Major Depressive Disorder (MDD)

The short version

●MDD is defined by at least one major depressive episode: five or more symptoms (including depressed mood or anhedonia) most of the day, nearly every day, for at least two weeks, causing significant impairment.
●First-line treatment is an antidepressant (SSRI/SNRI) and/or evidence-based psychotherapy (CBT, IPT, behavioral activation); most antidepressants take 4-8 weeks to work.
●A landmark network meta-analysis (Cipriani 2018) confirmed all 21 studied antidepressants beat placebo, with modest differences between them — choice is often driven by side-effect profile.
●About one-third of patients do not respond adequately to a first antidepressant, and roughly a third remain symptomatic after multiple trials (treatment-resistant depression).
●Ketamine works through a different mechanism (NMDA/glutamate) and produces measurable response within hours rather than weeks, with published response rates of 60-70% in treatment-resistant depression.
●Ketamine is not first-line; it is for treatment-resistant MDD, after adequate trials of standard antidepressants and therapy.

Clinical definition

Major depressive disorder is diagnosed when a person has one or more major depressive episodes without a history of mania or hypomania (which would indicate a bipolar disorder). A major depressive episode requires at least five of nine symptoms present most of the day, nearly every day, for at least two weeks, and at least one must be depressed mood or loss of interest or pleasure (anhedonia). The remaining symptoms span significant weight or appetite change, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, worthlessness or excessive guilt, impaired concentration or indecisiveness, and recurrent thoughts of death or suicide. The episode must cause clinically significant distress or functional impairment and not be attributable to a substance or medical condition. MDD is recurrent for most patients, varies in severity from mild to severe with psychotic features, and is specified by features such as anxious distress, melancholic, atypical, peripartum onset, or seasonal pattern.

How it differs from related conditions

vs. Persistent depressive disorder (dysthymia)

Chronic, lower-grade depression lasting two or more years; can coexist with major episodes ("double depression"). MDD episodes are more acute and severe.

vs. Bipolar depression

Identical depressive symptoms but with a lifetime history of mania or hypomania; the distinction is critical because treatment differs (mood-stabilizer-first). Always screened before treating "MDD."

vs. Adjustment disorder with depressed mood

A time-limited reaction to an identifiable stressor that does not meet full MDD criteria.

vs. Grief / bereavement

A normal response to loss, distinguished from MDD by preserved self-worth, the wave-like rather than pervasive quality of sadness, and absence of the full symptom cluster — though complicated grief and MDD can co-occur.

First-line treatments

SSRIs (escitalopram, sertraline, fluoxetine, etc.)

First-line for most patients; comparable efficacy across the class, so choice is driven by side effects and interactions. 4-8 weeks to assess.

SNRIs (venlafaxine, duloxetine)

First-line alternatives, useful with comorbid pain or when an SSRI fails.

Evidence-based psychotherapy (CBT, IPT, behavioral activation)

As effective as medication for mild-to-moderate MDD and protective against relapse; combined treatment is superior for severe or recurrent depression.

Atypical/other agents (bupropion, mirtazapine)

Chosen for specific profiles — bupropion for low energy and to avoid sexual side effects, mirtazapine for insomnia and appetite loss.

When standard treatments fail

Treatment-resistant depression (TRD) is typically defined as inadequate response to at least two adequate antidepressant trials (right dose, 4-8 weeks each). The standard sequence: optimize dose and confirm adherence → switch antidepressant (within or across class) → combine an antidepressant with psychotherapy → augment (lithium, atypical antipsychotic, thyroid hormone, or bupropion) → consider rapid-acting and neuromodulation options. This is where ketamine, esketamine (Spravato), TMS, and — for severe or psychotic depression — ECT enter. The most important step is often the simplest: ensuring each prior trial was actually adequate in dose and duration, since most "resistance" is under-treatment.

Where ketamine fits

MDD is the condition with the strongest ketamine evidence base. In randomized controlled trials (Murrough 2013, American Journal of Psychiatry, and many since), a single sub-anesthetic ketamine infusion produced response in roughly 60-70% of patients with treatment-resistant depression within 24 hours — a fundamentally different timescale from the 4-8 weeks of standard antidepressants — and the American Psychiatric Association has issued consensus guidance on its clinical use (Sanacora 2017). The mechanism is distinct: NMDA-receptor antagonism and downstream glutamatergic plasticity rather than slow serotonergic adjustment, which is part of why patients who have failed multiple serotonergic antidepressants often still respond. The limitations are durability and the need for a maintenance plan: a single dose wears off over days to weeks, so ketamine is delivered as a course followed by spaced maintenance, ideally alongside psychotherapy. Ketamine is not first-line for MDD; it is for the treatment-resistant subgroup after adequate standard trials.

Where this fits with Tovani

MDD is Tovani's core indication. Eligibility centers on treatment-resistant depression — typically at least two adequate antidepressant trials without sufficient response — and screening captures treatment history, suicide risk, bipolar history (to avoid treating unrecognized bipolar depression as unipolar), and contraindications (uncontrolled hypertension, active substance use disorder, active psychosis, pregnancy). Treatment is structured as an induction course followed by spaced maintenance, with telehealth visits for evaluation and dose decisions, an at-home session with a support person and the KetAI companion, and encouragement to continue or begin psychotherapy to consolidate response between sessions.

Check eligibility The science behind ketamine

Frequently asked

How is ketamine different from antidepressants for depression?

Antidepressants adjust serotonin slowly over 4-8 weeks; ketamine acts on the glutamate/NMDA system and can produce measurable mood improvement within hours. That is why people who have failed several antidepressants often still respond to ketamine — it is a different mechanism, not just another serotonin drug.

Do I have to fail other treatments before trying ketamine?

Generally yes. Ketamine is for treatment-resistant depression — usually after at least two adequate antidepressant trials. Making sure each prior trial was actually adequate in dose and duration is an important first step, since much "resistance" is really under-treatment.

How long does ketamine's effect last?

A single dose typically lasts days to a few weeks, which is why treatment is structured as an induction course followed by spaced maintenance, ideally with psychotherapy to consolidate the gains between sessions.

Will I have to stop my antidepressant to try ketamine?

Usually not. Ketamine and SSRIs/SNRIs work through different mechanisms and are generally compatible; many patients continue their antidepressant. Your physician reviews your full medication list during the consultation.

References

Cipriani A et al. 2018, The Lancet — Network meta-analysis of 21 antidepressants for major depressive disorder; all outperformed placebo, with modest between-drug differences. (PMID 29477251)
Murrough JW et al. 2013, American Journal of Psychiatry — Randomized controlled trial of ketamine in treatment-resistant depression; about 64% response within 24 hours versus 28% with active control. (PMID 23982301)
Sanacora G et al. 2017, JAMA Psychiatry — American Psychiatric Association consensus statement on the clinical use of ketamine for mood disorders. (PMID 28249076)

Last reviewed by Dr. Ben Soffer, DO on May 30, 2026. This page is educational and not a substitute for clinical evaluation. A physician determines whether ketamine therapy is appropriate for your specific situation.