Major depressive disorder
Mood disorder characterized by persistently depressed mood, loss of interest and pleasure, and cognitive, somatic and autonomic symptoms lasting at least two weeks.
ICD-10 F32.920 drugs
Also known as: MDD, Clinical depression, Depression, Unipolar depression
Drugs used for this condition
- ABupropionFirst line · Other antidepressants (NDRI)Per APA 2023 and NICE NG222, bupropion is a first-line agent for major depression. Efficacy comparable to SSRIs, with a different side-effect profile: less sexual dysfunction, less sedation, no weight gain. Often chosen for depression with hypersomnia or increased appetite, or in SSRI patients with sexual side effects – as switch or augmentation. Not registered in Russia; available via individual import.
- AEscitalopramFirst line · Selective serotonin reuptake inhibitors (SSRIs)Escitalopram is a first-line antidepressant per APA 2023 guidelines. Start at 10 mg once daily, increase to 20 mg after 3–4 weeks if needed. Maximum dose 20 mg daily. The Cipriani meta-analysis (2018, Lancet) ranked escitalopram among the top antidepressants for the balance of efficacy and tolerability out of 21 agents. Assess response at 4–6 weeks.
- AFluoxetineFirst line · Selective serotonin reuptake inhibitorsFirst-line treatment for major depressive disorder in adults. Efficacy confirmed in numerous RCTs and meta-analyses. Starting dose is 20 mg daily; therapeutic effect develops over 2–4 weeks. The long half-life allows once-daily dosing. Side-effect profile is comparable to sertraline.
- AMirtazapineFirst line · Other antidepressants (NaSSA)First-line for major depression per APA 2023 and NICE NG222. Per the Cipriani 2018 Lancet meta-analysis, mirtazapine is among the most effective antidepressants. Especially useful in depression with anxiety, insomnia, anorexia, or weight loss. Start 15 mg at bedtime; target 30–45 mg.
- AParoxetineSecond line · Selective serotonin reuptake inhibitor (SSRI)Second-line for major depressive disorder per NICE NG222 (2022) after sertraline and escitalopram. Dose 20–50 mg once daily in the morning. Worse tolerability than other SSRIs due to severe discontinuation syndrome, weight gain, and sexual dysfunction. Cipriani 2018 showed efficacy comparable to other SSRIs but worse tolerability.
- ASertralineFirst line · Selective serotonin reuptake inhibitors (SSRIs)Sertraline is a first-line agent for major depression in adults per APA 2023 and NICE NG222. Starting dose 50 mg once daily in the morning, maximum 200 mg. Response is assessed at 4–6 weeks. If remission is not achieved, options include dose escalation, switching, or combining with psychotherapy. Maintenance after a first episode is at least 6–9 months from the point of remission; recurrent disease requires years of therapy.
- AVortioxetineFirst line · Multimodal antidepressantFirst-line for major depressive disorder in adults per APA 2024 and the Spanish SEP 2024 alongside other modern antidepressants (SSRIs, SNRIs). Dose 5–20 mg once daily. Particularly suitable in patients with cognitive complaints in depression and in those with marked SSRI sexual dysfunction. The Cipriani 2018 meta-analysis showed efficacy comparable to other antidepressants with better tolerability (5.2% dropout for adverse effects vs 7.7% with SSRIs).
- BAgomelatineThird line · Antidepressant – melatonin agonist and 5-HT2C antagonistA later-line option for major depressive disorder: NICE NG222 (2022) reserves agomelatine for after an inadequate response to at least two other antidepressants, and the Spanish GuiaSalud depression guideline (2023 revision) keeps SSRIs as first-line. First-line is SSRIs and SNRIs (sertraline, escitalopram, venlafaxine). Agomelatine is used with concomitant sleep and circadian rhythm disturbance, with SSRI-related sexual side effects, or in seasonal depression. Dose 25 mg at bedtime; up to 50 mg. Effect develops over 2–4 weeks. The 2013 Cochrane review (Guaiana et al.) found no significant advantage over other antidepressants, with conclusions limited by few trials and a high risk of publication bias, since most RCTs were manufacturer-sponsored. The key safety requirement is liver-enzyme monitoring before treatment and at 3, 6, 12, and 24 weeks; agomelatine is contraindicated in active liver disease or transaminases above three times the upper limit of normal, needs caution in patients over 75, and must not be combined with strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin), which sharply raise its exposure and hepatotoxicity risk.
- BAmitriptylineSecond line · Tricyclic antidepressants (TCA)Amitriptyline works in major depressive disorder: in the Cipriani 2018 network meta-analysis it had the largest effect versus placebo (OR 2.13) but also one of the highest dropout rates, and per Cochrane 2007 withdrawals for side effects are more frequent than on SSRIs. NICE NG222 (2022) and the Spanish GuiaSalud guideline (2014, reviewed 2023) put SSRIs first, and CANMAT 2023 places tricyclics in the second line because of tolerability and overdose toxicity; for chronic depressive symptoms NICE allows tricyclics among the starting options. The niche is depression with comorbid chronic pain, including migraine (CANMAT 2023). In Spain the indication is licensed (Tryptizol SmPC, section 4.1); for depression it is not used under age 18. Contraindicated after a recent myocardial infarction, with heart block or arrhythmia, coronary insufficiency, severe liver disease and with MAOIs. It prolongs QT; a dose of 750 mg or more can be fatal, so a tricyclic is not the starting drug for people at risk of suicide, and in patients under 25 antidepressants raise the risk of suicidal behaviour. Caution in angle-closure glaucoma, urinary retention, epilepsy and bipolar disorder (switch to mania). The AGS Beers Criteria 2023 advise older adults to avoid it; over age 65 start with 10–25 mg. Fluoxetine, paroxetine and bupropion raise its levels; with tramadol and buprenorphine the risk of serotonin syndrome increases. In pregnancy only when clearly needed; 0.6–1% of the dose passes into breast milk.
- BAripiprazoleAdd-on therapy · Atypical antipsychotic – dopamine partial agonistUsed as antidepressant augmentation in inadequate response to SSRIs or SNRIs (treatment-resistant depression). Dose 2–5 mg daily. Efficacy shown in several RCTs (CN138-139, CN138-141). Not used as monotherapy for major depressive disorder.
- BMoclobemideThird line · Reversible MAO-A inhibitor (RIMA)Reversible MAO-A inhibitor (RIMA) for major depressive disorder. SEPB places moclobemide as third-line after SSRI and SNRI failure.
- BQuetiapineSecond line · Atypical antipsychoticsIn treatment-resistant unipolar depression, quetiapine 150–300 mg is used as SSRI/SNRI augmentation per APA 2023. Effective, but metabolic side effects limit long-term use.
- BTrazodoneSecond line · Serotonin antagonist and reuptake inhibitor (SARI) antidepressantSecond-line for major depressive disorder, particularly with concurrent insomnia and anxiety. NICE NG222 (2022) and APA 2024 set SSRIs and SNRIs (sertraline, escitalopram, venlafaxine) as first-line. Trazodone is used when sedation is desired, at 150–400 mg/day with titration over 2 weeks. Not preferred due to marked sedation and orthostatic hypotension risk.
- CAdemetionineAdd-on therapy · Amino acids and derivatives. Hepatoprotective agentSAMe has been studied as an adjunct in major depressive disorder in small RCTs. APA 2010 listed it as a level C option. Recent meta-analyses (2020) did not confirm clinically meaningful superiority over placebo in large, well-designed trials. NICE NG222 does not include the drug.
Marketing claims without evidence base
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
- CCurcumin (Curcuma longa extract)Not recommended · Herbal anti-inflammatory agentsEvidence for curcumin in depression is conflicting. The WFSBP/CANMAT 2022 nutraceutical guideline provisionally recommends curcumin as an adjunct to standard therapy in unipolar depression, alongside saffron and St John's wort. The Wang 2021 meta-analysis (10 RCTs, 594 patients) found only a small effect (SMD -0.32) with low-quality evidence: it rests on small high-risk trials and does not replicate in larger RCTs. General depression guidelines (NICE NG222, APA) do not list curcumin. Use is adjunctive only, not monotherapy or first line. Core treatment of depression is psychotherapy and antidepressants.
- DFolic acidNot recommended · Vitamins. Haemopoietic stimulantsThe 2019 Cochrane review (3 RCTs, 247 participants) did not find a clinically meaningful effect of folic acid or L-methylfolate as monotherapy or adjunct in major depression. Small positive RCTs in patients with folate deficiency or MTHFR polymorphism have not been reproduced. APA and NICE mental health do not include folate in depression treatment standards.
- DL-tyrosineNot recommended · Conditionally essential amino acid, precursor of catecholamines and thyroid hormonesL-tyrosine is marketed as a natural precursor of dopamine and noradrenaline that supports mood in depression. Direct testing does not back this up: in a double-blind trial of 65 patients with major depression, tyrosine at 100 mg/kg per day for 4 weeks did not beat placebo and showed no antidepressant activity (Gelenberg, 1990). Reviews by Parker and Brotchie (2011) and Jongkees (2015) confirm the lack of benefit in depression and limit tyrosine's effect to short-term attention under acute stress or sleep loss. The European Food Safety Authority (EFSA) did not accept health claims linking L-tyrosine to attention. Tyrosine is absent from depression treatment recommendations and has no proven benefit, though no harm at usual doses is documented either.
- DLevomefolate (L-methylfolate, 5-MTHF)Not recommended · Active form of vitamin B9, ready for methylation reactionsLevomefolate is marketed as an «antidepressant adjunct» based on the hypothesis that MTHFR polymorphism impairs methylation, raises homocysteine and reduces monoamine synthesis. In the US, Deplin is registered as a medical food; in the EU it is not. Cochrane 2019 on folate for depression: adding folate to standard therapy in 13 RCTs produced no clinically meaningful improvement on depression scales. In patients with confirmed folate deficiency, correction is justified; in non-deficient patients it is not. If levomefolate was recommended «for depression» based on MTHFR testing without folate and B12 measurements, consider seeking a second opinion.
- DProbiotics (Lactobacillus spp., Bifidobacterium spp., Saccharomyces boulardii)Not recommended · Probiotic microorganismsProbiotics are live microorganisms (Lactobacillus, Bifidobacterium, the yeast Saccharomyces boulardii) taken for gut health. Riding the interest in the gut–brain axis, they are also promoted for mood and marketed as a supplement for depression. So far probiotics have not shown convincing benefit in depressive disorder: there is no evidence base for this use. What works for depression is psychotherapy and antidepressants, with the plan chosen by a doctor.
- FAlprazolamNot recommended · Benzodiazepines. Short-to-medium-acting anxiolyticsAlprazolam is not an antidepressant, although 'alprazolam for depression' and 'is alprazolam an antidepressant' are frequent queries. First-line treatment for major depression is SSRIs and SNRIs together with psychotherapy. A Cochrane review (van Marwijk, 2012) found only a short-term effect on depressive symptoms, comparable to tricyclic antidepressants, but the studies were short and of poor quality, and the authors caution against use because of the dependence properties of benzodiazepines. Spanish and international guidelines do not recommend benzodiazepines for depression: they mask symptoms, cause dependence and withdrawal, and delay effective treatment. Alprazolam should be tapered gradually, not stopped abruptly.
How to read tiers A–F
Evidence tiers belong to the drug-indication pair, not to the drug as a whole: the same substance can be A for one condition and F for another.
- AStrong evidence – first or second line in international guidelines
- BRecommended in selected cases
- CStudy data contradict each other
- DBenefit not proven, no documented harm
- FDocumented harm, or risk without benefit