogue the book proposes with Walker Percy. 

 

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