Is Depression Just Bad Chemistry?

Hmmm, seems it’s more than that. It’s not just lower levels of Serotonin, like those cute little rock people show us in the commercial for Zoloft. Some antidepressants that decrease Serotonin levels actually help with the symptoms of depression. Seems a lot of areas in the brain, eg. the amygdala, the hypothalamus, the anterior cingulate cortex, all may be of different sizes and activities than in people who do not suffer from depression. Also deep brain stimulation of the subcallosal cingulate gyrus alleviates depression symptoms. Well, it seems the whole thing is much more complicated than little rock people becoming happy and hopping around with little bluebirds… the red bolds are mine.

A commercial sponsored by Pfizer, the drug company that manufactures the antidepressant Zoloft, asserts, “While the cause [of depression] is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance.” Using advertisements such as this one, pharmaceutical companies have widely promoted the idea that depression results from a chemical imbalance in the brain.

The general idea is that a deficiency of certain neurotransmitters (chemical messengers) at synapses, or tiny gaps, between neurons interferes with the transmission of nerve impulses, causing or contributing to depression. One of these neurotransmitters, serotonin, has attracted the most attention, but many others, including norepinephrine and dopamine, have also been granted supporting roles in the story.

Much of the general public seems to have accepted the chemical imbalance hypothesis uncritically. For example, in a 2007 survey of 262 undergraduates, psychologist Christopher M. France of Cleveland State University and his colleagues found that 84.7 percent of participants found it “likely” that chemical imbalances cause depression. In reality, however, depression cannot be boiled down to an excess or deficit of any particular chemical or even a suite of chemicals. “Chemical imbalance is sort of last-century thinking. It’s much more complicated than that,” neuroscientist Joseph Coyle of Harvard Medical School was quoted as saying in a blog by National Public Radio’s Alix Spiegel.

Indeed, it is very likely that depression stems from influences other than neurotransmitter abnormalities. Among the problems correlated with the disease are irregularities in brain structure and function, disturbances in neural circuitry, and various psychological contributions, such as life stressors. Of course, all these influences ultimately operate at the level of physiology, but understanding them requires explanations from other vantage points.

Are Your Chemicals out of Balance?
Perhaps the most frequently cited evidence in support of the chemical imbalance hypothesis is the effectiveness of antidepressants, many of which increase the amounts of serotonin and other neurotransmitters at synapses. Zoloft, Prozac and similar selective serotonin reuptake inhibitors (SSRIs) result in such an increase and can often relieve depression, at least when it is severe. As a result, many believe that a deficiency in serotonin and other neurotransmitters causes the disorder. But just because a drug reduces symptoms of a disease does not mean that those symptoms were caused by a chemical problem the drug corrects. Aspirin alleviates headaches, but headaches are not caused by a deficiency of aspirin.

Evidence against the hypothesis comes from the efficacy of a newly developed antidepressant, Stablon (Tianeptine), which decreases levels of serotonin at synapses. Indeed, in different experiments, activation or blockage of certain serotonin receptors has improved or worsened depression symptoms in an unpredictable manner. A further challenge to the chemical imbalance hypothesis is that many depressed people are not helped by SSRIs. In a 2009 review article psychiatrist Michael Gitlin of the University of California, Los Angeles, reported that one third of those treated with antidepressants do not improve, and a significant proportion of the remainder get somewhat better but remain depressed. If antidepressants correct a chemical imbalance that underlies depression, all or most depressed people should get better after taking them. That they do not suggests that we have only barely begun to understand the disorder at a molecular level. As a result, we must consider other, nonchemical leads.

This Is Your Brain on Depression
A possible clue lies in brain structures. Imaging studies have revealed that certain brain areas differ in size between depressed and mentally healthy individuals. For example, the amygdala, which responds to the emotional significance of events, tends to be smaller in depressed people than in those without the disorder. Other emotional regulatory centers that appear to be reduced in volume are the hippocampus, an interior brain region involved in emotional memory, the anterior cingulate cortex, which helps to govern impulse control and empathy, and certain sections of the prefrontal cortex, which plays an important role in emotional regulation. Nevertheless, the effects of these shrinkages on depression, if any, remain an open question.

Neuroimaging studies have revealed that the amygdala, hypothalamus and anterior cingulate cortex are often less active in depressed people. Some parts of the prefrontal cortex also show diminished activity, whereas other regions display the opposite pattern. The subcallosal cingulate gyrus, a region near the anterior cingulate, often shows abnormal activity levels in depressed individuals. These differences may contribute to depression, but if they do, scientists are not sure how.

In 2012 neurosurgeon Andres M. Lozano of the University of Toronto and his associates studied the effects of deep brain stimulation of the subcallosal cingulate gyrus in depressed patients who had not benefited from standard treatments. The intervention led to a significant reduction in symptoms of depression, supporting the idea that a dysfunction in this brain area may be involved in the illness.

Findings also point to a crucial role for psychosocial factors such as stress, especially when it arises from a loss of someone close to you or a failure to meet a major life goal. When someone is under a good deal of stress, a hormone called cortisol is released into the bloodstream by the adrenal glands. Over the short term, cortisol helps humans cope with dangers by mobilizing energy stores for flight or fight. But chronically high cortisol levels can harm some bodily systems. For example, at least in animals, excess cortisol reduces the volume of the hippocampus, which in turn may contribute to depression. Despite such data, we still do not know if stress alters the human brain in ways that can lead to depression.

Seeing the Elephant
Throughout this column, we have described associations between various brain changes and depression. We have not talked about “causes,” because no studies have established a cause-and-effect relation between any brain or psychosocial dysfunction and the disorder. In addition, depression almost certainly does not result from just one change in the brain or environmental factor. A focus on one piece of the depression puzzle—be it brain chemistry, neural networks or stress—is shortsighted.

The tunnel-vision approach is reminiscent of a classic story in which a group of blind men touch an elephant to learn what the animal looks like. Each one feels a different part, such as the trunk or the tusk. The men then compare notes and learn that they are in complete disagreement about the animal’s appearance. To understand the causes of depression, we have to see the entire elephant—that is, we must integrate what we know at multiple scales, from molecules to the mind to the world we live in.


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Insight may be the single most important factor in determining how well a person with a mental illness does. Major mental illnesses, of course, come with delusions, thought disturbances, illusions, and the seeming inability to accept the very fact or total or partial denial that “I” have a mental illness. This can lead to bad things. Then “I” will not go to see a psychiatrist, “I” will not take my medication, because “I” do not think there is anything wrong with me. In the meantime the disease is getting more severe and more difficult to treat. Also as time passes, bipolar disorder and schizophrenia will cause neuronal cell death in brains and this will be worse in unmedicated brains.

So the important thing then is to help the mentally ill patient realize that they have an illness. Make them aware of the symptoms, for example in mania the symptoms are:

  • Euphoria
  • Inflated self-esteem
  • Poor judgment
  • Rapid speech
  • Racing thoughts
  • Aggressive behavior
  • Agitation or irritation
  • Increased physical activity
  • Risky behavior
  • Spending sprees or unwise financial choices
  • Increased drive to perform or achieve goals
  • Increased sex drive
  • Decreased need for sleep
  • Easily distracted
  • Careless or dangerous use of drugs or alcohol
  • Frequent absences from work or school
  • Delusions or a break from reality (psychosis)
  • Poor performance at work or school

These (except for the break from reality or psychosis) may seem like normal human behaviors, but when many of them are present at the same time and with a high intensity, then it may be fair to assume that this is an illness and not just normal behavior. If untreated, people will bipolar 1 disorder will go into a psychosis, meaning they will have delusions and be out of touch with reality. This is the most dangerous part of the disease. And psychosis happens at the extreme end of mania as well as at the extreme end of depression. Both very bad places to be. In mania you may think you are super man and you can fly and literally try to do so, causing yourself harm. In depression you may think other bizarre, unreal thoughts, such as you are a “dark lord” with powers, who knows, at this point in someone’s illness, they can think anything and may do some very strange things, that can result in self injury or injury to others.

So, as I said, insight, which is the ability to judge who you really are, and when in one of these episodes, realize that this is not you, it is your illness which has taken over your brain and is now making the decisions of how you act for you.

I think I was “lucky” in a way because I didn’t manifest bipolar 1 disorder till I was 25 years old. So, I had 25 years to be ME, so when the illness took over me and my life, at some point I knew it wasn’t me and called the doctor. Even when I had reached the psychosis stage, in between periods of being out of touch with reality, when I would come back to myself, I realized I needed to be in the hospital and even though it was done with a lot of drama and emotion, I did have my self hospitalized. And I strongly believe that because of my insight, I have only been hospitalized twice in the last 29 years. Most of the time, I and my doctor, we have caught the disease early enough so that it was treatable by increasing the doses of the meds I was on, or temporarily adding another medicine. My champion of course is Lithium Carbonate extended release (ER.) Since last March, I have been on 900 mg of Lithium and have experienced no major mood disturbance. Most notable is the absence of the yearly foray into mania around the end of the year.

I have had minor mood fluctuations, mostly towards the depressive side, but thankfully nothing too extreme. Also, these may be happening because I am totally off Zoloft, a selective Serotonin reuptake inhibitor (SSRI,) and I have been on it since 1991, when it first came out. So, having been on it for so long, there are changes in the brain that happen, and these changes (changes such as Serotonin receptor down regulation and Serotonin synaptic vesicle up regulation, both of these result in less Serotonin reaching the Serotonergic neurons) make Serotonin less available to the neurons. And since Serotonin is needed for normal mood, not having enough of it would cause depressive episodes. These changes take about 6 months to a year to reverse themselves. This is what makes it so difficult to come off of SSRI’s. And this problem only happens specifically for SSRI’s 😦 But I’ve done difficult things before and coming off Zoloft successfully is just going to get added to that list of difficult things.

But, back to insight, if we can somehow cultivate insight, or perhaps find someone whose judgement we trust and listen to them when they say “Uh oh it’s happening again,” meaning the disease is acting up again, then I seriously believe we’ll have a fair chance of beating mental illness.

So lets all keep a check on our moods and actions and feelings and take action when it seems like they are running rampant upon out lives. Insight can and will help us keep our illnesses from destroying our lives.

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