Neuroscience of Depression: Simplified

What’s actually going on in the brain behind depression?

Let’s explore the brain chemistry behind depression, related symptoms, and how antidepressant medications actually work. While depression is a complex condition that we still don’t know everything about, there are certain neuroscience concepts that I’ve broken down to help better explain what we do know about this mental illness.

What Is Depression?

Let’s start with the basics. “Depression,” more formally known as “major depressive disorder,” is a common and serious medical condition that negatively impacts how one feels, thinks, and acts. Symptoms of depression can vary in severity and can include:

  • Feeling sad or having a depressed mood
  • Loss of interest or pleasure in activities once enjoyed
  • Changes in appetite — weight loss or gain unrelated to dieting
  • Trouble sleeping or sleeping too much
  • Loss of energy or increased fatigue
  • Feeling worthless or guilty
  • Difficulty thinking, concentrating or making decisions
  • Thoughts of death or suicide

Symptoms must last at least two weeks for a diagnosis of depression. While it may be tempting to diagnosis yourself, meet with a mental health professional if you suspect you feel you may be depressed.

Depression vs. Sadness/Grief

We can experience sadness and grief in reaction to painful events in our lives, such as the death of a loved one, loss of a job, or the ending of a relationship. While grief and depression share traits, they are not the same:

  • In grief, self-esteem is usually unaffected. In depression, it’s common to feel worthless.
  • In grief, painful emotions tend to come in waves, often mixed with positive memories. In depression, mood and/or pleasure are decreased for the majority of two weeks.
  • For some, traumatic events can lead to the combination of grief and depression, and grief can be exacerbated when coupled with depression.

The Brain Behind Depression

Did you know that the roots of your emotions reside in your brain? Although we may feel that our hearts guide our emotional decisions, the amygdala, an almond-shaped structure part of your limbic system, is the mastermind behind it all.

Brain Regions Affected by Depression

The limbic system in the brain, as highlighted above, deals with emotions and memory.

Amygdala: This structure is associated with emotions like fear, anger, pleasure, grief, and sexual arousal. Activity in the amygdala is higher when a person is sad or depressed, and activity may remain high even after one recovers.

Thalamus: This structure receives most sensory information and transmits it to the cerebral cortex, which is responsible for high-level functions like thinking, speech, movement, and learning. When impaired, it may contribute to symptoms of depression. Additionally, impairment may contribute to bipolar disorder as the thalamus helps connect sensory input to comfortable and uncomfortable emotions.

Hippocampus: This structure processes long-term memory and memory recollection. The interaction between the hippocampus and amygdala can be protective from dangerous situations. For example, if you felt scared by a certain situation, your amygdala registers this fear, your hippocampus processes the memory, and together they make you wary of being in the same feature situation again. It’s been found that the hippocampus can shrink in those with recurrent and untreated depression.

Neuronal Communication

The goal in treating the biology of depression is to enhance the brain’s capacity to regulate mood. Neurons, or nerve cells, communicate with each other via neurotransmitters, or chemicals that transmit messages between neurons. As neurotransmitters are integrally involved in how neurons communicate, antidepressant medication can target these communication processes to aid the brain’s natural function.

How Your Brain Regulates Mood

Electrical and chemical signals allow communication within and between neurons.

When a neuron is activated, it sends an electrical signal that allows the release of neurotransmitters, or chemical messengers, in the synaptic cleft, or space between the neuron and a neighboring neuron. When the concentration of these neurotransmitters increases in the synapse, they begin to bind with receptors on the membrane of the neighboring neuron.

Once the neuron has released enough neurotransmitters, a feedback mechanism directs the neuron to stop secreting the neurotransmitter and start reabsorbing it. This process is called reabsorption or reuptake. Enzymes break down the remaining neurotransmitters in the synapse. An imbalance of neurotransmitters in the synaptic cleft can contribute to feelings of depression.

Neuronal Miscommunication Can Breed Depression

Neurons normally produce adequate levels of neurotransmitters to maintain mood. However, in someone who is depressed, the communication between cells via neurotransmitters can be impaired. More specifically, cell receptors may be oversensitive or insensitive to a specific neurotransmitter, leading to an excessive or inadequate response (i.e., feelings of depression, anxiety, bipolar disorder, etc.). Similarly, if enzymes break down neurotransmitters in synapse too efficiently, it can prevent receptors on the neighboring neuron from responding appropriately.

Neurotransmitters Implicated In Depression

The three main neurotransmitters involved in depression are serotonin, dopamine, and norepinephrine, and help regulate the following body functions:

  • Serotonin: mood, digestion, sexual function
  • Dopamine: mood, pleasure, motivation, movement, memory
  • Norepinephrine: increased blood sugar, increased heart rate

Self-Medicating Depression

Trauma, life stressors, and imbalances in neurotransmitters, among other factors, contribute to depression and can underlie the desire to self-medicate with substance use. Biologically, recreational drug use is used to self-medicate depression as it stimulates the release of neurotransmitters and produces feelings of pleasure and well-being. Some narratives on how substance use is used to self-medicate depression and other mental illness can be found in Untold Stories of Addiction.

Antidepressant Medications

There are various types of antidepressants that affect different neurotransmitters to boost mood and alleviate symptoms of depression. While we don’t know if low levels of neurotransmitters cause depression, we know that it’s a piece of the puzzle.

Neurotransmitter Reuptake Inhibitors: SSRIs, SNRIs, and NDRIs

SSRIs: Selective Serotonin Reuptake Inhibitors

As their name implies, they specifically target serotonin molecules, and are some of the most commonly prescribed antidepressants. They block the reabsorption of serotonin, increasing the concentration of available serotonin. Examples: citalopram (Celexa), sertraline (Zoloft), fluoxetine (Prozac), escitalopram (Lexapro), paroxetine (Paxil)

SNRIs: Serotonin and Norepinephrine Reuptake Inhibitors

These medications block the reuptake of both serotonin and norepinephrine. Examples: duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine ER (Khedezla),

NDRIs: Norepinephrine and Dopamine Reuptake Inhibitors

These medications block the reuptake of norepinephrine and dopamine. Examples: bupropion (Wellbutrin), dexmethylphenidate (Focalin), and amineptine (Survector, Maneon, Directim)

Older Antidepressants: Tricyclics and MAOIs

TCAs: Tricyclic Antidepressants

These medications block the reabsorption of norepinephrine and serotonin. Because of potential side effects, these medications may not be safe for people with certain heart problems.

MAOIs: Monoamine Oxidase Inhibitors

Monoamine oxidase is a natural enzyme that breaks down serotonin, norepinephrine, and dopamine. MAOIs block this enzyme, therefore resulting in higher levels of these neurotransmitters. Unfortunately, the body’s capacity to break down other medicines metabolized by this enzyme (e.g., Sudafed, stimulants) is also impaired. Also, MAOIs inhibit the body’s ability to break down tyrosine, an amino acid, found in foods like aged meats and cheeses.

Other Antidepressants: Tetracyclics and SARIs

Tetracyclic Antidepressants

These medications block the reuptake of serotonin and norepinephrine, and are used less commonly because of their side effects. Examples: mirtazapine (Remeron), asamoxapine (Asendin), and maprotiline (Ludiomil)

SARIs: Serotonin Antagonist and Reuptake Inhibitors

These medications act in two ways. They prevent the reuptake of serotonin and also redirect serotonin released in the synapse to receptors that can better help neurons improve mood. Examples: nefazodone (Serzone), trazaone (Desyrel)

Nutraceuticals or “Medical Food”

Depression is often associated with low levels of folate which affects neurotransmitters that regulate mood. L-methylfolate (Deplin) has been found to effectively boost folate levels and stimulate the production of neurotransmitters.

Understanding Antidepressants

It’s important to be informed about any medication that you take or consider taking. One must consider the side-effects and risks as well as the potential efficacy in order to gain a full perspective.

Antidepressants can take between six to eight weeks before they build up in the body and gain their full effect. Many people initially placed on antidepressants don’t adhere to their prescription for this long, due to uncomfortable side-effects or loss of hope in its efficacy, and don’t experience the medication’s full benefits. Additionally, it’s been found that antidepressants, when combined with talk therapy, is more effective in treating depression than simply with antidepressants alone. However, sometimes this isn’t enough.

Treatment-Resistant Depression

For some, various antidepressant medications are insufficient to treat chronic, severe depression. In cases like these, there are other treatment options that may be helpful. Some examples include:

Medication Strategies

  • Allow your current medications more time as some antidepressants can take six to eight weeks, or longer, to gain full effect
  • Increase your dose, if indicated. Speak with your doctor about whether this is a good option for you.
  • Change your antidepressant.
  • Add another medication to have a wider effect.
  • Utilize the Cytochrome P450 (CYP450) genotyping test, if available. Your doctor may use this test to help determine how your body processes medications based on genetic traits.


For many people, psychotherapy combined with medication is most effective to treat depression. Psychotherapy can help with identifying coping strategies, processing past trauma, managing relationships, etc., and can encourage neural pathways that boost mood in addition to the effects of antidepressant medication.

Procedures to Treat Depression

Electroconvulsive therapy (ECT)

While under general anesthesia, a measured dose of electricity is passed through the brain, triggering a small, brief seizure. ECT seems to cause changes in brain chemistry that can alleviate symptoms of depression.

Repetitive transcranial magnetic stimulation (rTMS)

Often only used if ECT isn’t effective, rTMS utilizes magnetic fields to stimulate neurons to alleviate symptoms of depression. An electromagnetic coil is placed against the scalp near the forehead, and the electromagnet produces electric currents that stimulate neurons involved in mood regulation.

Vagus nerve stimulation (VNS)

VNS is generally only used if ECT, rTMS, or other brain stimulation treatments are ineffective. VNS stimulates the vagus nerve with electrical impulses. The method uses a device implanted in one’s chest that’s connected by a wire to your vagus nerve. Depression may be alleviated as electrical signals from the implant travel along the vagus nerve to mood-regulation regions in the brain.

Enhancing Depression Treatment

To enhance your treatment, whether it entails medication and/or psychological counseling, there are certain steps you can take. Adhering to your medication prescription, abstaining from alcohol and recreational drugs, focusing on stress management, practicing sleep hygiene, and regularly exercising can optimize the effects of your depression treatment.

Depression Is A Biological Condition

Research has shown us that brain chemistry and functioning are affected when one experiences depression. While there is still much we don’t know about the causes and complexity behind mental illnesses such as depression, we know that interventions such as psychotherapy and pharmacotherapy can be effective treatments. In an era that is only beginning to address the stigma associated with mental illness and its treatments, it’s imperative that we educate ourselves on what science is revealing about the inner-workings of the brain. It’s critical that we remain informed to have agency in our treatment and to empower others to do the same.

Arnold Arboretum, Jamaica Plain, MA : Fall 2018

10 Comments Add yours

  1. Excellent analysis and simplification. Thank you for the continued education!

    Liked by 1 person

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