ast week one commentator, talking about depression, quoted a person taking
antidepressants as saying: “You're still depressed, you just can't feel it
anymore.” This illustrates a profound truth about depression. It's not just
extreme sadness; it's also anhedonia, the inability to experience pleasure.
It's also an indictment of how we treat depression. Our latest drugs, the SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors), are based on the observation that increasing the levels of monoamines like serotonin and norepinephrine has an antidepressant effect. But they don't work as well as they should: one study by the NIMH found that fewer than 33% of patients actually achieve remission by the end of twelve weeks of therapy despite taking four different drugs.
These drugs are designed to counteract sadness, but many now think that sadness and anhedonia are two different processes. Treat one, and the other remains, creating a sense of emptiness and hollowness.
Most doctors recognize that pharmacology does not cure depression. Its purpose, as with many other things in modern medicine, is to keep the patient alive long enough for nature's healing mechanisms to work. But our biological need to find value in raising children, experiencing a vibrant culture, and contributing to the success of a civilization cannot be provided by blocking the reuptake of 5-hydroxytryptamine.
In the early 1970s, Aaron Beck, Martin Seligman, and others proposed ‘cognitive’ theories of depression. These theories said that a mismatch between expectation and reality would make a person depressed. Depressed individuals, the theories claimed, had dysfunctional attitudes or unrealistic expectations. People who excessively value social relationships and approval become depressed after social rejection, while people who value autonomy become depressed when they experience loss of personal control.
Gloomy, depressing clouds
One of the most bizarre things to come out of subsequent research was that Beck's theory was completely wrong in that respect: it turned out that depressed people were more accurate in their assessments of control over their environment. It was non-depressed subjects who were deluded into thinking that they controlled their own fate.
This depressing finding isn't telling us that the only way to happiness is to ignore reality. When people with a fragile sense of identity lie to themselves, it is a defense mechanism that they learned during childhood. Depression may be a natural response to being trapped in a civilization that has a harmful culture, or an “open marriage” which deprives one from fulfilling their biological imperative, that is made all the more acute by the isolation caused by everyone else living in a state of pretense and denial.
Depression is telling us there is some major thing in our lives that we must change. Anhedonia serves to wrench us away from those things that give us pleasure but keep us from fulfilling our biological imperatives. When we pretend that these biological imperatives don't exist, our coping strategies fail to operate, we don't take the necessary action, and we become depressed.
Neurochemistry
The dualism of depression is also a dualism between the physical and mental. We all know of people who may not be clinically depressed but suddenly and mysteriously lost all interest in music or some other activity that gave them enjoyment, as if some part of their mind simply got closed off. What if the same thing is happening in depressed people? If so, the anti-depressants would counteract the sadness, but the anhedonia would remain untreated, and create what must feel like a gaping hole in one's being: the feeling that nothing is worthwhile.
Maybe abandoning the dopamine model, which at one time was believed to be instrumental to the brain's reward system, has led to an overemphasis on affect and relative neglect of anhedonia. Indeed, pathological sadness and apathy are only two symptoms of a soul in distress: stress is another strong risk factor for depression.
We actually know little about depression because it's hard to do experiments. How do you measure anhedonia in rats? The closest model we have is the learned helplessness model; at best, this only captures part of what humans experience.
Is depression a physical disease?
The two faces of depression are also seen in how we talk about it. Some insist clinical depression is a biological disease, while others say the human mind cannot be reduced to a mixture of chemicals and nerve impulses. Indeed, as far as the brain is concerned, depression acts like a disease. We have two new biological theories about depression: the neurotrophic hypothesis and the inflammation hypothesis.
The neurotrophic hypothesis says that antidepressants increase neuronal plasticity and raise the levels of a protein in the brain called BDNF, a neurotrophin that acts as a signal to synapses telling them to grow. We know synapse loss occurs in depression. This is how some drugs, like ketamine, which produces a rapid antidepressant effect, are believed to work. Ketamine, of course, has devastating side effects, and a massive effort is underway to find derivatives of it that separate the good and bad effects.
The other hypothesis is that depression is a type of inflammation. When inflammation occurs in the brain, it's called neuroinflammation. It doesn't necessarily mean that bacteria or viruses are present. It can also result from stress and other factors we don't fully understand.
When a person gets a peripheral infection, immune cells release proteins called cytokines that act on the brain to cause a phenomenon known as sickness behavior which induces the patient to withdraw from others and rest in order to recover from an infection. When one such cytokine, interferon-alpha, was used to treat hepatitis C, it was found that up to 58% of those receiving it became depressed. Some remained depressed for years afterward.
The two theories don't conflict. There are strong connections between neurotrophins such as BDNF and inflammation. There are also deep connections in the brain between inflammation and pain. Neuroinflammation can cause a phenomenon called neuronal stripping, where the microglial cells — which help process pain — ruthlessly rip off all the synapses on neurons. This protects the neurons by eliminating excess stimulation, allowing them to rest and recover. The cells then gently nurse the neuron back to health. It is tough love. But if they do too much, and the inflammation doesn't “resolve”, you get depression, with devastating effects on well-being.
People shouldn't get the impression that the existence of antidepressants means we understand what depression really is. A chemical change may no more cause depression than an imbalance of arachidonic acid metabolites causes a headache. Taking aspirin blocks the the production of pain signaling molecules, but it's not “curing” the headache—it only makes it impossible to feel the pain. And that might also be true in depression.
jun 16 2018, 6:18 am. edited 8:48 am. updated jul 30 2018, 7:51 pm
