Major Depressive Disorder Treatment

Major depressive disorder is an episode lasting at least two weeks in which mood stays low or interest and pleasure are lost, along with changes to sleep, appetite, energy, concentration and self-worth.

Also called: Depression, Clinical depression, Major depression, Unipolar depression.

ICD-10 F32, F33 · ICD-11 6A70

Two routes into the same circuit.

The strangest thing about treating depression is a gap in time, and almost nobody is told about it before they start. An antidepressant reaches its target in the brain within hours of the first dose. The person taking it usually notices almost nothing for weeks.

That gap is not the drug failing. It is the drug working at the speed a brain actually changes. Blocking the target is quick. What that starts off is slow. Receptors adjust, growth chemicals rise, and connections are slowly rebuilt.

Therapy hits the same wall from the other side. Very few people leave a first session feeling different. Change comes through repetition. New experience is laid down again and again, until the brain has something different to work with.

So this tab is about two routes that look nothing alike and end in the same place. You can watch the first one below. Pick a drug, let it dock, and drag the weeks forward.

WHERE TREATMENT STARTS

More cautious than most people expect

What doctors offer first depends on how severe the depression is. The official guidance is more cautious than most people expect. For less severe depression, NICE, the National Institute for Health and Care Excellence, advises against routinely offering antidepressants first, unless the person wants them. For more severe depression, the leading option is CBT and an antidepressant together.

Sertraline

Serotonin transporter (SERT)

A selective serotonin reuptake inhibitor, or SSRI. Brain cells send serotonin into the gap between them, then pull it back in through a transporter. This drug blocks that transporter, so serotonin stays in the gap for longer.

Fluoxetine

Serotonin transporter (SERT)

This works the same way, but it stays in the body much longer. That makes it more forgiving if you miss a dose, and slower to clear when you stop.

MOLECULAR

Within hours

The drug sits in the serotonin transporter and blocks it. Serotonin is no longer pulled back in, so the amount in the gap between brain cells rises. This part is fast. It is finished long before anyone feels better.

CIRCUIT

Two to four weeks

Brain cells carry sensors that detect serotonin and tell the cell to fire less. Weeks of raised serotonin make those sensors less responsive, so that brake eases off. Growth chemicals rise, and the hippocampus starts rebuilding connections again.

EXPERIENCE

Two to six weeks, unevenly

Sleep and appetite usually change first. Energy comes next. Mood and interest come last. Many people say that others noticed the change before they did.

DOSE 1

The drug reaches the gap between brain cells within hours. How you feel has not changed at all.

WEEK 2

The drug is now at full strength. The sensors that act as a brake are starting to ease off. This is the point where most people decide it is not working.

WEEK 4

The brain is rebuilding connections faster. Sleep and appetite usually move first.

WEEK 6

This is when a first proper trial is judged. If nothing has changed by now, the dose or the drug is usually reconsidered.

How well does this actually work?

The largest study of this question compared 21 antidepressants across 522 trials. All 21 worked better than a dummy pill for adults with major depression.

The average size of that benefit was modest, about 0.30 on the standard measure. People have argued about that number ever since. Two things are true at the same time. Antidepressants do work, and they are not the decisive fix they are often sold as.

People also respond very differently. The first drug tried does not work for most people. Finding the right one is usually a sequence of attempts, not a single decision.

THE OTHER ROUTE

Therapy, and why it reaches the same place

Therapy is not the soft option offered when someone refuses medication. For less severe depression, the guidance recommends it first, ahead of drugs.

Cognitive behavioural therapy (CBT)

This works on how thoughts, feelings and actions affect each other. Depression produces automatic negative thoughts. CBT teaches you to spot them and test them against the evidence, instead of accepting them as true.

Behavioural activation

This puts back the activities that used to give you something, before the motivation returns. It reverses the usual order. You act first and the feeling follows. It works well, and it is simpler to deliver than full CBT.

Interpersonal psychotherapy (IPT)

This treats the episode through what is happening around it. It focuses on relationships and changes of role, such as grief, arguments, big life changes and being cut off from people.

The same circuit, from the other end

This is what joins the two halves of this tab. Say depression is largely a problem of a brain that has lost some of its ability to update itself. Then medication and therapy are both acting on that one problem. Medication works on the machinery from the inside. Therapy supplies the repeated experience that the machinery is meant to record. Neither replaces the other. For more severe depression, the guidance puts them together from the start.

IF THE FIRST ONE DOES NOT WORK

Most people are not treated once. They are treated in steps.

The largest trial ever run on this question was built around that fact.

A trial called STAR*D enrolled over 4,000 people. It did something unusual. Instead of comparing two drugs once, it followed what actually happens next. Everyone started on the same SSRI. Anyone who did not recover moved to a second step, which meant switching drug or adding one. Then a third step, then a fourth.

About 37% recovered on the first drug. Of those who moved to a second step, about 31% recovered there. Adding up all four steps gave a published figure of 67%. That is the number most people quote.

That figure is disputed. A later reanalysis used the original patient data and the original plan, and got a figure closer to 35%. It argued that the 67% counted people in ways the agreed plan did not allow. It also treated dropouts as if nobody had dropped out, when in fact most participants did.

The honest summary is not a number. It is a shape, and it has three parts. A first antidepressant fails more often than it works. Trying another is the normal next step, not a sign that the illness cannot be treated. And the chance of success falls with each step. Hearing this at the start is the difference between having a plan and feeling let down.

COMING OFF

Stopping is a process, not an event

Withdrawal is not the same thing as the illness coming back.

An antidepressant is usually continued for at least six months after the symptoms clear. It is not stopped as soon as someone feels better, which is exactly when most people want to stop. Stopping early raises the chance of the illness returning.

When the time does come, the dose is lowered in stages rather than simply ended. Most people stop without trouble. Some get withdrawal symptoms. These include irritability, anxiety, low mood, tearfulness, dizziness, poor sleep, and sensations people often describe as electric shocks. They can start within days of a dose change. They vary a lot between people and between drugs. Where they are severe, the dose is lowered more slowly, sometimes over many months.

Telling withdrawal apart from relapse matters, because they feel similar but call for opposite decisions. Withdrawal usually starts soon after a dose change. It includes physical symptoms that were not part of the original episode. It eases if the dose goes back up. Relapse usually comes on later, and it looks like the illness did before.

None of this makes antidepressants addictive. Addiction means craving the drug, needing bigger doses, and using it even though it is causing harm. None of that happens here. A body that has adapted to a drug and needs it reduced slowly is a different thing. Confusing the two causes real harm. Some people stop suddenly to prove they are not dependent, and that is the one approach that reliably makes it worse.