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The Hacking of the American Chapter 7. Contentment and Serotonin
Author: Robert H. Lustig Publisher: New York, NY: Penguin Random House. Publish Date: 2017 Review Date: Status:📚
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Question: Over the course of history, what prescription medication has evidenced the greatest societal impact? Answer: fluoxetine (Prozac). Psychiatric hospitals once were the saddest places on earth (think One Flew Over the Cuckoo’s Nest [1962]: I still have nightmares about Nurse Ratched), chock-full of patients with schizophrenia (e.g., patients who thought people were out to kill them and/or plotted to kill others, due to dopamine dysfunction) and patients with clinical depression (e.g., people who would have welcomed being killed, due to serotonin dysfunction). But, at its worst, schizophrenia affected only about 1 percent of the population. Consider the fact that major depressive disorder (MDD) affects 16 to 18 percent of the U.S. population at some time in their lives, and that at any given moment 6 to 8 percent of the people you know are affected.1 This is a very big deal and takes a huge toll on the individual, on his or her family, and on society.
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For many years, scientists and doctors had been trying to understand what made some people suffer from severe depression while others seemed preternaturally happy and stars of their own Disney movie.
Note
Its their attitude, not brain chemicals
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In 1952 a serendipitous finding launched the field of modern psychopharmacology. As is the case with the first generation of many mood-stabilizing treatments, we used it to treat a different malady altogether. Patients with tuberculosis (TB) treated with a drug known as isoniazid (INH, still the drug of choice when you are exposed to someone with TB) out of the blue experienced a lifting of their depression. INH worked on the neurotransmitter serotonin (as well as other areas of the brain), and with more trials and focus, scientists were able to pinpoint that it was the effect of serotonin that caused depressed TB patients to reemerge into the world of the living. Thus, scientists learned that serotonin was responsible, in part, for the feelings of happiness and contentment. And, when out of whack, could cause severe irritability and depression.
Note: drugs give temproary relief and don’t adress the root causes
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There are two kinds of depression. People with “retarded” depression can’t get out of bed, and would kill themselves if they had the energy to do so. They often need to be hospitalized to be kept away from themselves. But they pale in numbers compared to the people with “agitated” depression, who are anxious, irritable, sleepless, and just plain miserable. Both types are associated with individuals eating and sleeping either far too much or far too little, both of which are activities that involve serotonin (see Chapters 9 and 18). When Prozac, the first in the class of selective serotonin reuptake inhibitors (SSRIs), hit the market in 1986, prescriptions for antidepressants shot up a record 400 percent over the next fifteen years.2 The genius of Prozac was that it didn’t matter which form of depression you had. Whether you were climbing the walls or plumbing the depths of your psyche, Prozac could bring you to ground. Figure 7-1 demonstrates how both retarded and agitated depression can be helped by improving serotonin status. Due to both Reagan’s funding cutbacks and Prozac’s successes, over the next two decades, in-patient psychiatric facilities closed faster than Blockbuster Video.
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Fig. 7-1: The highs and lows of depression. Depression comes in two varieties—retarded depression (slow thinking and behavior: I can’t get out of bed); and agitated depression (flight of ideas and inability to concentrate: I can’t get into bed). SSRIs are antidepressants that, by increasing the amount of serotonin in the synapse, can restore normal levels of mood in either type of depression.
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Today, SSRIs are the number three most prescribed class of drugs; more people under age sixty-five take antidepressants than any other medication,3 and as many prescriptions were filled for antidepressants as for cholesterol-lowering drugs.4 Currently 11 percent of all adolescents are taking an antidepressant5, 6 not just for depression but for anxiety, anger management, premenstrual syndrome, and obsessive-compulsive disorder as well. The frequency of diagnosis of depression is still on the rise. However, we don’t know if this is due to an increased awareness among the medical community (ascertainment bias), if insurance coverage has provided the impetus for overdiagnosing (pills are lucrative to drug companies, and cheaper than psychotherapy), if more adolescents are depressed because of bullying and school pressures, or if people and doctors want to provide a quick fix.
Note: or because psychiatric drugs worsen sypmtoms in the long run
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Before we start talking about serotonin and contentment, let’s go back to dopamine and motivation. Dopamine is the reward initiator, and firing of dopamine neurons changes behavior. Remember, the dopamine neurons in the VTA have two primary targets: (1) the nucleus accumbens (NA), where the dopamine signal is translated into desire and reward (I’m stressed, give me a Krispy Kreme), and (2) the prefrontal cortex (PFC), where the dopamine signal is tempered by cognitive control (your personal Jiminy Cricket). But serotonin differs from dopamine in many ways, which makes it difficult to understand and to study
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First, serotonin is utilized by different parts of the body. The overwhelming majority (90 percent) is produced and used in the gut, where serotonin is involved in neural and hormonal responses to feeding and how full you are. Another 9 percent can be found in the platelets of our bloodstream, where serotonin helps our blood to clot. That leaves a total of 1 percent of all of your body’s serotonin in the brain itself.7 This is why we can’t just measure the amount of serotonin in blood or urine to diagnose depression—because the amount is more a reflection of what’s going on in the gut or the bloodstream than in the brain. As an example, carcinoid, which is a tumor of the intestine that overproduces serotonin, causes severe diarrhea, flushing, and abdominal pain and cramping, but it doesn’t have very much in the way of central nervous system actions, and it certainly doesn’t make its victims happy. But your urine and blood will definitely show high levels of serotonin and its breakdown products (Fig. 7-2). There’s no biomarker for depression, no blood test that your doctor can administer. To diagnose clinical depression, doctors use a questionnaire known as the Beck Depression Inventory (BDI), which scores different subjective symptoms of depression. This validated instrument is equivalent to your brain’s serotonin meter.
Note: if they cant measure serotonin levels in the brain, then how do they know depression its a problem of serototin production.
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Serotonin neurons fan out to many different part of the brain. When these signals are interpreted either separately or together, we describe the neural experience as some version of happiness. Presumably this is one reason why happiness has so many different definitions, manifestations, and inputs: because different interactions between regions of the brain influence different phenomena—joy, elation, love, etc. We know that serotonin is partially involved in contentment and well-being, but we don’t yet have all the details. What’s more, dopamine has only five different receptors in the brain (although most of the reward effects are mediated by the D1 and the D2 receptors). In contrast, serotonin has at least fourteen different brain receptors to which it binds, and while there are certain receptors that exert the majority of the serotonin effect, it makes it very difficult to piece together what is happening in any specific brain area. Thus, unlike dopamine, unraveling the role of serotonin in human happiness is a much tougher affair.
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Fig. 7-2: Synthesis and metabolism of serotonin. The amino acid tryptophan receives a hydroxyl group from the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan. This compound is then acted on by DOPA decarboxylase (the same enzyme in the dopamine pathway) to form serotonin. From there, serotonin clearance is achieved by monoamine oxidase.
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Isolating serotonin neurons and figuring out what they do in humans would require some very questionable neurosurgery from some very questionable neurosurgeons (Gene Wilder as Dr. Fronkensteen?). For this reason we have had to primarily use animal models for this work. But this leads to a big question: Is happiness a human attribute exclusively? How can you tell if an animal is happy? Are there any behaviors that animals demonstrate that are reflections of happiness rather than the result of overlay by reward or pleasure? I’ve talked to several animal behaviorists at the Society for Behavioral Neuroendocrinology about this. One form of happiness, the nurturing behavior that occurs between parents and offspring, is mediated by oxytocin (the “bonding” hormone) rather than serotonin. But what about general happiness in animals? Ken Locavara, an eminent paleontologist (he discovered the biggest dinosaur remains in Patagonia), suggests that Antarctic penguins repeatedly slide down ice chutes into frozen water, with no secondary gain or reward. There’s no food involved, just an expenditure of energy. This behavior can’t have any survival advantage—just a general sense of “Wheeeee!!!” So perhaps this is their amusement park and they are demonstrating joy. Or is it pleasure? And that’s penguins. Are rats or mice happy? How are we able to tell when a rat or mouse is depressed? For one, we know what they like: sex and sugar. And when they don’t perform to get it, they’re depressed. Just like us. And we know that antidepressants will alter their behavior. And from the rodent work, we end up extrapolating to humans.
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There still exists a large stigma toward the diagnosis and treatment of depression, as if it is a personal moral failing. For many who suffer from depression or have loved ones who do, the idea of it being their fault makes no sense. Who would choose this? Indeed, people with genetic differences anywhere in their brain’s serotonin system are at greater risk for suicide.8 Hardly a choice for these people. Similar to that recounted for dopamine (see Chapter 3), serotonin physiology also has the same three points of regulation. Many things can go wrong, which may cause symptoms of depression. Optimizing each step in the process is necessary to reach our own individual Zen.
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(1) Synthesis. Serotonin is an ongoing requirement throughout life. Its primary building block is the amino acid tryptophan, which you must eat—you can’t make it. It also happens to be one of the least available items in the human diet. Tryptophan is found in greatest quantity (but still pretty rare) in eggs, fish, and poultry. Many vegetable protein sources are notoriously low in tryptophan. Fewer building blocks means less product: not enough tryptophan in the diet means less serotonin can be made. (More about diet in Chapter 9.) So, you have a limited amount of tryptophan in your system to make serotonin, which is actually a hot commodity in your brain (Fig. 7-2). Most of the tryptophan consumed is going to be used to produce serotonin in your gut. Only 1 percent is available for your brain. There isn’t just one serotonin factory in the body. In fact, once serotonin has been made in the gut or elsewhere, it can’t cross the blood-brain barrier. Your brain is on its own, it’s got to make serotonin itself. And the brain serotonin factory is localized to a long thin area deep in the most primitive part of the brain, called the raphe nuclei. (We’ll focus on the dorsal raphe nucleus, or DRN, from here on. See Fig. 2-1.)
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Tryptophan is only one type of amino acid (one of the building blocks of protein) that needs to make it into the brain. These building blocks hop on amino acid transporters to cross over from blood into brain. The problem is, the transporters, like a taxicab at 11:00 p.m. on a snowy New Year’s Eve, are sometimes difficult to come by. Tryptophan is in competition with at least two other amino acids, phenylalanine and tyrosine, which are the building blocks for dopamine. So guess what, folks? The more building blocks for dopamine (i.e., reward-seeking behavior) in your blood, the fewer taxis that are available for tryptophan to head to party central in the brain and whip up some contentment for the evening. This competitive mechanism of tryptophan transport into the brain is but one way by which reward trumps contentment. More are coming (see Chapter 10).
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(2) Action. Similar to dopamine, serotonin is released from its nerve terminals and must traverse the synapse to meet up with its receptor. Serotonin nerve terminals are all over the brain in order to bind to different receptors to exert different effects. Thus, the actions of serotonin are much harder to quantify because: (a) there is no clear anatomic location, (b) there are too many receptors to keep track of, and (c) there are many different kinds of responses among people, and even within the same person. Unfortunately, we aren’t entirely sure which receptors work which way. For instance, triptans are a class of drugs that bind to two specific serotonin receptors, and they are the best anti-migraine medications that we physicians have at our disposal. But taking these medications does nothing for your state of mind (although if you’ve ever had a migraine, then not having one is a state of bliss).
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One receptor in particular, the serotonin-1a receptor, seems to be uniquely involved in decreasing anxiety and mitigating depression. It’s the binding of serotonin to this receptor that is equated to well-being and contentment. We know this because we have been able to genetically remove that specific receptor from mice. When they don’t have it, they are extremely anxious and no amount of antidepressant is going to fix it because the receptor is gone.9 The serotonin-1a receptor has been a hotbed of concern for psychiatric disease for decades.10 In one Japanese study, genetic serotonin-1a receptor differences are associated with bipolar disorder (formerly called manic-depressive illness).11 Drugs that bind to the serotonin-1a receptor (known as agonists, or chemical mimics) are a mainstay of antidepressant therapy,12 and new drugs are coming online at a relatively rapid pace.13 For instance, buspirone (Buspar) is a commonly used serotonin-1a agonist in the treatment of severe anxiety.
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(3) Clearance. After the packets of serotonin transmitters are released from the neuron, they need to traverse the synapse to get to the receptor. After they have bound to the receptor, they hang out in the synapse waiting to be recycled or deactivated. The same process takes place here as it does with dopamine, using the same enzyme monoamine oxidase (MAO), which will degrade serotonin into its waste product 5-hydroxyindole acetic acid (5-HIAA) (Fig. 7-2). The MAO acts as a Pac-Man here as well, essentially gobbling up and destroying serotonin molecules. This is why MAO inhibitors such as phenelzine (Nardil) work as antidepressants, by keeping the levels of serotonin elevated, fostering more chance to bind to a receptor. Alternatively, the serotonin transporter is a protein that recycles serotonin from the postsynaptic neuron back to the presynaptic neuron so it can be repackaged and used again the next time the neuron fires. These serotonin recyclers/transporters perform the same function as the dopamine transporter mentioned in Chapter 3, acting as “hungry hungry hippos.” They will suck the serotonin back into the neuron to be recycled and released again. This is the site of action of all the newer selective serotonin reuptake inhibitors (SSRIs), like fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro) to increase the amount of serotonin within the synapse in order to elevate mood. So what these SSRIs do is basically put a muzzle on the hungry hungry hippos. They are still functional, just less so.
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However, you don’t want to knock them out of the game completely. Having too much serotonin in the synapse can also be a problem (read on). How well your serotonin recycler/transporter works has a lot to do with how happy you are. Temperament goes a long way in explaining happiness, and differences in the serotonin transporter go a long way in explaining differences in temperament.14 For instance, those born with a specific allele (genetic variation) of their serotonin transporter (the 5-HTTLPR) are quite anxious as children, and are more likely to suffer into adulthood as a result of an unstable home life15 (i.e., have a greater propensity for anxiety, depression, and drug abuse16).
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But just as with dopamine, too much of a good thing can become a bad thing. Serotonin can have serious side effects, including irritability and suicidal thoughts and actions.21 Excessive serotonin effects can lead to negative levels of mood, and outward behaviors such as impulsive aggression, because of binding to receptors other than the-1a receptor.22 Serotonin syndrome, which results from too much serotonin activity because of SSRI overdose or interactions with other drugs, is characterized by changes in mental state and muscle tone, and autonomic nervous system problems.23 Going overboard on serotonin can take someone who’s morose and give them just enough brain activity and mental energy to make them suicidal, which is why people on antidepressants shouldn’t dose themselves. Just as with dopamine, the goal is not to increase your serotonin status indiscriminately but rather to find your sweet spot.
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Most of us, as numerous surveys indicate, concede that the most important goal of life is happiness. But the quest for happiness begins and ends with optimization of your serotonin neurotransmission24—clearly no easy feat. More aid is needed. Even for those of us who do not suffer from depression, few of us know how to attain contentment. Short of SSRIs, what hope do we have of achieving any meaningful happiness in this life? Are we really Prozac Nation? Not quite. Read on.