Antidepressant medications can improve depressed mood and relieve anxiety; they can seemingly alter negative perceptions in some people struggling with anger or obsessions. How is this possible? How is it that ingestion of chemicals can have a prolonged positive impact on emotions?

The connection is presumably via the brain and the chemical processes taking place therein. Two centuries of observations in clinical neurology have taught us that the functioning of our brain is intimately connected to our mental experience: how we think, feel and perceive—our very conscious awareness, our mind. And during the latter half of the twentieth century, researchers made great advances in elucidating cellular and molecular processes within the brain, a trajectory that continues today. Nonetheless, just how brain physiology is connected to the nature of our mind, including our emotions, remains a deeply mysterious question.

Beginning in the 1940s and 1950s, the operations of the brain and how these operations impacted feeling and thinking were viewed increasingly as chemical processes. Serendipitous events in the field of medicine led to the discovery of drugs that provided relief of symptoms related to mania, depression and psychosis. Psychiatry began moving its focus away from psychodynamics and behavioral therapy and toward brain biology.

The first commercial antidepressant drugs were introduced in the 1950s and were called monoamine oxidase inhibitors (MAOIs). They are known to inhibit or slow the breakdown of certain neurotransmitters, including serotonin, norepinephrine and dopamine. Tricyclic antidepressants (TCAs), mainstays of the pharmacologic approach to treating depression during the 1960s through the 1980s, are known to inhibit or slow the reuptake transport of serotonin and norepinephrine, allowing them to have prolonged effects at synapses (connections between neurons). The selective serotonin reuptake inhibitors (SSRIs), introduced into the marketplace at the end of the 1980s (now among the best-selling drugs in history), are known to more selectively inhibit the reuptake of serotonin at synapses, thereby prolonging its effects in signaling adjacent neurons. What does all this mean and why is it related to the experience of emotion?

The human brain is awesomely complex. It consists of hundreds of billions of cells (various kinds of nerve cells and glial cells) interconnected in wonderfully intricate ways. There are trillions and trillions of intercellular connections—synapses—in the human brain. Dozens of different molecules function as chemical signaling agents between cells at these synapses; such molecules are called neurotransmitters. The two most abundant neurotransmitters in the human brain are glutamate and gamma-aminobutyric acid (GABA). Among the other neurotransmitters are acetylcholine, dopamine, serotonin, norepinephrine, histamine and several molecules collectively called endorphins and endocannabinoids. As more is discovered about the structure and function of the brain, the complexity is appreciated as ever more strikingly beautiful. A single synapse connecting two neurons together has an enormous amount going on.

Briefly, neural communication at a synapse works something like this: Within a nerve cell, a signal moves along a nerve fiber like a wave of electricity, governed by the opening and closing of channel proteins within the cell membrane and the flow of ions (atoms having electric charges) across that membrane. When the signal reaches the end of the nerve fiber, a series of processes results in the release of tiny bags of neurotransmitter molecules into the synaptic cleft, the narrow gap (approximately twenty-five billionths of a meter) between one neuron and the next. Neurotransmitter molecules rapidly move throughout the synaptic cleft and interact with various receptor proteins embedded in the membranes of nearby neurons and glial cells. The interaction of a neurotransmitter with a receptor may result in an immediate flow of ions across the cell membrane and a transient change in cell excitability (often the case with the neurotransmitters glutamate and GABA). Or the interaction may result in more prolonged effects on cells—including changes in excitability, metabolic activity, and the turning on and off of the genes that govern cell structure (often the case with the neurotransmitters serotonin, dopamine and norepinephrine).

In order to prepare the synapse to receive the next signal when it comes, neurotransmitters must be removed from the synaptic cleft so that new signals can be discriminated from old ones. To this end, proteins called reuptake transporters rapidly remove neurotransmitter molecules from the synaptic cleft, returning the molecules to the neuron that released them. This entire sequence of events constituting neurotransmitter-based signaling at a synapse is over in a flash—perhaps one-thousandth of a second. And at every instant of our lives, this process is occurring at trillions of synaptic connections in the brain.

Ever since the first commercial antidepressant drugs were introduced nearly sixty years ago, there has been a consistent finding that these medications increase the availability of certain neurotransmitters for signaling at synapses. From this was born the idea that depressed mood was related to some sort of underactivity in brain circuits using serotonin, norepinephrine, or perhaps some other neurotransmitter for signaling. Prolonging the action of serotonin, for example, at synapses was seen as providing a boost to underactive circuits. Depression and anxiety increasingly came to be viewed as kinds of “chemical imbalances” in the brain, and antidepressant medications were promoted as agents to correct these imbalances. Pharmaceutical companies continue to endorse these ideas in advertising targeted to healthcare professionals as well as to consumers. But the story just isn’t that simple.

Relationships surely exist between brain chemistry, neural connectivity, and emotion. These relationships are complex, no doubt involve numerous circuits within the brain, and are far from being understood. Recent scientific studies suggest that antidepressant medications have effects on gene expression that lead to the production of nerve growth factors, and the subsequent growth of new synaptic connections and even new nerve cells. These could be very relevant components of the clinical efficacy of these drugs. But we’re still likely only glimpsing the tip of the iceberg.

It is true that antidepressant medications are helpful to some individuals some of the time. Even in these cases, however, the drugs will be most helpful when used in conjunction with psychotherapy and other practices that contribute to learning and consolidating desirable behaviors. Psychotherapy using a variety of techniques—including those drawn from mindfulness practices—helps make the changes stick, with or without the drugs. And attending to a healthy lifestyle seems to add to the recovery process.

One thing contemporary neuroscience has established is that practicing new behaviors lays down new neural tracts in the brain that get strengthened with repeated use over time. It may be that by perturbing brain physiology, certain drugs facilitate the change of neural connections in the brain. But these changes by chemicals alone are most likely temporary. Real transformation comes from intention, action and practice.

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From the Fall 2012 issue of Inquiring Mind (Vol. 29, No. 1)

© David E. Presti & Kristi Panik