16.3: Major depressive disorder (MDD)

Symptoms of MDD

The fundamental criteria that are used to diagnose people with MDD is a depressed mood/ self-esteem, low energy, and anhedonia, the decrease in sensitivity to pleasure. Because of the decrease in pleasure, they have a lessened desire to engage in activities that once produced happiness, thus leading them to become withdrawn from their friends and family.

Short-term changes in mood are completely normal and not clinical. The main diagnostic criteria for MDD is the severity and duration of the symptoms. When the depression begins to affect other aspects of life, including feelings of worthlessness, changes in sleep or appetite, difficulty concentrating, or suicidal ideation that persist daily for two weeks or longer, then a person may be diagnosed as clinically depressed.

To diagnose MDD, a trained psychiatrist or psychologist would use a combination of interview with a self-report questionnaire such as the Hamilton Rating Scale for Depression (HAM-D scale) or the Beck Depression Index. Items that appear on these sorts of tests include:

“Feels like life is not worth living”

“Experience frequent weeping”

“I blame myself all the time for my faults”

To date, there is no biomarker for depression.

Treatments for MDD

There is currently no completely effective treatment for MDD that reliably works for everyone. The currently accepted strategies can be divided into behavioral treatments and chemical treatments.

Cognitive behavioral therapy (CBT) is a therapist-guided form of talk therapy that may help a person manage their depression. In CBT, a patient’s behavior, including their coping mechanisms, erroneous thoughts, and emotional responses, is analyzed through careful clinical examination and patient self-reflection. Then, the patient is taught mechanisms to counteract those maladaptive behaviors and replace them with adaptive behaviors. For example, a person undergoing CBT for MDD might learn to identify the moments when they dwell on something negative in their lives, and then learn to tell themselves “that thought does not function to make my day better. Let’s start the day by getting out of bed and see what happens next.” It should be known that CBT is not exclusively for the treatment of MDD; CBT can also be effective for anxiety, OCD, PTSD, insomnia, substance use disorders, behavioral addictions, and many others.

Clinical connection: Seasonal affective disorder (SAD)

Seasonal affective disorder (SAD) is one type of depression that has a dependence on daytime sunlight, increasing in prevalence in the winter and decreasing in the summer. The prevalence of SAD is heavily correlated with distance from the equator: people living closer to the poles experience longer nights in the winter, which increases SAD risk. In the US, for example, SAD affects about 1% of people in Sarasota, Florida, but about 9% of people in Anchorage, Alaska.

Light exposure therapy, while controversial, may show benefits for people with SAD, particularly intense broad-spectrum light or blue wavelength light. People with SAD may have something unusual about their intrinsically photosensitive retinal ganglion cells.

A wide variety of drugs are used for the treatment of depression. The first-generation antidepressants were developed in the 1950s and 1960s. These drugs acted to increase the action of the monoamine neurotransmitters: primarily dopamine, norepinephrine, and serotonin. Our body uses an enzyme called monoamine oxidase (MAO) which degrades these chemicals into inactive components that do not signal at receptors. These first generation antidepressants block the action of MAO; biochemically, we call them monoamine oxidase inhibitors (MAOIs). In the presence of an MAOI, the neurotransmitter signal remains in the synapse longer, similar to how an acetylcholinesterase inhibitor increases ACh signaling (Chapter 10).

Most of the MAOIs, while sometimes effective, have fallen out of fashion clinically because of the adverse side effects associated with their biochemical activity (however, they are still commonly used in treatment of Parkinson’s disease). Some of them interact dangerously with foods rich in tyramine (particularly fermented foods, such as aged cheeses or beer, as well as beans and processed meats), an amino acid that is degraded by MAO. Excess tyramine can activate the sympathetic nervous system, and body levels of tyramine can rise to dangerous levels in the presence of an MAOI, leading to adverse cardiovascular events like stroke.

Many of the common MAOIs, like phenelzine and isocarboxazid, can be damaging to the liver. Some MAOIs also produce unwanted side effects, such as psychosis or nausea.

A different class of antidepressant drugs called the tricyclic antidepressants (TCAs), named for the shape of their chemical structure, was also developed around this time. They generally act as monoamine reuptake inhibitors, resulting in elevated neurotransmitter signaling. Unfortunately, these tricyclics may produce many severe side effects, such as seizures, tachycardia, and heart attacks, so prescriptions must be monitored closely. The tricyclics are still prescribed today for several other nervous system disorders, ranging from insomnia to neuropathic pain, but due to their potential cardiotoxicity, they are not often the first line of treatment in depression.

Our current, most often prescribed class of compounds for MDD, called the third-generation antidepressants, are focused on boosting the signaling activity of serotonin. Instead of preventing degradation, like the MAOIs, these compounds block the reuptake of serotonin out of the synapse. These chemicals are called selective serotonin reuptake inhibitors (SSRIs), of which fluoxetine (Prozac) is one of the most well-known examples.

While SSRIs can be effective at reversing the side effects of depression, they are not perfect drugs. One shortcoming is that a person needs to be on the drug for 2-4 weeks before they start to experience a clinically meaningful reversal of depressive symptoms. This finding is highly unusual since the pharmacological, molecularlevel effects of SSRIs take place within hours after taking the medication. Similar to SSRIs, SNRIs (serotonin and norepinephrine reuptake inhibitors) can also be used to treat depression.

One of the unsavory side effects of SSRIs is serotonin syndrome, a set of somatic changes resulting from excessive serotonergic signaling. In mild cases, a person may have an elevated body temperature, excessive sweating, rapid heart rate, and elevated blood pressure. In more severe cases, a patient may have fevers or seizures. Serotonin syndrome can happen in the event of an SSRI overdose, or as a consequence of some interaction between an SSRI and other drugs like MAOIs, MDMA (ecstasy), amphetamines, or cocaine.

Our newest treatment options for depression, recently approved by the FDA in March of 2019, is ketamine, a dissociative anesthetic typically used as a veterinary tranquilizer and a recreational club drug. Branded as Spravato, it can be administered rapidly via nasal spray. The strength of esketamine is the speed of its action. After taking a dose, the antidepressant effects of the substance can be observed within hours.

For severe or treatment-resistant depression, electroconvulsive therapy (ECT) is a treatment option. Introduced in 1938, the procedure has since been refined over the years (it is currently performed under anesthesia) and is considered to be well-tolerated and highly effective. However, side effects include aches, nausea, and memory loss.

One future therapy that is currently making significant medical advancements in curing depression is the use of psychedelic drugs, particularly psilocybin – a substance found in some species of wild mushrooms. As a potent serotonergic agonist, a single dose of psilocybin has been shown to decrease depression scores in various self-report studies with little to no adverse side effects.

Animal behavioral tests of depression

Behavioral neuroscientists have developed a variety of tests to assess the effectiveness of antidepressant drugs in non-humans. They are roughly divided into two categories.

1. Despair-based tests. One symptom of depression is that a person “gives up,” a behavior that can be modeled in a variety of rodent tests. One such example is in a tail suspension test. The mouse is held by the tail upside down. While it does not cause injury to the animal, they do experience discomfort, and will generally struggle to either free themselves or to get upright again. The sooner they stop struggling (more time spent immobile), the more despair they experience, or the more depressive they are. Giving a mouse an antidepressant like fluoxetine causes them to fight for a longer duration.

A similar test to assess “giving up” is the forced swim test. Here, a rodent is put into a container with some water. While they are naturally buoyant and are not at risk of drowning, they do not like being wet and will try to swim so that they can climb out of the water-filled container. As in the tail suspension test, they are unable to escape their predicament, and will eventually become immobile. Giving them an antidepressant decreases time spent immobile.

2. Reward-based tests. These tests seek to measure the severity of anhedonia, one of the main symptoms of depression. For example, a rodent may be presented with a two-bottle choice task, where they are put into a cage with two different bottles to drink from: one filled with standard water, and the other filled with a more desirable sugar-water solution. A depressed rat will not drink from the sugar-water bottle as frequently as a healthy rat but give that rat an antidepressant, and they will prefer the sweet water.

An intracranial self-stimulation paradigm can also be tested here in the context of depression (see chapter 11). When an electrical stimulator is placed in a reward area of the brain and the rodent is trained to perform some operant task to receive activation of these areas, we find that depressed mice do not activate these areas of their brain as much as one on antidepressants.