Depression: More Than A Chemical Imbalance

By Carey A. Krause, D.O.

“I’m just suffering from a chemical imbalance, right, doc?”

I have become used to hearing this as I work to treat individuals seeking treatment for their depression. They ask the question in a hopeful way, and I think I know why. For many, it has been a struggle just to get to my office. Depression has robbed them of the willpower necessary to take care of tasks as straightforward as getting to the doctor. Every waking moment is a form of misery: nothing is enjoyable anymore, it is difficult to concentrate on work, and the future seems hopeless. They arrive desperate for some relief from their misery, and the idea of a chemical imbalance suggests their suffering is definable and treatable. It suggests a problem with a solution. Fix their chemical imbalance, they hope, and their depression should improve. And what are medications but chemistry in pill form? If depression is nothing but a chemical imbalance, then relief from suffering should be just a prescription away.

Unfortunately, depression continues to be a difficult illness to treat. Few people respond immediately to medication, and some require a trial of a second or a third medication before they experience relief. At the same time, some people find relief from their depression with counseling alone. This raises very good questions about the nature of an illness that can be treated with medication, but also with talk therapy. What is depression, and how did we come to refer to it as a chemical imbalance anyway?

The first antidepressants were accidental discoveries. While searching for drugs that might be helpful in other conditions, scientists discovered that some of them improved mood in test participants who had depression symptoms. At the same time, doctors were aware of other drugs that could actually worsen depression in their patients. Scientists searched for some central process that was being affected in opposite ways by these drugs. They found the answer in the brain chemicals serotonin and norepinephrine. The drug imipramine, one of the first effective antidepressants to be marketed, seemed to affect the amount of active serotonin and norepinephrine in the brain. On the other hand, the drug reserpine—an effective blood pressure medicine due to its ability to reduce the effectiveness of norepinephrine in the body—was causing depression symptoms in some people. Scientists concluded that brain chemicals, serotonin and norepinephrine in particular, must play an important role in depression. Perhaps, they speculated, people with depression had an imbalance of these chemicals. Drugs that affected serotonin and norepinephrine could be used to put things back in balance. The idea of a chemical imbalance was born.

For many depressed people, this idea was a God-send. Up until that time, they had been telling themselves (and other people were telling them) their depression was just a problem with willpower. “Pull yourself together. Get over it,” they would hear. When they could not will themselves to get better, they felt a sense of failure on top of their sense of hopelessness. To find out there might be something that had actually gone wrong in their brain, something that could be fixed, meant they weren’t “guilty” of failing to get better on their own. Suddenly, depression was like other medical illnesses. There was a cause. There was a treatment. Someday, they hoped, there could be a cure.

Why doesn’t depression respond immediately to medication? After all, we know the brain itself can respond rapidly to medicines. Pain relievers, such as morphine, act directly on the brain, and can improve symptoms in a matter of minutes. Yet, even when antidepressant medications work well, they take days to weeks to become fully effective. If depression were nothing but a chemical imbalance, it ought to be an easy enough matter to re-balance the brain with the right amount of medication. In fact, Dr. Steven Hyman, a psychiatrist and former director of the National Institute of Mental Health, noted that psychiatric drugs cause greater changes in brain chemicals than anything that occurs in nature.1 In other words, antidepressant drugs actually appear to cause a chemical imbalance in the brain. What is going on? What do we really know about how the brain works?

THE BIOLOGY OF EMOTION

From day to day, and from hour to hour, our emotional state is not something we choose, but something that is chosen for us by our deeper, preconscious brain. We have the ability to choose how we are going to act, based on our emotions, but we do not have the ability to decide which emotions we are going to experience. Our preconscious brain stays busy analyzing our world, comparing current information to our previous experiences, and then presents that analysis to our conscious selves as an emotional sensation. When we feel sad, for example, we cannot simply decide we are going to feel happy. We can, when everything is working properly, choose to do things that may improve our mood over time, but we cannot switch emotions on and off at will.

Scientists continue to collect information pointing to particular areas in the brain that are responsible for creating the sensation of emotion. Using cutting-edge research techniques such as PET scanning, they can monitor the energy of a brain at work. Some parts of the brain are specifically associated with sad or unpleasant emotional states. Not surprisingly, in individuals with depression, these areas are more active and stay active much more of the time than in those without depression.

In other words, there is evidence that certain areas of the brain are responsible for creating the emotional states we feel. In depressed individuals, those areas responsible for creating sad, negative emotional states are overactive. This creates a persistently unhappy emotional state, which is then presented to our conscious selves.

The brain is a massively complex system of circuits, much like the inside of a computer. The areas of the brain implicated in depression are parts of the circuits which make decisions on emotional states and forward that information to the rest of the brain. In a sense, depression is not a chemical imbalance, but a circuit imbalance. It is as if the circuits responsible for experiencing negative emotions are in

If depression were nothing but a chemical imbalance, it ought to be an easy enough matter to rebalance the brain with the right amount of medication... In a sense, depression is not a chemical imbalance, but a circuit imbalance. overdrive, while the circuits for positive emotions are shut down.

CIRCUITS AND EXPERIENCES

What causes some people to experience the weight and misery of depression, while others do not? If brain circuits that carry emotion are involved, why are some people affected and others not?

Depression researchers have long known that individuals with depression are somewhat more likely to have close relatives who also have suffered from depression. That suggests a tendency toward depression can be inherited; there is a genetic trait that contributes to it. Recently, a gene was identified that functions poorly in some people, causing them to have difficulty regulating serotonin. These people are more likely to develop depression than others. Clearly, there is the risk that one’s biological make-up can contribute to developing depression. But inheritance and genetics only explain part of the depression illness.

We like to compare the human brain to a computer, and often it is a useful analogy. A computer is made up of millions of circuits, too. But all of the connections within a computer are made before it is turned on for the first time. At best, computer circuits stay the same during the life of the computer; at worst, they become old and break down with use.

Unlike a computer’s circuits, the circuits in the brain are constantly undergoing change and renewal. Even though most of the nerve cells that make up the brain are present shortly after birth, the connections between those cells can change and become more complex throughout life. In fact, the act of using brain circuits actually strengthens them over time. Repeated firing of brain circuits causes the nerve cells to change the number of chemical receptors on their surface and to “fatten” the connections that link nerve cells together into complex circuitry webs. The more a brain circuit is used, the stronger it becomes.

At the same time, brain circuits that do not get used become less effective over time. The phrase “use it or lose it,” applies particularly well to brain circuits.

Some people lead unhappy lives. They are in abusive relationships, or work in unfulfilling jobs, or struggle with inadequate income, to name a few reasons. Repeatedly, day after day, the circuits that give rise to negative emotions are stimulated. These circuits tell the individual to be on guard for trouble, to avoid unpleasant experiences, to stop wasting energy on unhappy interactions. Other individuals may experience an overwhelmingly sad event, like the death of a child, or feel trapped by events too big to avoid. For them, the repeated firing of these negative emotional circuits strengthens them until their activation becomes routine. From then on, it is hard for them to escape having the experience of negative emotions. The circuits are so strong they fire almost continuously. On the other hand, circuits designed to experience positive emotions, such as joy or attraction, anticipation or excitement, have been shut down for so long they rarely fire. Clearly, a state where negative emotional circuits are much stronger than positive emotional circuits can leave an individual feeling profoundly depressed.

Everyone who suffers from depression has a unique story to tell. Some people have trouble identifying any events from their life that have contributed to their depressed mood. Other people can suffer tremendous losses and not develop evidence of a clinical depression. Of course, everyone’s brain is unique, as well. Depression is a complex interplay between inheritance, brain circuitry, and life experience. The combination of biological and social circumstances that lead to depression is as varied as the individuals who suffer from it. Fortunately, there are treatments that have been proven to be beneficial to almost any depression sufferer, regardless of the uniqueness of their experience.

TREATMENT: THERAPY

Psychiatrists were treating depression sufferers long before effective medications were available, and many

In fact, the act of using brain circuits actually strengthens them over time... At the same time, brain circuits that do not get used become less effective over time. of those treated got well. Along the way, many different theories have arisen to explain depression and justify certain forms of treatment. Psychoanalysis, where the patient lies on a couch and talks (sometimes for years) to the inscrutable therapist, has become a cultural stereotype. It is one so often parodied in movies and cartoons that it has become synonymous with psychiatry. (Some of my patients have expressed surprise when they discover I don’t even have a couch in my office.) But despite this popular image, there are other, briefer and more direct forms of therapy that have been proven to be very effective in the treatment of depression.

Two forms of therapy, in particular, warrant description. They have been proven effective through rigorous study, using the same study techniques used to prove the effectiveness of medications.

Cognitive Behavioral Therapy
One (actually a combination of two other forms of therapy) is known as Cognitive-Behavioral Therapy. Cognitive-Behavioral Therapy, or CBT for short, focuses on the patient’s thoughts and experiences that are occurring in their current life. Just as we develop habits of behavior that are not good for us, we can develop habits of thinking which are not good for us. These habits tend to reinforce negative emotional circuits. Thoughts such as “nothing ever goes right for me,” or “I hate my whole life,” are more than just idle comments. When repeated daily, they can have a negative effect on the brain. Skilled CBT therapists help patients identify and tear apart these bad thinking habits, and then replace them with repetitive positive thoughts. These thoughts are designed to stimulate positive emotional areas of the brain.

In addition to cognitive techniques like the ones just described, CBT therapists know it is often necessary to teach patients to practice positive behaviors, which allow their brains the opportunity to experience positive emotions again. Patients are taught to get out among friends, to go to movies or museums, to make an effort to do things that used to be enjoyable. With time, the brain begins to recognize these things as an expected part of life and they can become enjoyable again. Other patients learn effective relaxation techniques, designed to counter the constant sense of anxiety and avoidance that so often accompanies depression. With practice (and practice is the key with all of these techniques), patients can train their brain and body to relax at will.

Interpersonal Psychotherapy
The other, well-proven form of therapy is a variation of cognitive therapy known as Interpersonal Psychotherapy (IP for short). IP therapists help their patients look at the most significant people and events in their current lives. They are searching for unhealthy patterns of thought and behavior that are only aggravating those situations, and contributing to the patient’s sense of depression. For example, how many of us have had the same argument over and over with a spouse or a boss, without ever stopping to see if the argument improves our situation? Yet, without evidence that it has ever truly improved our situation, we readily have the same argument again! Correcting unhelpful behavioral patterns such as this is the goal of IP. Relationships with relatives or co-workers may be explored. Struggles with major life changes (such as a job change, a move, or a significant loss) are examined, in hopes of finding ways to improve coping strategies, and eliminate repetitive thoughts and behaviors that are only serving to reinforce the depression.

Quality psychotherapy is as effective as medication in treating “mild to moderate” depression. It is a vital part of the combination of therapies needed to treat severe depression most effectively. Patients engaged in effective therapy learn to practice therapy techniques between office visits to maximize their effectiveness. Though no therapy response is immediate, quality psychotherapy can help a depression sufferer begin to feel better within the first few sessions and on the road to recovery within a few weeks. For those who have suffered from depression for years, a few weeks can seem like a pretty good deal.

TREATMENT: MEDICATION

It is one thing to say antidepressant medications work by affecting serotonin, norepinephrine, and other chemicals in the brain. It is another to understand how brain chemicals affect mood and behavior in the first place.

Brain chemicals called neurotransmitters play a vital role in controlling the flow of information in brain circuits. Serotonin, norepinephrine, and other neurotransmitters of interest to psychiatrists, are not directly responsible for information flow. Instead, they regulate the circuits, much as a thermostat regulates whether your home furnace runs. Serotonin or norepinephrine-containing nerve cells interact with information circuits by enhancing or inhibiting their operation. When it comes to our emotions, as well as many other functions, these chemicals act as the brain’s “thermostats.”

Although antidepressant medications may not actually be fixing a chemical imbalance within the brain, they are affecting the function of serotonin and norepinephrine. That results in these chemicals having a different regulatory effect on information circuits in the brain. We can surmise that alterations in serotonin and norepinephrine levels are somehow improving the flow of information in positive emotional circuits, while slowing down the flow of information in negative emotional circuits.

A revolution occurred in the 1980s with the design and approval of Prozac, the first medication designed from the start to be an effective antidepressant. Prozac was not an accidental discovery. It was engineered to affect serotonin in the brain. Prozac and the antidepressants that followed have proven to be some of the safest and most successful medications ever manufactured. Yet, as safe as they are, all have potential side effects, some of which end up being intolerable for a few people. Manufacturers work to limit side effects, but some are inevitable. This is because these drugs affect the target compounds, such as serotonin or norepinephrine, anywhere in the body where those chemicals are used, and not just in the brain. The gastrointestinal system uses many of the same neurotransmitters used by the brain. So it is not a surprise that many of the potentially unpleasant side effects of antidepressants, ranging from dry mouth to diarrhea, are GI-related side effects.

Rarely antidepressants have been implicated in more severe side effects including, paradoxically, evidence that some people have become more suicidal on the medication, rather than less. It is important to remember that individuals who are diagnosed with depression may have other mental illness diagnoses or adverse behavior patterns, in addition to suffering from a depression. It is conceivable that antidepressant medications may cause these people to experience unexpected emotional extremes, or a greater lack of inhibition, which could lead to their suicidal thoughts. The vast majority of individuals who take antidepressants do not have worsened suicidal thoughts while taking medication. Undoubtedly, antidepressants have helped save a far greater number of people from suicide than might have contributed to suicide. Nonetheless, this represents an example of why physicians with knowledge and skill in using these medications remain an essential part of antidepressant treatment.

Psychiatrists who prescribe antidepressants will base their choice of a particular medication on an individual patient’s past history, family history, and potential for side effects. Occasionally, those side effects can be put to good use. For example, an antidepressant that is somewhat sedating can be prescribed to be taken before bedtime, helping to improve a patient’s sleep while it also improves their mood.

Some patients fear that antidepressant medications will change their personality and make them into “another person.” These fears are unfounded. Antidepressants do not affect personality. Others are concerned they will become dependent on the medication, or the medication will lose effectiveness over time. They have an underlying fear that somehow medication is a substitute for real treatment of depression.

In fact, some people do become dependent on having a medication prevent them from descending into the misery of depression once again. But this is no more sinister than having to depend on blood pressure medication to manage hypertension. Few people today feel as if it is cheating, or addicting, to take a pill that controls their blood pressure (and lowers their risk for a stroke or a heart attack along the way). Hopefully, soon, the stigma of accepting treatment for depression will give way to a matter-of-fact recognition of the value of effective treatment, and the genuine danger of attempting to suffer through life without treatment.

Finally, although not a medication, electro-convulsive therapy (ECT) remains a safe and highly effective treatment for depression in those whose suffering is most severe, or have not responded to other treatments. Given under general anesthesia, ECT often works faster than medication and therapy combined. It is literally a lifesaver in the right circumstances, and many patients who have chosen this form of therapy become its most enthusiastic supporters.

THE FUTURE

Major depression has become one of the largest causes of disability in the United States. More and more, employers and health insurers are recognizing the tremendous loss of productivity and the social costs of depression and are looking for the most effective treatments available. Exploration of what are called the somatic therapies has generated considerable interest. Trans-cranial magnetic stimulation seeks to re-create the benefit of ECT without the need for general anesthesia or a seizure event. Vagal nerve stimulation takes advantage of an implanted electrical stimulator that affects one of the largest nerve bundles running to and from the brain, and helps improve the mood of a portion of patients who have not responded to any other treatment.

As marvelous as these new treatments may prove to be, they are superfluous until we have attempted to treat the majority of depression sufferers with solid, proven therapy techniques as well as safe, modern medications. Unfortunately, too many depression sufferers are still trying to live their lives without having experienced effective treatment. In some cases they have not even sought help, perhaps due to the stigma, or because they thought they just needed to show more willpower. For others, treatment has been ineffectively applied. Hopefully, every day we get a little closer to the goal of effective, efficient, and widely available treatment. The golden age of psychiatry will begin, not with new technology, but when most everyone who suffers from depression is receiving effective, scientifically proven therapy and medication treatment.

1. Hyman S., “Initiation and adaptation: a paradigm for understanding psychoactive drug action.” The American Journal of Psychiatry, 1996, vol. 153:151-162.