The Biology of Depression: Neuropharmacological Approaches

In the six months I’ve been writing this blog I have never addressed the disorder, which, along with anxiety, is the bread and butter of clinical psychiatry. The biology of depression is a murky and complex field, and I had hoped that learning about the basic workings of the brain would prove useful in understanding it, as well as the other major psychiatric disorders. In preparation for a discussion of a possible role for the anesthetic agent ketamine in treating depression, I have begun to look at what we know about depression. This post will focus on neuropharmacological and neuroendocrine research; I expect to look at imaging studies in a future post.

Depression is defined by a group of symptoms and signs—depressed mood, lack of interest, inability to experience pleasure, guilt, negative thinking, suicidality, lack of energy, poor concentration, and disturbances of sleep and appetite. When several of these occur together, they define a syndrome which tends to run in families, recur, and improve with antidepressant medication, psychotherapy, electroconvulsive therapy, and exercise.

Depressive disorders are heterogeneous and may include a number of biological dysfunctions which psychiatry has not yet learned to parse. Depression may also be a final common pathway, a syndrome with many possible causes, like fever or anemia. Although a number of biological markers have been associated with depression, they do not come close to explaining the emotional, cognitive, behavioral, physiological, and experiential features of the disorder.

Many of our ideas about the biology of depression began with observations about drug effects. When depression in humans, or an animal model of depression, improves or worsens with a particular drug, studying that drug’s mechanism of action may help understand what goes on in the brain of a depressed person.

In 1965, Joseph Schildkraut (who a few years later was one of my teachers at the Massachusetts Mental Health Center) published the catecholamine hypothesis of affective disorders, which argued that low levels of the amine neurotransmitters norepinephrine and dopamine were associated with depression, and excesses with elation. He based this on observations of mood changes with drugs that increase or deplete these neurotransmitters in the brain. This idea was quickly expanded to include serotonin, an indoleamine . It stimulated several decades of research and drug development and led to popular concepts like “serotonin deficit.” However, as Steven Hyman and Eric Nestler described in a review of the mechanisms of antidepressant drug action, mood turns out not to be directly related to levels of amine neurotransmitters in synapses. Instead, synaptic neurotransmitters initiate a cascade of events inside postsynaptic nerve cells which results dendrite growth, new synapses, and changes in receptors. All this requires gene transcription in the cell nucleus, as well as protein synthesis, which take time. This is thought to account for the fact that treatment for depression takes days or weeks to work.

The amine hypothesis stimulated research on the serotonin transporter gene, which codes for the protein which removes serotonin from the synaptic cleft back into the presynaptic neuron. This transporter is a site of action of numerous antidepressants. Marije aan het Rot, Sanjay Matthew, and Dennis Charney have described how one variant of this gene, the short allele, slows synthesis of the serotonin transmitter protein, thereby reducing the speed at which neurons can respond to changes in their stimulation. People with the short allele form of the gene show greater amygdala activation in response to stressful stimuli. Having the short allele is also associated with increased susceptibility to depression under stressful life circumstances.

Aan het Rot and colleagues describe other mechanisms which appear related to depression. Brain-derived neurotrophic factor (BDNF) is a protein which supports neuron survival and promotes growth and differentiation of new neurons and synapses. Environmental stress leads to lower levels of BDNF in the brain as well as shrinkage of the hippocampus. Pharmacologic and other treatments for depression are associated with increases in levels of BDNF and can reverse this hippocampal atrophy. A polymorphism of the BDNF gene further increases the risk of depression in people with the short allele of the serotonin transporter gene who are exposed to stress.

David Petrik, Diane Lagace, and Amelia Eisch have recently reviewed other aspects of the role of the hippocampus in stress response and depression. The 1990’s saw the development of a hypothesis that high levels of stress hormones such as cortisol, which are associated with depression, interfere with the generation of new neurons in the dentate nucleus of the hippocampus, and that this results in symptoms of depression. Further, evidence suggested that treatments for depression worked by restoring hippocampal neurogenesis. Later research, however, has not supported the idea that decreased neurogenesis causes depression, and the relationship of hippocampal neurogenesis to response to antidepressant treatment has not yet been clarified.

Aan het Rot and colleagues describe abnormalities in other brain systems, including corticotropin releasing factor and dopamine. Their significance in the pathophysiology of depression is being studied.

In recent years there has been considerable interest in the role of glutamate in depressive disorders. Glutamate is the main excitatory neurotransmitter in the brain and is widely distributed—glutamate is involved in more than half of the brain’s synapses. A glutamate synapse consists not only of a presynaptic and a postsynaptic neuron, but also includes an astrocyte, forming a “tripartite synapse.” Astrocytes are glial cells which participate actively in a host of essential operations of the nervous system.

While there are several types of glutamate receptors in the brain, research has focused on the N-methyl-D-aspartate (NMDA) receptor. This complex receptor depolarizes the postsynaptic neuron only when three conditions are present: both glutamate and coagonist, either glycine or D-serine, have to bind to it, and an electrophysiological signal must be triggered at another receptor on the neuron. This, as well as the active participation of the astrocyte in synaptic transmission, means the NMDA receptor is suited to integrate information from multiple sources. Interest has focused on antagonists of this receptor, such as the ketamine, for treatment of depression.

Todd Hillhouse and Joseph Porter recently reviewed the role of NMDA receptors in depression and concluded that the data support hypotheses of hyperfunction of NMDA receptors in subcortical regions such as the hippocampus, locus coeruleus, and amygdala, and hypofunction in the prefrontal, perirhinal, and temporal cortices.

This review of major findings about molecular and neuro-chemical mechanisms in depression it is far from complete. Like so much in neuroscience, questions about depression lead to layers and layers of increasingly complex biological mechanisms. Evolution has indeed given us wondrous brains! And while decades of research have generated effective treatments, we still do now understand how these chemical dysfunctions contribute to the multidimensional features of depression.

Further reading:

aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder.CMAJ. 2009 Feb 3;180(3):305-13.

Hyman SE, Nestler EJ. Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am J Psychiatry. 1996 Feb;153(2):151-62.

Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015 Feb;23(1):1-21

Petrik D, Lagace DC, Eisch AJ. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology. 2012 Jan;62(1):21-34

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