Depression: what it is, symptoms, causes and treatment

Depression is not passing sadness or a weakness of character: it is an illness, common and treatable. In this article we look at how to recognize it, how widespread it is, what causes it and which treatments have been shown to work, from psychotherapy to medication and the most recent therapies.

What is depression

We speak of major depression when, for at least two weeks, nearly every day, there is a depressed mood or a loss of interest and pleasure in things that used to be enjoyable, together with other symptoms that make everyday life difficult. What matters is not only how intense the sadness is, but how long it lasts and how much it weighs on work, relationships and self-care.

Depression tends to come back: people who have had one episode are at higher risk of having others. That is why treatment aims not only to end the episode but also to prevent relapses.

How common is it

According to the World Health Organization (WHO), depression affects about 5.2% of adults worldwide, more women (6.2%) than men (4.1%): about 322 million people. In Italy, data from the PASSI surveillance system of the Istituto Superiore di Sanità (the Italian National Institute of Health) for 2023-2024 show that just over 6% of adults aged 18 to 69 report depressive symptoms; only 65% of them turn to someone for help.

What causes it

Depression does not have a single cause: it arises from a combination of several factors:

• biological: family history, changes in the functioning of certain brain networks and of the systems that regulate stress;
• psychological: a tendency towards pessimism, low self-esteem, difficult experiences in childhood;
• environmental: bereavement, separation, job loss, isolation, poverty, violence;
• medical: some illnesses, such as hypothyroidism, chronic diseases and chronic pain, and some medicines can cause or worsen depressive symptoms.

Symptoms

The most common symptoms are:

• sadness, emptiness or irritability for most of the day;
• loss of interest and pleasure;
• tiredness and lack of energy;
• sleep problems, sleeping too little or too much;
• changes in appetite and weight;
• difficulty concentrating and remembering;
• feelings of guilt or worthlessness;
• slowing down or agitation;
• thoughts of death or suicide.

In older people, depression may show up mainly as physical complaints, memory loss or withdrawal, and for this reason it is recognized later.

How it is diagnosed

The diagnosis is clinical: it is based on an interview with a doctor or psychiatrist, who reconstructs the symptoms, how long they have lasted and the person's history. Questionnaires such as the Beck Depression Inventory help to measure severity and to follow its course over time (the Italian edition of Med4Care offers it as an online depression test), but they do not replace a medical visit. Blood tests, for example thyroid tests, are used to rule out medical causes that can mimic or worsen depression.

An important point is to distinguish depression from the depression that occurs in bipolar disorder, because the treatments are different.

Treatment

Psychotherapy

Psychotherapy is as effective a treatment as medication. A large meta-analysis of 331 randomized trials and more than 34,000 patients showed that all the main types of psychotherapy, such as cognitive behavioral therapy, interpersonal therapy, behavioral activation and problem-solving therapy, work better than usual care, with minimal differences between them. For this reason, the choice depends mainly on the person's preferences and on availability.

Another meta-analysis of 101 studies showed that psychotherapy and medication on their own have similar efficacy, while combining the two works better than either one alone, especially in moderate or severe depression.

Antidepressant medicines

Antidepressants are divided into classes:

• selective serotonin reuptake inhibitors (SSRIs), usually the first choice because they are well tolerated;
• serotonin and norepinephrine reuptake inhibitors (SNRIs);
• tricyclic antidepressants, the oldest, effective but with more side effects;
• monoamine oxidase inhibitors (MAOIs), which block the enzyme that breaks down serotonin, norepinephrine and dopamine, now rarely used because of their interactions with other medicines and with some foods;
• other antidepressants with different mechanisms, such as bupropion, mirtazapine, trazodone, vortioxetine and agomelatine.

The largest meta-analysis available, of 522 trials and more than 116,000 patients, confirmed that all 21 antidepressants studied work better than placebo in major depression, with modest differences between them. The right medicine is therefore chosen on the basis of side effects, other illnesses and the person's preferences. The effect usually appears after a few weeks, and treatment should never be stopped suddenly or without talking to your doctor.

Esketamine nasal spray

For depression that does not respond to at least two different antidepressants, known as treatment-resistant depression, there is esketamine, a nasal spray. In the United States, the Food and Drug Administration (FDA) approved it in 2019 for treatment-resistant depression in adults, in conjunction with an oral antidepressant; since January 2025 the FDA-approved prescribing information also allows it to be used on its own (as monotherapy). In a randomized trial of 676 patients with treatment-resistant depression, remission after 8 weeks was more frequent with esketamine than with add-on quetiapine (27.1% versus 17.6%). In the United States it is available only through a restricted program, the SPRAVATO REMS (Risk Evaluation and Mitigation Strategy): it is dispensed and administered only in certified healthcare settings, the patient takes it under the direct observation of a healthcare provider and is monitored for at least 2 hours afterwards, because it can cause sedation, dizziness and a feeling of detachment (dissociation). The Italian edition of Med4Care also has a dedicated article on esketamine.

Transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) uses magnetic pulses, generated by a coil placed on the head, to stimulate the brain areas involved in regulating mood. It is done as an outpatient procedure, without anesthesia, with repeated sessions over several weeks. A meta-analysis published in 2026, of 141 studies and more than 10,000 patients, confirmed that several types of stimulation work better than sham stimulation, including in treatment-resistant depression, although the effects are moderate.

Transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) passes a very weak current between two electrodes on the forehead, and it can also be used at home with remote supervision by a center. The evidence is weaker: a 2025 meta-analysis found no significant benefit in major depression when tDCS is used on its own, but did find one when it is combined with antidepressant medication. A 2026 study that paired it with a cognitive video game gave no better results than sham treatment: we describe it in our article on transcranial stimulation with a video game.

Electroconvulsive therapy

In the most severe forms, when the risk is high or other treatments have not worked, electroconvulsive therapy, performed under general anesthesia, may be used. A comparison between ketamine and electroconvulsive therapy is available in the Italian edition of Med4Care.

St. John's wort

Hypericum and St. John's wort are two names for the same plant, Hypericum perforatum. It is available without a prescription, but it should not be taken lightly: according to the US National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (page updated May 2025), it can weaken the effects of many medicines, including crucially important ones such as warfarin (an anticoagulant), cyclosporine (which prevents the body from rejecting transplanted organs), some HIV drugs, some cancer medicines and birth control pills. Taken with certain antidepressants or other drugs that affect serotonin, it may lead to increased serotonin-related side effects, which can be serious. For this reason it should only be used after talking to your doctor, and never together with antidepressants.

Lifestyle

Regular physical activity, sleep that is as regular as possible, cutting down on alcohol and keeping up social contacts help recovery, but they do not replace treatment in moderate or severe depression. Diet also plays a role, which is still being studied.

When to see a doctor

In my experience as a doctor, the hardest thing for many patients is taking the first step: they often come after months, convinced they had to “manage on their own”. It is worth seeing your family doctor or a psychiatrist when symptoms have lasted more than two weeks, when they make it hard to work or to look after yourself and others, and immediately if thoughts of death appear.

References

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