What is depression?
Depression is not sadness. Everyone feels sad. Depression is a medical condition characterised by persistent low mood or anhedonia (loss of the ability to experience pleasure) lasting at least two weeks, accompanied by a cluster of cognitive, physiological, and behavioural changes that significantly impair daily functioning.
Modern neuroscience understands depression as a disorder of neuroplasticity, neuroinflammation, and disrupted connectivity between brain networks — particularly the default mode network (involved in self-referential rumination) and the prefrontal cortex (involved in emotional regulation). The old "chemical imbalance" model of simply low serotonin is an oversimplification that has been largely superseded.
Call or text 988 (Suicide & Crisis Lifeline) — available 24/7. You can also chat at 988lifeline.org. For immediate danger, call 911.
Types of depression
| Type | Key features | Duration | Typical treatment |
|---|---|---|---|
| Major Depressive Disorder (MDD) | Most common; 5+ DSM-5 criteria for ≥2 weeks; often episodic; single or recurrent episodes | Episode: months without treatment | Antidepressants + CBT; combination most effective |
| Persistent Depressive Disorder (PDD/Dysthymia) | Chronic low-grade depression; ≥2 years; less severe than MDD but more disabling long-term | By definition ≥2 years | Antidepressants; CBT; often requires long-term treatment |
| Bipolar Depression | Depressive episodes in the context of bipolar disorder; often misdiagnosed as unipolar MDD | Variable; cycling with hypomania/mania | Mood stabilisers; quetiapine; lamotrigine — NOT antidepressants alone (risk of switch) |
| Seasonal Affective Disorder (SAD) | Recurrent depression in autumn/winter; hypersomnia; carbohydrate craving; reactive mood | Seasonal pattern — resolves spring/summer | Light therapy (10,000 lux, 30 min/day); bupropion-XL prophylactically |
| Postpartum Depression (PPD) | Onset within 4 weeks of delivery; distinct from baby blues; affects 10–15% of mothers | Weeks to months without treatment | Zuranolone (FDA 2023 — first PPD-specific drug); SSRIs; therapy; support |
| Premenstrual Dysphoric Disorder (PMDD) | Severe mood symptoms limited to luteal phase; remits with menstruation | 1–2 weeks per cycle | SSRIs (continuous or luteal-phase only); hormonal approaches |
Symptoms and diagnosis
Major Depressive Disorder requires 5 or more of the following DSM-5 criteria, present nearly every day for at least 2 weeks, representing a change from previous functioning — and at least one must be depressed mood or loss of interest/pleasure:
- Depressed mood most of the day (or irritability in children/adolescents)
- Markedly diminished interest or pleasure in all or most activities (anhedonia)
- Significant weight change or appetite disturbance (±5% body weight in a month)
- Insomnia or hypersomnia
- Psychomotor agitation or retardation (observable by others)
- Fatigue or loss of energy
- Feelings of worthlessness or excessive/inappropriate guilt
- Diminished ability to think, concentrate, or make decisions
- Recurrent thoughts of death, suicidal ideation, or a suicide attempt
Before diagnosing MDD, medical causes must be excluded: hypothyroidism, anaemia, sleep apnoea, vitamin D and B12 deficiency, medication side effects, and substance use disorders can all cause depressive symptoms.
Antidepressants
| Class | Examples | Mechanism | Best for | Key considerations |
|---|---|---|---|---|
| SSRIs | Sertraline, Escitalopram, Fluoxetine, Paroxetine | Serotonin reuptake inhibition | First-line MDD, anxiety disorders, OCD, PMDD | Safest overall; sexual dysfunction common; serotonin syndrome risk with combinations |
| SNRIs | Venlafaxine, Duloxetine, Desvenlafaxine | Serotonin + noradrenaline reuptake inhibition | MDD with pain, anxiety, fibromyalgia | Duloxetine approved for neuropathic pain; dose-dependent BP elevation with venlafaxine |
| Bupropion (NDRI) | Wellbutrin, Zyban | Noradrenaline + dopamine reuptake inhibition | MDD with fatigue/concentration issues; smoking cessation; no sexual dysfunction | Lowers seizure threshold; avoid in eating disorders/seizure history; also used in SAD |
| Mirtazapine (NaSSA) | Remeron | α2-antagonist; 5-HT2 and 5-HT3 blockade | MDD with insomnia, anxiety, anorexia or weight loss; augmentation with SSRIs (California Rocket) | Sedating; promotes weight gain; low sexual dysfunction; antiemetic via 5-HT3 |
| TCAs | Amitriptyline, Nortriptyline, Clomipramine | Non-selective monoamine reuptake inhibition | TRD, chronic pain (low-dose), OCD (clomipramine) | Effective but poor tolerability; fatal in overdose — not first-line; useful in low doses for pain/migraine |
| MAOIs | Phenelzine, Tranylcypromine; Patch: Selegiline (Emsam) | Monoamine oxidase inhibition | Atypical depression, TRD | Dietary tyramine restriction (hypertensive crisis); multiple drug interactions; rarely used |
| Vortioxetine (multimodal) | Trintellix | SERT inhibitor + 5-HT receptor modulator | MDD with cognitive symptoms | Less sexual dysfunction than SSRIs; evidence for cognitive improvement |
After a first depressive episode: continue for at least 6–12 months after achieving remission before cautious tapering. After a second episode: 2 years or more. After three or more episodes: indefinite maintenance is typically recommended, as recurrence risk is very high. Never stop antidepressants abruptly — this can cause discontinuation syndrome (flu-like symptoms, electrical "brain zaps," dizziness).
Psychotherapy options
| Therapy | Format | Evidence in MDD | Best for |
|---|---|---|---|
| CBT (Cognitive Behavioural Therapy) | Individual or group; typically 12–20 sessions | Very high — equivalent to antidepressants for mild-moderate; preventive for relapse | MDD, anxiety, OCD, PTSD, eating disorders |
| Behavioural Activation (BA) | Individual; 6–16 sessions | High — equal to full CBT in some trials | MDD where anhedonia and withdrawal dominate; simpler to deliver |
| IPT (Interpersonal Therapy) | Individual; typically 12–16 sessions | High — particularly effective for postpartum depression | MDD linked to grief, life transitions, relationship conflicts |
| MBCT (Mindfulness-Based Cognitive Therapy) | Group; 8 weekly sessions | High — specifically for relapse prevention after ≥3 episodes (reduces risk by ~43%) | Recurrent MDD; residual symptoms after antidepressant treatment |
| Psychodynamic therapy | Individual; longer-term | Moderate — effective for chronic/complex presentations | Long-standing personality-level difficulties underlying depression |
New and emerging treatments
Ketamine and esketamine (Spravato)
Ketamine is an NMDA receptor antagonist that produces rapid antidepressant effects — often within hours — compared to the weeks required by conventional antidepressants. Esketamine (S-ketamine nasal spray, Spravato) received FDA approval in 2019 for treatment-resistant depression and 2020 for MDD with acute suicidal ideation. It is administered in certified healthcare settings due to dissociative effects and abuse potential. Effect typically requires maintenance dosing (twice weekly → weekly → biweekly).
Transcranial magnetic stimulation (TMS)
TMS uses magnetic pulses to stimulate or inhibit specific brain regions — typically the left dorsolateral prefrontal cortex (DLPFC). Standard TMS involves 30–36 sessions over 6–9 weeks. Accelerated TMS protocols (including Stanford's SAINT protocol delivering 50 sessions over 5 days) show response rates of 80%+ in small trials. TMS is non-invasive, does not require anaesthesia, and has few systemic side effects. FDA-cleared for TRD and OCD.
Zuranolone (Zurzuvae)
The first oral neurosteroid antidepressant, FDA-approved in August 2023 for MDD and PPD. Zuranolone is a positive allosteric modulator of GABA-A receptors — a completely different mechanism from existing antidepressants. It acts rapidly (response within 3 days), is taken as a 14-day course once daily at night, and does not require long-term daily dosing. Particularly significant for postpartum depression.
Psilocybin-assisted therapy
Psilocybin (the active compound in "magic mushrooms") is being studied in FDA-designated Breakthrough Therapy trials. Phase 2 and early Phase 3 trials show large effect sizes in MDD and TRD — 67–71% response rates in some studies, with effects lasting 12 months from a single or two-session treatment. Not yet FDA-approved; available in clinical trials and in several U.S. states (Oregon, Colorado) via regulated frameworks.
Treatment-resistant depression (TRD)
TRD — defined as inadequate response to at least two adequate antidepressant trials — affects approximately 30% of people with MDD. A systematic approach is required:
- Confirm diagnosis — rule out bipolar disorder, personality disorder, medical causes, substance use
- Confirm adequate trial — correct dose for at least 4–6 weeks
- Switch to a different antidepressant class
- Augmentation — add lithium, atypical antipsychotic (quetiapine, aripiprazole, brexpiprazole), or thyroid hormone
- Esketamine (Spravato) — for TRD with or without acute suicidality
- TMS — particularly the intensive SAINT protocol for rapid results
- ECT (electroconvulsive therapy) — still the most effective treatment for severe TRD; vastly safer than its reputation; response rates 60–80%; essential in catatonia and psychotic depression with suicidality
Lifestyle and self-care
Lifestyle factors have strong evidence for antidepressant effects — not as alternatives to medical treatment, but as essential adjuncts that improve treatment outcomes and reduce relapse risk.
- Exercise: Meta-analyses show effects equivalent to antidepressants for mild-moderate depression. The SMILE trial showed aerobic exercise reduced MDD symptoms by 47% over 16 weeks. Aim for 150 minutes/week of moderate aerobic activity.
- Sleep: Sleep and mood have bidirectional effects. CBT for insomnia (CBT-I) is the first-line treatment for insomnia in depression — more effective and durable than sleep medications.
- Social connection: Social isolation both causes and worsens depression. Behavioural activation — scheduling pleasurable activities and social contact — is a cornerstone of evidence-based treatment.
- Diet: The SMILES trial showed a Mediterranean diet intervention produced significantly greater improvements in depression scores than social support alone at 12 weeks (32% remission vs 8%).
- Daylight exposure: Light therapy (10,000 lux, 30 minutes in the morning) is first-line for SAD and has additive effects in non-seasonal MDD.
Frequently asked questions
Antidepressants typically take 4–8 weeks to produce meaningful improvement, though changes in sleep and energy may occur within 1–2 weeks. Full therapeutic benefit can take 12 weeks or longer. If no meaningful response after 4–6 weeks at adequate dose, the medication should be changed or augmented. Psychotherapy (CBT) typically shows meaningful improvement after 8–12 sessions. Ketamine and esketamine act within hours to days.
The simple serotonin deficiency model has been largely superseded by a more complex understanding. Depression involves disrupted connectivity between brain circuits, neuroinflammation, impaired neuroplasticity (reduced BDNF), HPA axis dysregulation, and genetic vulnerability. Antidepressants work through multiple mechanisms — including promoting neurogenesis in the hippocampus — not simply by correcting a chemical imbalance. This does not mean depression is "not real" or "all in your head"; it is a genuine neurobiological condition.
TRD is generally defined as inadequate response to at least two adequate antidepressant trials (correct dose for at least 4–6 weeks). It affects approximately 30% of people treated for MDD. Before labelling depression as treatment-resistant, confirm the diagnosis (rule out bipolar disorder), ensure adequate dosing, and address factors that maintain depression (sleep disorders, substance use, relationship stressors). Options include augmentation, medication switching, esketamine, TMS, and ECT.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5-TR). 2022.
- Cipriani A, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder. Lancet. 2018;391(10128):1357–1366.
- Cuijpers P, et al. Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis. World Psychiatry. 2014;13(1):56–67.
- Cole EJ, et al. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT). Am J Psychiatry. 2020;177(8):716–726.
- Deligiannidis KM, et al. Zuranolone for the Treatment of Postpartum Depression (ROBIN). NEJM. 2023;389:895–907.
- Carhart-Harris R, et al. Trial of Psilocybin versus Escitalopram for Depression. NEJM. 2021;384(15):1402–1411.