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Day # 30: Antidepressant Medications

Today will kick off our discussion of antidepressant medications. We will discuss different classes of antidepressants, the STAR-D trial, clinical pearls, and a general treatment algorithm.

Today's Content Level: Beginner, Intermediate


•It is important to note that antidepressants are not recommended as a first‐line treatment in recent‐onset mild depression. Active monitoring, individual guided self‐help, cognitive behavioral therapy (CBT), or exercise are preferred. 1

•Antidepressants are recommended for the treatment of moderate to severe depression and for dysthymia (persistent depressive disorder).

•Approximately 60–70% of patients with major depression will respond to an antidepressant medication. 2

•There are a number of available antidepressant classes that have evidence for the treatment of depression, anxiety, and other disorders. Each class of antidepressants have a unique mechanism but they all act to manipulate the levels of neurotransmitters in the brain that are responsible for modulating mood and emotions. Examples include serotonin, norepinephrine, and dopamine.

•All antidepressants have similar treatment response rates in treating major depression but vary in their mechanism of action, safety, and side effect profiles.

•We will discuss each class of antidepressant in great detail in the coming lessons but here is a brief overview of the medication classes that we will be discussing.

  • Selective serotonin reuptake inhibitors (SSRIs)

  • Serotonin-norepinephrine reuptake inhibitors (SNRIs)

  • Tricyclic antidepressants (TCAs) and Tetracyclic antidepressants

  • Monoamine oxidase inhibitors (MAOIs)

  • Miscellaneous = sometimes called novel or atypical antidepressants

STAR-D Trial

•The Sequenced Treatment Alternatives to Relieve Depression (STAR-D) trial is a landmark study that every mental health provider should be aware of. It is the largest study to date (published in 2006) that attempted to characterize a tiered protocol for antidepressant therapy. The following summary is from WikiJournalClub.

•This study employed a four-step treatment protocol to outpatients with non-psychotic depression with total remission as the goal. Step 1 was citalopram (an SSRI) only.

•Those with remission were entered into a 12-month follow up protocol.

•Those who did not attain remission were randomly enrolled in step 2 treatment, which consisted of 7 different treatment options. The stratified design allowed patients to choose a switch or augmentation strategy for steps 2 and 3.

These are the 4 steps in more detail:

  • Step 1: All participants received flexible-dose citalopram. If in remission, enter 12-month naturalistic follow up. If no remission, proceed to step 2.

  • Step 2: 3 augmentation strategies (citalopram + bupropion; citalopram + buspirone; citalopram + CBT) and 4 switch strategies (buproprion, sertraline, venlafaxine, CBT). If in remission, enter 12-month naturalistic follow up. If no remission, proceed to step 3.

  • Step 3: 2 augmentation strategies (lithium or triiodothyronine [T3]) and 2 switch strategies (nortriptyline, mirtazapine). If in remission, enter 12-month naturalistic follow up. If no remission, proceed to step 4.

  • Step 4: randomized to treatment with either tranylcypromine or combination venlafaxine XR and mirtazapine.

  • Color key for beginners: SSRI, SNRI, atypical antidepressant, TCA, MAOI, miscellaneous augmentation strategy.

•As expected, remission rates were higher in earlier steps, with step 1 achieving remission in ~40% of patients. Among the individuals that progressed to step 2, remission was achieved in ~30%. Steps 3 and 4 achieved remission in ~15% each step.

•STAR-D sheds light on the success of a specific tiered approach at treating unipolar depression. However, the study was limited in part by its open-label design and lack of a placebo control, rendering it difficult to tease out the impact of pharmacological therapy and CBT from the natural history of depression.

Treatment Guidelines and General Algorithm

•Most antidepressant medications do not work right away. Increasing neurotransmitter levels have downstream effects on receptor and synaptic activity that take time to develop.

•Most antidepressants require a trial of at least 3–4 weeks for any effect with some people requiring as little as 1–2 weeks and some 6–8 weeks for significant improvement.

•Duration of treatment: treat for at least 6 months for a patients first depressive episode. Treat for at least 2 years for patients with multiple episodes or those with dysthymia (persistent depressive disorder).

•General principles: Always discuss addition and use of non-pharmacologic measures, use at least the minimum effective dosing before switching medications, and withdraw/taper the antidepressant slowly if deciding to stop.

•Because of their safety and tolerability, SSRIs and related antidepressants (SNRI's) have become the most common agents used to treat major depression and often used as first-line treatment.

However, the choice of a particular medication used in a given patient should be made based on:

  • Patient’s particular symptoms

  • Previous treatment responses or a family member to a particular medication

  • Side-effect profile

  • Comorbid (medical and psychiatric) conditions

  • Risk of suicide via overdose on the medication

  • Cost

  • These nuanced treatment decisions will become more clear once we dive into specific medication classes.

Basic algorithm if starting antidepressant:

  • Titrate initial medication (typically SSRI or buproprion) to at least minimum effective dose, assess after 3-4 weeks.

  • If effective, continue for duration of treatment and can titrate as necessary

  • If no effect whatsoever, switch to another antidepressant (can switch to another medication in same class or different class), and wait another ~3-4 weeks at therapeutic dose. A switching sequence may look like this: SSRI -> bupropion -> SNRI -> mirtazapine, TCA, or MAOI.

  • If some effect, consider initial augmentation strategies (SSRI or SNRI + bupropion or mirtazapine)

  • If still no effect with switching or initial augmentation: maximize non-pharmacologic measures, and progress towards treatment refractory” strategies

Treatment refractory depression and additional options are discussed on day # 37: Treatment Resistant Depression.

Antidepressant Use in Other Conditions

The use of antidepressant medications are not limited to depressive disorders. There is evidence for a variety of indications. Some of these will be summarize below.

  • Obsessive compulsive disorder: SSRIs (in high doses), TCAs (clomipramine)

  • Panic disorder: SSRIs, TCAs, MAOIs

  • Eating disorders: SSRIs (in high doses), TCAs

  • Social anxiety disorder (social phobia): SSRIs, SNRIs, MAOIs

  • Generalized anxiety disorder: SSRIs, SNRIs (venlafaxine), TCAs

  • Posttraumatic stress disorder: SSRIs

  • Irritable bowel syndrome: SSRIs, TCAs

  • Enuresis: TCAs (imipramine)

  • Neuropathic pain: TCAs (amitriptyline and nortriptyline), SNRIs

  • Chronic pain: SNRIs, TCAs

  • Fibromyalgia: SNRIs

  • Migraine headaches: TCAs (amitriptyline)

  • Smoking cessation: Bupropion

  • Premenstrual dysphoric disorder: SSRIs

  • Insomnia: Mirtazapine, trazodone, TCAs (doxepin)


Now that we have a good baseline for antidepressant medications we can start talking in detail about various antidepressant classes. We will discuss their mechanism of action, clinical indications, side effects, and prescriber tips. Medication classes that will be covered include SSRI's, SNRI's, atypical/novel antidepressants, TCA's, MAOI's, and augmentation strategies.

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