The Science Behind Antidepressants:

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Beyond Chemical Imbalance

While the jury is still out on how, in every detail, the benefits of antidepressants are achieved, the long-standing view that they redress a chemical imbalance is no longer considered adeqaute.  In the next few paragraphs we will take a look at the facts that show us that antidepressants are not what we have long been told they are–they are much more and much more impressive in their effects on the brain.

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Mechanism of Action of Antidepressants

Underlying the effects of most antidepressants are sophisticated neurobiological schematics that hardly fit the conventional “chemical imbalance” theory of depression that has been heralded in psychiatry so often and for so long . Rather, a far more transformative understanding has arisen: the structure- and function-enhancing attributes of these medications. This idea centers on the discovery that they work by promoting new neuronal growth and increased inter-neuronal connectivity in brain regions shown to be underactive in psychiatric conditions such as depression and anxiety. One example is how the selective serotonin reuptake inhibitor (SSRI) fluoxetine, for instance, has been shown to increase neurogenesis in the hippocampus by stimulating the proliferation of neuronal progenitor cells. The hippocampus is one part of the main brain circuit responsible for emotion. The moderating effect of exercise on depression has likewise been shown due to how it promotes both neurogenesis and synaptogenesis, putting this aspect of holistic treatment on a neuroscientific basis. This discovery is consistent with what has long been known as a clinical finding: More than mental exercises, physical exercise slows down the loss of memory and cognitive function in degenerative diseases such as Alzheimer’s where neurons slowly die off.

This newly discovered “neuroplasticity” further means that the brain’s response to antidepressants is dynamic; in fact it’s entirely feasible that the increase in brain-wide serotonin that accompanies the administration of SSRIs is simply the concomitant of an increased output from more active serotonin brain networks. Similarly, the “deficit” in serotonin associated with depression may be the coincident of there simply being too few, too weakly connected serotonin neurons. This is also the probable explanation as to why simply increasing serotonin in the body has only a weak effect on mood, if any at all. 

The bottom line is that an enhanced level of overall activity is crucial in the optimization of brain circuitry and the enhancement of neural communication, particularly within regions that subserve emotional processing and mood regulation.

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By promoting the growth of new neurons and the connectivity between neurons, antidepressants can serve to repair the compromised circuits within the brain, thereby aiding in the restoration of those pathways that may be disrupted in conditions such as depression. This multifaceted mode of action thus underlines the fundamental importance of neurogenesis and synaptic plasticity in the mechanism of the therapeutic effects of antidepressants, representing a much more functional and holistic perspective on their mode of action than the the simplistic chemical imbalance theory.

This growth of new nerve cells in the brain and new connections among them is a growth process that takes time. This is likely why it is so difficult to find antidepressants whose action is immediate. But now that the delay is understood, there have been found agents that rapidly induce neuroplasticity and some of these, including ketamine, dextromethorphan, ropinerole and others, are now in use at treatment centers that deploy cutting edge treatments, for example at the Sterling Institute.

The serotonin deficiency theory of depression has long dominated as a scientific rationale explaining why some individuals develop depressive symptoms. Development of antidepressants since the 1950s, and notably selective serotonin reuptake inhibitors (SSRIs) since the 1980s, has been directed at increasing serotonin in the brain, at least primarily, on the basis that low serotonin (5-hydroxytryptamine [5-HT]) levels underlie symptoms of depression. Other neurotransmitters, such as dopamine and norepinephrine, also play indispensable roles in depression physiology, and much more is yet to be discovered and understood about the myriad interactions of a plethora of brain chemicals in mood regulation. However, an increase in any neurotransmitter level associated with improved mood is most likely the result, and not the cause, of enhanced neurogenesis, enhanced synaptogenesis and increased regional brain activity as well.

Low dopamine has not just been associated with depression, but also with conditions such as Parkinson’s disease, which is a neurodegenerative disorder. In Parkinson’s Disease dopamine levels are also low but we have long known that this is caused by the loss of dopaminergic neurons, not by dopamine per se. By shifting our attention away from the chemicals alone, scientists and practitioners can take a more comprehensive look at the diverse functional manifestations of depression, leading to interventions that are more personalized and more effective.

Antidepressants and Neurogenesis in Other Regions

The increase of neuronal interconnectivity by antidepressants is not restricted to the hippocampus. The prefrontal cortex (PFC) has also been implicated in depression, and a number of papers have demonstrated the effect of antidepressants on synaptic plasticity in this region. They have been shown to blunt stress-induced atrophy in the PFC, promote dendritic branching and increase spine density–two connectivity features of synapses between neurons. This new connectivity between neurons in the prefrontal cortex enables these neurons to talk to each other in a more regulated fashion and is thought to be linked to some of the cognitive enhancing effects of antidepressants as well. These data are part of a considerable literature that antidepressants have a much broader effect on neural circuits than just those necessary for the regulation of mood, and that one of the results of this increased connectivity may be to restore overall brain function and not just emotional stability. narrowly defined It is also noteworthy that the prefrontal area targeted by TMS has repeatedly shown increased brain activity post treatment (in statistically valid patient populations as a whole). This region cannot be selectively targeted by medications as medications are dispersed throughout the body. 

How Stress Affects Brain Regions: Another Key to Mood Regulation

Antidepressants have a robust influence on the function of brain regions important for mood regulation, including the hippocampus and the prefrontal cortex. Although the role of the hippocampus in learning and memory has been relatively well understood, the detrimental effects of chronic stress on this region have only recently been appreciated. Chronic stress leads to a number of structural alterations and reduces neurogenesis, or the birth of new neurons, in the hippocampus, contributing to reduced emotional resilience and cognitive dysfunction. Treatment with an antidepressant, however, can reverse the effects of stress by increasing neurogenesis and restoring homeostasis in the hippocampus so the individual can regain mood stability, in part through improved cognitive function. The close relation between stress and anxiety helps explain why antidepressants are equally indicated for the treatment of anxiety disorders, including panic, phobias and OCD.

As noted, another brain region that is a key target of antidepressant action is the prefrontal cortex, which is involved in decision-making and emotion control. Studies have shown that chronic stress also exerts profound effects in this brain region, including dendritic atrophy and loss of synapses, which contribute to emotional dysregulation and cognitive deficits. Antidepressants work to oppose these changes and do so by promoting neuronal growth and increased synaptogenesis, which improves neuronal connectivity in this region and leads to an improvement in the capacity for flexible, adaptive responses to an emotional stimulus. The fact that CBT–Cognitive Behavioral Therapy–is effective reflects the role of cognition in mood regulation and is also reflected in the fact that antidepressant treatment makes this approach to therapy more effective as well.  In summary, antidepressants are intimately involved in the restoration of mood stability and cognitive functioning in individuals who are depressed by enhancing neuroplasticity in the hippocampus and prefrontal cortex.

Brain-Derived Neurotrophic Factor (BDNF) and the MAP kinase pathway

Brain-Derived Neurotrophic Factor (BDNF) and the MAP kinase pathway are both critical players in the mechanisms through which antidepressants operate to promote neurogenesis and synaptic connectivity. BDNF is a growth factor that supports the survival and differentiation of new neurons, and it appears to be involved in the structural changes produced by antidepressant treatments. Antidepressants increase BDNF levels, which, in turn, raises the new generation of neurons in the hippocampus. In addition, the MAP kinase pathway is a signaling mechanism that is involved in the regulation of many cellular processes, including neuronal plasticity. Antidepressants activate this pathway, thereby inducing the expression of genes involved in promoting synaptic growth and connectivity. By modulating the MAP kinase pathway, antidepressants stimulate the elaborate array of events involved in growing new synaptic connections, and in changing them in such a manner as to strengthen the communication between neurons. Together, the actions of BDNF and the MAP kinase pathway underscore the elegance and complexity of the molecular pathways through which antidepressants facilitate neuroplasticity and produce antidepressant behavioral effects.

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