Today, my decision about topics comes down to two choices, both born of recent posts or replies to comments: 1) Bad Thought and Behavior Habits and how hard it is to change them; or 2) Discontinuing Psychiatric Drugs and how it is made difficult by receptor downregulation. The first has to do with why I often ignore the things that have been taught to me about how to be healthy. The second is about why I get so depressed when I try to stop (e.g.) Cymbalta. Then I realized that the two are related. They both have to do with fixed patterns of response in the brain. So this essay deals with both those issues. It is long (despite my resolution to keep posts under 500 words), and involves some physiology. But I think the connection between habits, drugs, and changes in the brain lies at the heart of many difficult emotional problems.
Of course, science understands drugs better than habits. When a negative behavior becomes habitual, so that we repeatedly cave in to it rather than do the harder thing that will make us feel better in the long run, millions (or billions) of cells across the brain may get involved. Many complicated neural centers of thought and action determine such bad habits. On the other hand, when our brains become habituated to the effects of psychiatric medications, the problem largely can be explained by changes in the levels of one or a few proteins. Since I know little about the psychology behind habits and resistance to change, most of this post will focus on receptors. I will try to draw (hopefully not make up) parallels between the brain’s adjustment to pharmaceuticals and its development of habits.
Many people on psychiatric medications have found that a drug may improve ‘symptoms’ after a few weeks, but then gradually works less and less well. This happens, in part, because the body reduces the number of receptor-proteins that respond to that drug, or to one of the natural chemicals the drug increases.
I started my medication odyssey with Prozac (fluoxetine). This drug blocks the removal (reuptake) of serotonin from the synapses in parts of the brain that use serotonin as a signalling molecule. The synapse is the small area that separates the pre-synaptic cell that sends a signal, in this case one carried by serotonin, from the post-synaptic cell that receives it. Removing the released serotonin from the space between the cells–the synapse–attenuates the message, so that it is time-limited, and doesn’t just go on ‘forever’. Since compared to earlier antidepressants Prozac is relatively selective in blocking reuptake of serotonin–but not other transmitters, it is an example of the SSRI class: Selective Serotonin Reuptake Inhibitors.
Under normal circumstances, the pre-synaptic cell releases serotonin, but then sucks it back out of the synapse using ‘reuptake’ proteins. Without the reuptake mechanism, serotonin would persist in the cleft for much longer times, and at higher concentrations, than normal. In fact, Prozac accomplishes exactly that: it blocks the reuptake protein and so causes an increase in synaptic serotonin.
As an aside, only about one-thousandth of one percent of brain nerve cells use serotonin to send signals. Despite their small numbers, serotonin neurons affect many different parts of the brain. That explains, in part, why they have unwanted side effects: areas of the nervous system we’d rather not mess with (like parts mediating sexual response) are modulated by serotonin, just like the parts that alter moods. Another important point is that to date there is no evidence that depression results from an actual deficiency in serotonin levels, even though increasing serotonin activity does elevate moods.
So why does Prozac often quit working over time? In part, it may be because the cells respond to abnormal increases in serotonin by reducing the number of post-synaptic receptors for that transmitter. It’s kind of like what happens with noise. If you want to hear something really faint, like a soft whisper, you cup your hand behind your ear to increase your ability to make out the words. As the person speaks louder, you remove your hand because it’s not so hard to detect their voice anymore. If they start yelling, you might even plug your ears to tone down the volume. The post-synaptic neuron that detects the serotonin signal no longer has to listen so hard. So it reduces the number of proteins in its cell membrane that ‘hear’ the serotonin molecule. And the drug that increases serotonin, and that once had terrific effectiveness, now has less.
Naturally, there are complicating factors. For instance, Prozac may have an immediate stimulating effect, but much of its antidepressant activity is delayed by several weeks. This is thought to be due to changes in receptor numbers on the pre-synaptic cell. I won’t go into this wrinkle, because it does not change the basic fact that eventually serotonin levels increase, and that soon after the system adjusts to the elevated transmitter levels. Regardless of the details, the end result is that the brain settles back toward its natural state. It adapts to the increase in transmitter by reducing its sensitivity.
What happens when you stop the Prozac? At this point, your neurons are accustomed to increased serotonin levels. What was once abnormally high is now, according to your brain, the right amount. When you take the (reuptake inhibiting) drug away, reuptake goes back up, which (probably along with other changes) reduces synaptic serotonin. Since the brain has adapted to high serotonin, this reduction (back to levels that once were normal) feels like a deficiency. The serotonin system is under-stimulated, and you feel depressed. And because serotonin neurons are so widespread, other withdrawal symptoms are not uncommon. You might even be more depressed than when you first started Prozac. If you can weather the depression without killing yourself, there is a pretty good chance that your neurons will return to their original condition. Or maybe not. There is also a risk that not all of the changes are reversible. One line of evidence that suggests receptor downregulation may sometimes be irreversible comes from the fact that some people have long-term sexual dysfunction that continues after SSRI agents have been discontinued.
Either way, the habituation of your brain to the presence of Prozac (and other SSRIs) makes it a difficult drug to stop. The same thing happens with heroin users: the number of opiate receptors drops, and the addict feels horrible if her or she can’t get enough heroin. (In the brain, ‘opiate’ receptors normally detect peptides called endorphins; heroin and related drugs stimulate those receptors and thereby promote analgesia and euphoria.) Hence they have trouble springing back from ‘receptor downregulation’ just like Prozac users. A common name for this is ‘addiction’. For obvious reasons, drug companies and psychiatrists resist applying this term to the withdrawal symptoms people have when psychiatric drugs like SSRIs are stopped.
Now, back to habits. Could it be that similar adaptations to signal strength, protein levels, and other features in various parts of the brain account for why habits are so hard to break? When we try to alter our behavior away from the established pattern, do we experience a seeming deficit in some chemical important to feelings of well-being? This mechanism must be operative in bad habits involving substance abuse, like cigarette addiction. But would it be extending the analogy too far to suggest it explains my habit of retreating into depression after minor setbacks? Or how I avoid doing the things that I know will gradually lead to less depression (e.g., distraction, exercise, positive self-talk), and instead curl up in a darkened room because it somehow feels better at that moment?
To answer that, one confronts the question of whether all of our decisions result from neuronal activity. Surprisingly (to me) not all scientists agree with that notion, or at least not entirely. Jeffrey Schwartz, MD, published a book in 2002 with reporter Sharon Begley called, The Mind and Brain: Neuroplasticity and the Power of Mental Force. In it, he uses obsessive-compulsive disorder (OCD) as a model for how the mind and brain interact. On the one hand, he reports that PET imaging data imply that OCD results from faulty action patterns in the frontal lobe. he goes on to show how entraining OCD patients (via CBT techniques) with new behaviors changes those circuits, and that the better the patients become, the ‘better’ the circuits look. This supports the idea that bad habits can result from changes in neuronal circuitry (note that OCD behaviors are particularly bad and pernicious; I want to reassure OCD sufferers that I am not saying their condition is something you can just ‘quit’ like cigarette smoking–hard as that is).
(Note: these images taken from the site linked by clicking on them. They were not obtained via CC license. Since they are promotional pictures on an OCD clinic’s website, and this is a mental health blog, I assume the developers would not mind. I do not have any affiliation with that organization, by the way.)
Schwartz also conveys the optimistic message that with training and intention we can change cellular connections. In other words, we can physically alter our brains to improve our lives (which brings up the giant topic of neuroplasticity, a subject for another blog). So Schwartz agrees that structural and functional elements in the brain determine habits, and that changing those elements is the key to improvement.
On the other hand, however, he argues that the intention to change behavior (and hence the brain), originates from something outside the physical structure of the nervous system: a so-called ‘mental force’. He is doing nothing less than postulating a new physical entity to add to the nuclear strong, nuclear weak, electromagnetic and gravitational forces already known by physicists. His argument is well-constructed, though it fails to convince me. (That does not mean I don’t believe in forces outside of matter, only that his reasoning and supporting data are insufficient to establish non-material forces acting in this instance.)
Whether intention originates in neuronal tissue or outside of it, it is nevertheless clear that behavior is grounded in the brain, that we can and often do change our behavior, and that doing so probably involves changing the structure and/or function of neural circuits. My whole reason for this long discussion is to make the point that while drugs quickly and efficiently change synapses and brain circuits, we can do the same thing (more slowly) with willpower, training, and practice. Breaking the habits that promote depression is then not all that different from recovering from long-term use of psychiatric drugs, although it is probably easier. In both instances we need to readjust synaptic activity.
Cognitive research has shown that to some extent persistent depression is about bad habits of thought and action. If we can break those habits, we can reduce depression. It may even be that improving thought and behavior increases brain serotonin activity, just like Prozac. However, unlike using a synthetic drug, in this case the neurotransmitter gets increased in just the right locations, not the whole brain. There is no problem with, for instance, anorgasmia or weight gain. We can accomplish the same thing as drugs, but without the side effects. It just takes the desire to change, and enough motivation to step off the easy and well-worn path. One needs to muster the courage to forge new trails and conquer new horizons. But drugs are not required.
Medications all-too-often only provide temporary relief. In some cases, a period of drug-mediated improvement in depression can give one the solid ground needed to step in a new direction. After that, the ideal decision would be to withdraw the drug in short order. I believe medications can play a useful, even vital role. But pharmaceutical agents can not, and should not be the only compass used to find a new way to live. Lifelong treatment with psychiatric medications is questionable, and despite what we are led to believe, most pharmaceutical agents lack scientific evidence of usefulness over long term treatment. So if drugs are used at all, they should be used in the lowest number, at the lowest doses, and for the shortest time possible. It takes much effort and time to change neural pathways without drugs, but the improvement is longer lasting, without side effects, and far more natural.
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