What treatment can include
A useful treatment plan looks at four areas: the symptoms themselves, the conditions that may be feeding them, the daily life around the person, and safety. Each area has tools.
For the symptoms, there is psychotherapy and there are medications. For the conditions feeding the symptoms, there is medical workup for things like thyroid disease, anemia, sleep apnea, vitamin deficiencies, chronic pain, and substance use. For daily life, there is structure, sleep, movement, social contact, and work or school adjustments. For safety, there is a plan made with a clinician, and crisis resources kept close.
Therapy
Several psychotherapies have strong evidence in depression. Cognitive behavioral therapy works on the link between thoughts, feelings, and behavior. Behavioral activation focuses on doing small things that used to bring meaning or pleasure, even before the motivation returns. Interpersonal therapy looks at depression through the lens of relationships and roles. Acceptance and commitment therapy and mindfulness-based approaches help with rumination and avoidance.
A therapist who is trained in one of these approaches and who feels like a good fit is more important than the specific brand of therapy. For some people, brief problem-solving therapy is enough. For others, longer work is a better fit.
A therapist who feels like a good fit is more important than the specific brand of therapy.
Antidepressants
Antidepressants are a category, not a single drug. For most adults, the first medication tried is an SSRI. SNRIs are a reasonable alternative and a common second option, especially when pain or significant fatigue is part of the picture. Bupropion is another common choice, especially when fatigue and low motivation dominate, or when sexual side effects from other antidepressants are a concern. Mirtazapine can be useful when sleep and appetite are very disrupted. There are older medications that still have a place, including tricyclics and MAOIs, used by clinicians comfortable with them. For a class-by-class comparison of mechanism, common reasons to choose, side effects, cautions, and withdrawal severity, see Antidepressant comparison.
Antidepressants take time. Most people start to notice changes in two to six weeks, with sleep, appetite, and energy often shifting before mood does. The first medication tried is not always the right one. About one in three people reach full remission on the first antidepressant tried, and roughly half show a meaningful response. With sequential adjustments across up to four steps, cumulative remission rises further, though reanalyses with stricter outcome criteria report lower rates than the original report (Pigott, 2010). The number tried matters less than the willingness to keep adjusting.
Side effects vary by medication. Common ones include nausea, headache, sleep changes, sexual side effects, and a temporary increase in anxiety in the first weeks. Most settle. Anything serious, including new or worsening suicidal thoughts, should be brought to a prescriber the same day.
Psychiatric evaluation
A full psychiatric evaluation usually takes 45 to 60 minutes. It covers current symptoms, history of past episodes, family history, medical history, medications, substances, sleep, trauma history, and safety. It often includes screening for bipolar disorder, anxiety disorders, ADHD, trauma, substance use, and medical contributors. A good evaluation ends with a working diagnosis, a treatment plan, and a clear next step.
Medication management
Medication management is the follow-up work after a medication is started. Doses are adjusted. Side effects are reviewed. Other contributors are addressed. New symptoms are tracked. Most people do not need a complicated regimen. Most need a clinician who is paying attention.
Treatment-resistant depression, explained carefully
The term treatment-resistant depression usually means that two adequate trials of standard antidepressants have not worked. Adequate means the right dose for long enough, not a brief or low-dose attempt. When this happens, options open up, not close down.
These options can include switching medication class, adding a second medication, adding therapy if there has not been any, addressing untreated medical or sleep contributors, and considering treatments such as ketamine or esketamine, transcranial magnetic stimulation, or, in severe cases, electroconvulsive therapy. Each has its own risks, requirements, and evidence base. A psychiatrist familiar with these options can help sort out what fits.
When urgent care is needed
Some situations are emergencies. Active suicidal thoughts with a plan or intent. The means to act and the intent to use them. A sudden calm after a long period of distress. Giving away possessions. Severe self-neglect. Psychosis. Mania. Any threat to self or others. In these situations, call 911, call or text 988, or go to the nearest emergency department.
Antidepressant class comparison
Each class works through a different mechanism and tends to fit a different clinical picture. The table below is informational. Specific medication decisions belong with a prescriber who knows your full history.
| Class | Examples | How it works | Common reasons to choose | Common side effects | Notes |
|---|---|---|---|---|---|
| SSRI | Sertraline, escitalopram, fluoxetine, paroxetine, citalopram | Increases serotonin signaling | Most common first-line; broad effectiveness | Nausea, headache, sleep changes, sexual side effects | Generally well-tolerated; wide therapeutic window |
| SNRI | Venlafaxine, duloxetine, desvenlafaxine | Increases serotonin and norepinephrine | Depression with pain or significant fatigue | Similar to SSRIs; dose-dependent blood pressure increase possible | Duloxetine has indications in chronic pain |
| Atypical | Bupropion | Affects norepinephrine and dopamine | Low motivation, fatigue; avoiding sexual side effects | Insomnia, dry mouth, agitation, decreased appetite | Avoided in seizure history, eating disorders, active heavy alcohol use |
| Atypical | Mirtazapine | Different serotonin receptors; alpha-2 effect | Severe sleep and appetite disruption | Sedation, weight gain | Often given at bedtime |
| Tricyclic | Nortriptyline, amitriptyline | Multiple receptor effects | Specific cases under experienced clinicians | Dry mouth, constipation, weight gain, cardiac effects | Generally not first-line in modern practice |
| MAOI | Phenelzine, tranylcypromine | Blocks monoamine oxidase | Reserved cases | Hypertensive crisis risk with tyramine foods; many drug interactions | Requires dietary precautions |
| Multimodal | Vortioxetine | Multiple serotonin receptor effects | Some cognitive symptoms | Nausea | More expensive; coverage varies |
Psychotherapy comparison
A therapist who is trained in one of these approaches and who feels like a good fit is more important than the specific brand of therapy.
| Approach | Best fit for | Typical length | Evidence base |
|---|---|---|---|
| Cognitive Behavioral Therapy (CBT) | Self-critical thinking, persistent rumination, anxiety with depression | 12 to 20 sessions | Extensive; first-line in major guidelines |
| Behavioral Activation (BA) | Low motivation, loss of interest, withdrawal | 8 to 16 sessions | Strong; non-inferior to CBT in major trials |
| Interpersonal Therapy (IPT) | Depression tied to relationships, role changes, grief | 12 to 16 sessions | Strong; included in APA and NICE guidelines |
| Acceptance and Commitment Therapy (ACT) | Avoidance, rumination, values clarification | 8 to 16 sessions | Growing; comparable outcomes to CBT in trials |
| Mindfulness-Based Cognitive Therapy (MBCT) | Recurrent depression in remission, relapse prevention | 8 weekly group sessions | Strong for relapse prevention |
| Cognitive Behavioral Analysis System of Psychotherapy (CBASP) | Chronic depression and persistent depressive disorder | 16 to 32 sessions | Specific evidence in chronic depression |
Treatment-resistant depression options
When two adequate antidepressant trials have not worked, the options open up rather than close down. The choices and the order in which they are considered depend on the person, the prior trials, and the clinician. The table below summarizes the main escalation options.
| Option | How it works | When it is considered | Setting required |
|---|---|---|---|
| Re-evaluate the diagnosis | Reassess for bipolar disorder, medical contributors, substance use, sleep apnea, or unaddressed trauma | Always the first step before escalating treatment | Outpatient psychiatric or primary care visit |
| Confirm adequate prior trials | Verify that prior antidepressants reached therapeutic dose for adequate duration and that therapy was included | Before declaring a trial a failure | Outpatient visit with medication reconciliation |
| Switch antidepressant class | Change from SSRI to SNRI, bupropion, mirtazapine, or a multimodal agent such as vortioxetine | After one or two trials of the same class without response | Outpatient prescriber |
| Augment with lithium or T3 | Add lithium or triiodothyronine to an existing antidepressant; both are evidence-based but used off-label | Partial response to an antidepressant | Outpatient prescriber, lithium requires routine blood monitoring |
| Augment with atypical antipsychotic | Add aripiprazole, brexpiprazole, quetiapine, or the olanzapine/fluoxetine combination, all FDA-approved for adjunctive depression treatment | Partial response to an antidepressant | Outpatient prescriber with metabolic monitoring |
| Add psychotherapy | Add cognitive behavioral therapy, behavioral activation, or interpersonal therapy if not already in the plan | Whenever therapy has not been part of treatment | Outpatient therapist |
| Esketamine (Spravato) | Intranasal NMDA-receptor antagonist used with an oral antidepressant; FDA-approved for treatment-resistant depression and for major depression with acute suicidal ideation | After two failed antidepressant trials, or with acute suicidal ideation | Certified REMS clinic with at least two hours of post-dose monitoring |
| Off-label intravenous ketamine | Racemic ketamine given by infusion; not FDA-approved for depression but used off-label with rapid effects in some patients | Considered when esketamine is not accessible or appropriate | Specialty ketamine clinic with monitoring; usually not insurance-covered |
| Transcranial magnetic stimulation (TMS) | Noninvasive magnetic pulses applied to the prefrontal cortex; FDA-approved for depression | After one or more failed antidepressant trials | Outpatient TMS clinic, typically daily sessions for four to six weeks |
| Electroconvulsive therapy (ECT) | Brief electrical stimulation under general anesthesia; the most effective treatment available for severe depression | Severe, life-threatening, catatonic, or otherwise unresponsive depression | Hospital or specialty ECT suite with anesthesia |
FDA-approved augmentation options. When an antidepressant produces only a partial response, an additional medication may be added rather than switching. Aripiprazole, brexpiprazole, and the olanzapine/fluoxetine combination are FDA-approved as adjunctive treatment for depression. Lithium and triiodothyronine (T3) augmentation are evidence-based but used off-label. Augmentation decisions involve trade-offs in side-effect profile and should be made with a prescriber.
A psychiatrist familiar with these options can help sort out what fits a specific situation.
Questions to ask a clinician
- What is the working diagnosis, and what else are we considering?
- What treatments do you recommend, and why those?
- What are the most common side effects, and which ones should I call about?
- How long before we expect to see a change?
- What does follow-up look like?
- What should I do if I feel worse?
- What is the plan if the first treatment does not help?
In-depth treatment guides
The articles below go deeper on specific medications, side effects, therapy comparisons, and procedural treatments referenced above.
Treatment
Antidepressant withdrawal and discontinuation
Why discontinuation symptoms happen, how long they last, and how to taper safely.
Read →
Treatment
SSRI side effects
What is common, what passes on its own, and what is worth calling the prescriber about.
Read →
Treatment
CBT vs DBT for depression
How each approach works, what a session looks like, and which one tends to fit.
Read →
Treatment
TMS for depression
How transcranial magnetic stimulation works, who is a candidate, and what a course looks like.
Read →
Treatment
Ketamine and esketamine for depression
Evidence, safety, and access for ketamine and FDA-approved esketamine (Spravato).
Read →
Treatment
Light therapy for depression
Evidence in seasonal and non-seasonal depression, dose, timing, and what to look for in a lamp.
Read →shrinkMD is a multistate telepsychiatry practice that provides psychiatric evaluation and medication management where clinically appropriate. Learn more at shrinkmd.com.
Disclosure (FTC § 255). shrinkMD is a multistate telepsychiatry practice operated by an affiliate of shrinkMD Publishing Inc., which publishes this site. The editor of this site, Shariq Refai, MD, MBA, is the founder of shrinkMD and has a financial interest in it. shrinkMD is listed here as one of several resources, not as a recommendation. The site receives no fee, commission, or referral revenue for listing shrinkMD or any other practice.
Frequently asked questions
What treatments work for depression?
How long do antidepressants take to work?
What is the success rate?
Do I have to take antidepressants forever?
What is treatment-resistant depression?
Is therapy or medication better?
Sources▸
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd ed.
- NICE Guideline NG222. Depression in adults: treatment and management. 2022.
- Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients (STAR*D). Am J Psychiatry. 2006.
- Cipriani A, et al. Comparative efficacy and acceptability of 21 antidepressants. Lancet. 2018.
- FDA. Spravato (esketamine) prescribing information.
- Cuijpers P, et al. Psychotherapies for depression: meta-analytic update. World Psychiatry. 2023.
Medically reviewed by Shariq Refai, MD, MBA. Last reviewed March 15, 2026.