Click here to see the meta data of this asset.

Depression: Pharmacotherapy

Acute treatment

The goals for acute treatment of depression are full remission of symptoms and return to baseline function.

Of depressed patients in primary care, 60 to 80 per cent can expect to achieve remission. Remission is defined as having normal mood and minimal symptoms. It is best evaluated using a rating scale (e.g., a score within the normal range on the Patient Health Questionnaire [PHQ-9], Hamilton Depression Rating Scale or Beck Depression Inventory).

Antidepressant medications are first-choice treatments, especially for moderate to severe depression.

The newer antidepressants (selective serotonin reuptake inhibitors [SSRIs], bupropion, mirtazapine and venlafaxine) are first-line medications that are more tolerable and safe than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).

Maintenance treatment

The goal for maintenance treatment of depression is preventing relapse and recurrence.

  • Except for those with risk factors, patients should continue on antidepressants for at least four to six months after achieving remission.
  • Patients with risk factors (chronic, recurrent, severe or difficult-to-treat depressive episodes) should continue on antidepressants for at least two years. Some patients will require lifetime treatment.

Prescribing an antidepressant medication

Usually there is not one definite choice of antidepressant for any given patient because there is so much individual variability in efficacy and side-effects. The choice is based primarily on individual profiles of efficacy, tolerability and anxiety indications (See Table 2.1: First-line antidepressant medications, doses and profiles and Table 2.2: Second-and-third line antidepressant medications and doses). 

  • There is some evidence for increased efficacy with escitalopram, mirtazapine and venlafaxine, particularly in patients with more severe depression.
  • There is some evidence for better short-term tolerability with citalopram, escitalopram, moclobemide and sertraline. Bupropion, mirtazapine and moclobemide have fewer sexual side-effects than other antidepressants.
  • A broad-spectrum agent (indicated for both depressive and anxiety disorders) is recommended due to high comorbidity of these disorders. Evidence for efficacy in most anxiety disorders is demonstrated with escitalopram, paroxetine, sertraline and venlafaxine. Other antidepressants may also be effective for anxiety disorders, but no studies have been done. 

Managing no response to treatment

When the patient does not respond to the medication, options include the following:

  • Check diagnosis: Any bipolarity, missed comorbidity such as substance abuse?
  • Optimize the antidepressant: Increase to maximum tolerable dose within dose range, ensure adherence for at least several weeks, manage side-effects.
  • Switch to another antidepressant: There is no difference between switching within the same class of first-line antidepressants (e.g., SSRI to another SSRI) or to a different class (SSRI to venlafaxine or bupropion).
  • Use an augmenting agent: For example:
    • add triiodothyronine (25–50 μg/d) or lithium (600–900 mg/d, or to therapeutic serum levels of 0.6–1.0 mmol/L).
    • Alternatively, add an atypical antipsychotic (olanzapine 2.5– 0 mg/d, risperidone 0.5–3 mg/d, quetiapine 100–300 mg/d).
    • Be careful for increased side-effect burden, especially with lithium and atypical antipsychotics.
  • Combine with an antidepressant in a different class: For example, add bupropion to an SSRI. Be careful about drug–drug interactions and increased side-effect burden.
  • Add psychotherapy: Augmenting with psychotherapy is often beneficial. It can help to reduce stress that may contribute to the depression. Cognitive-behavioural therapy may be particularly useful.

Although there is little evidence to guide decisions when there is only partial response to treatment, most clinicians would augment or combine in order not to lose gains from the first antidepressant.

Switching between antidepressants

A washout period usually is not necessary when switching between most antidepressants (except to and from MAOIs). Therefore, the second antidepressant can usually be started at a low dose while tapering off the first antidepressant (the X approach).

Be careful for increased side-effect burden when starting a medication before stopping another. In some patients, such as those who appear sensitive to side-effects, taper off the first antidepressant before starting the second one (the V approach).

Avoiding drug interactions

Be aware of drug–drug interactions:

  • Fluoxetine and paroxetine can markedly inhibit cytochrome P450 (CYP 450) isoenzyme 2D6 and can increase blood levels of drugs that are metabolized primarily by that isoenzyme (caution with TCAs, beta blockers, codeine [reduces effect]).
  • Fluvoxamine can markedly inhibit CYP 1A2 and can increase blood levels of drugs that are metabolized primarily by that isoenzyme (caution with statin drugs, warfarin, quinidine, phenytoin, cyclosporine, sildenafil, vardenafil, clozapine, buspirone, diazepam).
  • Duloxetine is extensively metabolized by CYP 1A2, so avoid using with potent inhibitors of CYP 1A2 (such as fluvoxamine and quinolones).
  • MAOIs (and moclobemide) should not be combined with other antidepressants or serotonergic agents due to the risk of potentially fatal interactions (e.g., meperidine).

Stopping antidepressant medication

When stopping medications:

  • Gradually taper doses (e.g., at least one week for each dose reduction) whenever possible.
  • Caution patients about, and monitor for, discontinuation symptoms (which are usually mild and transient).

Use the mnemoni FINISH to remember discontinuation symptoms:

Flu-like symptoms



Imbalance (dizziness)

Sensory disturbances (electric shocks)

Hyperarousal (agitation)

Discontinuation symptoms are more likely associated with paroxetine and venlafaxine, and are less likely with fluoxetine and moclobemide.

Providing psychoeducation about medication

Use simple messages to help patients adhere to their medications:

  • "Antidepressants have a lag time of two to three weeks to response."
  • "Take your medications daily."
  • "Side-effects are usually mild and temporary."
  • "Continue on medications for at least six months, even after you feel better, or symptoms may return."
  • "Do not stop antidepressants before checking with your doctor."

Related Portico Network topics

Understanding psychiatric medications (patient handout):

  • Antidepressants
  • Antipsychotics
  • Mood stabilizers
  • Benzodiazapines

Psychiatry in primary care toolkit

A powerful mobile app packed with features that will streamline screening and assessment in primary care.

Download the Toolkit

Frequently asked questions