14 Depression

This lecture has three learning objectives:

1. Describe and analyze the hypotheses for the causes of depression.
2. Critically evaluate the validity of the hypothesized role of serotonin in depression.
3. Explain why different methods of treating depression differ in effectiveness.

It opens with a review question on how SSRIs work, carried over from the previous lecture on anxiety disorders. That question is collected with the others under “Check yourself” at the end.

Depression: an overview

The risk factors for depression are:

• genetics;
• major life changes;
• chronic health problems;
• substance abuse;
• stress or trauma.

The overview slide is illustrated with Vincent van Gogh’s painting At Eternity’s Gate (1890): an old man sits on a wooden chair by the fire, bent forward, with his face buried in his fists.

Neural correlates

Three brain regions are involved, labeled on a cutaway side view of the head: the prefrontal cortex (PFC), the amygdala and the hippocampus.

• The prefrontal cortex typically sends GABA, that is, inhibitory signals, to the amygdala.
• The hippocampus also typically sends GABA to the amygdala.
• In depression, not enough GABA information is being sent from the prefrontal cortex and hippocampus to the amygdala.

In essence, the amygdala is getting too little inhibition from the PFC. This is the same circuit hypothesized for anxiety and stress-related disorders in the previous lecture. (Later in this lecture we see how the PFC delivers its inhibition: glutamate neurons in the PFC activate GABA neurons inside the amygdala.)

Typical depression treatments

The lecturer’s verdict on the available medications: “When choosing medications you have two options: the ones that work badly, or the ones that work worse.” There are three main classes of antidepressant.

Selective serotonin and norepinephrine reuptake inhibitors (SSRIs and SNRIs). As covered in the previous lecture, these block the reuptake of serotonin or norepinephrine, so the neurotransmitter stays in the synapse.

• Depending on a person’s gene for MAO, the enzyme that degrades serotonin, these drugs may be ineffective or even dangerous.

• They can increase the risk of suicidal thoughts and behavior, especially in children, teenagers and young adults.

• Examples are Prozac, Lexapro and Zoloft (SSRIs) and Cymbalta (an SNRI).

Atypical antidepressants, which the lecture calls “basically weak ADHD meds.” These are usually norepinephrine and dopamine reuptake inhibitors (NDRIs), such as Wellbutrin.

Monoamine oxidase (MAO) inhibitors. These block monoamine oxidase, the enzyme that breaks down serotonin after reuptake. Examples are Parnate and Nardil. The slide’s warning that “salami will make you literally dead” is about diet: aged and cured foods such as salami are rich in tyramine, a compound that MAO normally breaks down, and on an MAO inhibitor it can push blood pressure to dangerous levels.

The monoamine hypothesis

The evidence in support of it:

• Drugs that increase monoamines decrease depression symptoms.
• Antidepressants increase monoamines in the synapse.

The initial conclusion drawn from this was that dysregulated monoamines cause depression. This is the argument for the serotonin theory of depression, and in the lecturer’s words, “It’s… flawed.” The theory has received much criticism, and the lecture asks why that may be.

The slide illustrates the hypothesis with a Venn diagram of the three monoamines. Each circle pairs a monoamine with a broad function and three narrower ones, and gives in parentheses the symptom of a deficit in each:

• Dopamine: alertness, made up of working memory (deficit: hyper), motivation (compulsion) and clarity (foggy).
• Norepinephrine: concentration, made up of execution (hesitation), perseverance (obsession) and recall memory (doubt).
• Serotonin: satisfaction, made up of learning memory (confusion), pleasure/pain (anxiety) and relaxation (restlessness).

Where the circles overlap, dopamine and norepinephrine share attention, dopamine and serotonin share appetite, and norepinephrine and serotonin share intuition. All three together give a balanced mood. Compulsion and obsession are starred, as is a “(Distractibility)” label beside the diagram; the slide does not explain the stars.

Criticisms of the monoamine hypothesis

The main flaws:

1. Drugs change monoamine levels quickly, but the therapeutic effect comes weeks or months later.

2. There is no relationship between drug dose and therapeutic effect.

3. Chronic SSRI use decreases serotonin levels.

4. There is no relationship between the level of monoamines in the brain and having depression.

5. Blocking tryptophan, the chemical precursor to serotonin, does not induce depression.

According to the lecture, for quite some time the leading consensus has been either that serotonin has nothing to do with depression or that it is at most slightly involved. The lecturer adds that most markers of serotonin in the brains of people with depression suggest that if serotonin is different at all, it is higher than in people without depression.

This is kind of an issue

• The serotonin link was suggested in the 1960s and gained traction in the 1990s with SSRIs.
• Despite widespread criticism since the early 2000s, the serotonin theory of depression is very influential. Textbooks still cite low serotonin as the cause of depression, and leading depression researchers still endorse serotonin.
• 80% of the general public believes depression is caused by low serotonin. Most general practitioners and psychiatrists still subscribe to this view, and popular websites still cite the theory.
• The lecture states that the effect of SSRIs is now largely considered an amplified placebo effect, or simply a general restricting or blunting of emotions. (Large analyses of clinical trials do find that antidepressants outperform placebo, by a modest margin.)

The SSRI market was also valued at 14.93 billion dollars in 2020 and 21.64 billion dollars in 2026.

What actually is dysfunctional in depression?

For background, the lecture points to the Wikipedia article Biology of depression. The lecture’s own answer centers on two proteins, BDNF and Reelin. In the lecturer’s words, this is a current theory, and we are still learning more.

BDNF and Reelin share two features:

• Both are inhibited by high stress hormones.
• Patients with depression have low levels of both BDNF and Reelin in the brain.

The current depression hypothesis

Depression is likely a result of low BDNF and Reelin caused by high stress hormones.

The chain of events runs as follows.

1. Stress causes overactivation of the HPA axis (hypothalamus, pituitary gland, adrenal gland).
2. The increase in stress hormones desensitizes glucocorticoid receptors, the receptors that detect cortisol, and this blocks the negative feedback that would normally rein the axis in.
3. High stress hormones are toxic to neurons, which inhibits BDNF and Reelin.
4. This causes a breakdown of neurons and synapses, specifically the GABA projections going from the prefrontal cortex and hippocampus to the amygdala.
5. That breakdown causes and perpetuates depression symptoms.

The slide shows the HPA axis as a chain: the hypothalamus releases CRH (corticotropin-releasing hormone) to the pituitary gland, the pituitary releases ACTH (adrenocorticotropic hormone) to the adrenal gland, and the adrenal gland releases cortisol, which acts throughout the body. A second image shows a brain with a bright pathway running from the prefrontal cortex to the amygdala.

As the lecturer puts it, this is a little less simple than “low serotonin,” but it holds up much better.

Support for the new hypothesis

• Studies repeatedly show that BDNF and Reelin are diminished in patients with depression.
• Effective depression treatments increase BDNF and Reelin, repairing neurons and synapses.
• Treatments that increase BDNF and Reelin work rapidly, and their effects are long-term.

So where are the BDNF and Reelin drugs?

There are no BDNF or Reelin agonist drugs on the market. In the lecturer’s words: “Sorry. Ketamine’s the best we got. I wish I was joking.”

BDNF and Reelin in depression: the therapeutic target

Given this hypothesis, the therapeutic goal would be to increase GABA activity across two pathways:

• PFC → amygdala, and
• hippocampus → amygdala.

Inhibition and disinhibition

To see how a drug can do this, the lecture distinguishes two processes.

The slides build the disinhibition chain one step at a time.

1. A GABA neuron inhibits a second GABA neuron (−).
2. The second GABA neuron, which would otherwise hold back a glutamate neuron, is now quiet, so the glutamate neuron becomes more active (+).
3. The glutamate neuron in turn excites a further GABA neuron that it projects to (+).

Placed in the brain, the second GABA neuron and the glutamate neuron sit in the prefrontal cortex, and the final GABA neuron sits in the amygdala. So disinhibition inside the PFC ends up increasing GABA activity in the amygdala, which is exactly the therapeutic goal.

Ketamine and depression

Ketamine is an anesthetic with an observed side effect of euphoria. (The ketamine slides show a hand holding a small vial of ketamine solution for injection, labeled as an anesthetic.) Its proposed action on depression runs through the disinhibition circuit:

• Ketamine suppresses “somatostatin” GABA neurons in the PFC, a class of GABA neurons named for the peptide somatostatin that they contain.
• The suppressed GABA cells disinhibit glutamate projections to GABA neurons in the amygdala.
• This creates spontaneous firing of neurons in this pathway.
• The increased firing strengthens synapses, increasing BDNF and Reelin.
• The net result increases the strength of inhibitory connections from the PFC to the amygdala, and rebuilds connections in the hippocampus.

The lecturer stresses that the benefit comes from the comedown, after the drug’s main effect has passed. The comedown increases spontaneous neuronal activity, and more or less by dumb luck it increases activity in the PFC neurons that project to the amygdala. By the “use it to improve it” principle of plasticity (from the lecture on learning and memory), this activity strengthens the GABA projections to the amygdala that treatment aims to restore. Micro-dosing psilocybin mushrooms may produce similar effects, but more research is needed.

Further facts about ketamine as a treatment:

• Its therapeutic effect appears within 2 hours. The slide says a single dose lasts 1 month; in clinical trials the benefit of a single dose has usually faded within one to two weeks.

• Ketamine has been described as a “vaccine” against PTSD (post-traumatic stress disorder): the idea is that if someone is treated with ketamine following a traumatic event, PTSD does not form. The evidence for this comes mostly from animal studies so far, and in people it is limited and mixed.

• It is FDA approved for depression in one form: esketamine, a nasal spray made from ketamine, is approved for treatment-resistant depression. Ketamine itself is approved as an anesthetic and is used off-label for depression.

• More drugs based on this mechanism are in development. In the lecturer’s view, ketamine is a decent placeholder, but we need to know more; the new drugs are being designed to target this goal specifically, where ketamine’s effect is a happy accident.

• Psilocybin mushrooms may have a similar mechanism.

Ketamine’s action on the PFC → amygdala circuit

Ketamine disinhibits prefrontal cortex glutamate projections to GABA neurons in the amygdala. This strengthens the pathway that suppresses amygdala activity.

Check yourself

The first question reviews the previous lecture.