Treating a Major Depressive Episode (without psychosis)

The following treatment guidelines are meant as a reference tool only, and are not intended as treatment advice or to replace the clinical decision-making process of psychiatrists or other health professionals who administer these treatments. In clinical practice there are often good reasons why treatment approaches differ from what is described here.

Step 1:  Start with either psychotherapy (option a), medications (option b), or a combination of both [level 1]. The combination can be modestly more effective than using either one alone.

1. Begin a course of psychotherapy.
   • CBT or IPT are the first-line choices for psychotherapy [level 1].
   • Psychodynamic Psychotherapy and Behavioral Therapy can also be considered [level 2] depending on the individual's preference and what is available in the community.
   • Marital Therapy could be considered if the episode seems linked to marital discord [ref].
   • Improvements in the depressive symptoms should be seen within 8 weeks of beginning psychotherapy. If by this time the symptoms have not improved significantly, go to Step 1b (if not already done) while continuing the therapy.
   • Once a course of psychotherapy has been successful, ongoing booster sessions are recommended [level 1]; see Step 3.
 
2. Start an SSRI or a novel antidepressant.
   
   • Therapeutic effects of antidepressants usually do not begin before 4 weeks of taking them on a daily basis, but a check-up with a physician should be offered after 1-2 weeks of starting the medication to check for any side-effects and monitor the individual's condition.
   • If there are no signs of improvement even after 6 weeks of treatment, including two weeks at an increased dose, or if the medication is not well tolerated due to side-effects, taper and discontinue the medication and at the same time choose one of the following options:
   • start psychotherapy according to Step 1a (if not already tried)
   • repeat Step 1b with a different medication
   • go to Step 2 to start a different treatment
   • On the other hand, if after 4-6 weeks there are signs of improvement, then continue the treatment with check-ups with a physician every 2 weeks.
     • As long as the depressive symptoms continue to improve, there is no need to increase the dose.
     • But if in a given 2-week period the symptoms show no further signs of improvement, the dose should then be increased. It is recommended to wait about 2 weeks after every dose increase to give a chance for improvements to take place before deciding to increase the dose further.
   • If with this approach the depressive symptoms resolve completely, go to Step 3.
   • On the other hand, if after 2 weeks at the maximum tolerated dose the condition has not resolved completely, go to Step 2.

Step 2:  Re-evaluate the person's condition and diagnosis and explore the possibility of an underlying Bipolar Disorder, a concurrent Substance Use Disorder, or difficulties adhering to the prescribed treatments. Then, consider choosing one of the following options (a, b, c or d):

1. Add one of the following kinds of medications to the antidepressant started in Step 1b:
   
   • An Atypical Antipsychotic [level 1]
     • Aripiprazole [level 1], Olanzapine [level 1], Quetiapine [level 2] and Risperidone [level 2] have the most amount of evidence in this regard.
     • Quetiapine may be particularly effective [ref, ref]
   • Another SSRI or a novel antidepressant [level 2]
     • Combining Bupropion or Mianserin with an SSRI, or Mirtazapine with an SSRI or Venlafaxine, have the most supporting evidence [level 2].
     • Common clinical practice is to combine antidepressants that have different mechanisms of action. This means giving low priority to combinations of two SSRIs, or of an SSRI with Venlafaxine.
   • Lithium [level 1]
   • Thyroid hormone [level 2]
     • This has been studied mainly as an add-on to Tricyclic Antidepressants, which are no longer used very often.
   • A Stimulant or Modafinil [level 3]
     • This can be used if the desired effect is to increase the person's energy, interest and motivation as well as to brighten their mood.
     • This should probably be avoided if the person is experiencing signficant anxiety or agitation as part of their Depression.
     • Some studies have found that Stimulants are not an effective add-on to antidepressants for treating Depression.
     • Use caution when combining a Stimulant with Venlafaxine, Buproprion or Duloxetine due to risk of cardiovascular side-effects.
       
   • Buspirone [level 2]
     • Some studies have found that it is not an effective add-on to antidepressants for treating Depression.
   • Lamotrigine [level 3]
     • Some studies have found that it is not an effective add-on to antidepressants for treating Depression [ref].
     • It takes up to 2 months to reach therapeutic levels with this medication.
   • Celecoxib [level 3] [ref]
     • Other non-steroidal anti-inflammatory medications can also be considered [ref]
       
   • Start any of the above add-on medications at the lowest therapeutic dose. As long as the depressive symptoms continue to improve with this intervention, there is no need to increase the dose.
   • But if in a given 2-week period the symptoms show no further signs of improvement, the dose should then be increased. It is recommended to wait about 2 weeks after every dose increase to give a chance for improvements to take place before deciding to increase the dose further.
     • If with this approach the depressive symptoms resolve completely, go to Step 3.
     • If there are no signs of improvement even after 4 weeks of this step, including two weeks at an increased dose, or if the medication is not well tolerated due to side-effects, taper and discontinue the medication and at the same time repeat Step 2.
     • If after 2 weeks at the maximum tolerated dose the symptoms have improved but not resolved completely, repeat Step 2 with or without continuing the medication that was added-on.
    
2. Add one of the following natural treatments to the antidepressant started in Step 1b:
• Omega-3 fatty acids [level 1]
• St John's Wort (Hypericum) [level 2]
• Light Therapy [level 2]
• An exercise or yoga program [level 2]
• A course of sleep deprivation [level 2]
• If within 4 weeks the depressive symptoms resolve completely, go to Step 3.
• If there are no signs of improvement after 4 weeks of this step, discontinue this treatment and repeat Step 2.
• If after 4 weeks the symptoms have improved but not resolved completely, repeat Step 2 with or without continuing the natural product that was added-on.
 
3. Taper and discontinue the antidepressant started in Step 1b and start one of the following:
   
   • Quetiapine [level 1]
   • A TCA [level 1]
   • An MAOI [level 1]
     • it will be necessary to wait 2 weeks after stopping the previous medication before starting the MAOI.
     • Significant dietary restrictions make using most MAOIs impractical.
   • As long as the depressive symptoms continue to improve with this intervention, there is no need to increase the dose.
   • But if in a given 2-week period the symptoms show no further signs of improvement, the dose should then be increased. It is recommended to wait about 2 weeks after every dose increase to give a chance for improvements to take place before deciding to increase the dose further.
     • If with this approach the depressive symptoms resolve completely, go to Step 3.
     • If there are no signs of improvement even after 4 weeks of this step, including two weeks at an increased dose, or if the medication is not well tolerated due to side-effects, taper and discontinue the medication and at the same time repeat Step 2.
     • If after 2 weeks at the maximum tolerated dose the symptoms have improved but not resolved completely, repeat Step 2 with or without continuing the medication that was added-on (but note that MAOIs cannot be combined with antidepressants, Atypical Antipsychotics, and Stimulants).
 
4. Begin psychotherapy as described in Step 1a (if this was not already tried).
   
   • If after 8 weeks the episode has resolved, go to Step 3.
     
   • If after 8 weeks the episode has not resolved, choose another option in Step 2 while continuing the psychotherapy.
 
5. Try a course of ECTor rTMS [level 1]
   
   • If the episode resolves, go to Step 3.
     
   • If after a full course the episode has not resolved, choose another option in Step 2

Step 3:  Once the Depressive Episode has resolved, treatment should still continue to prevent a relapse (this is called maintenance treatment):

1. Any medications that were useful should be continued for at least another 6-9 months without lowering the dose.  However, consider continuing treatment for at least 2 years if any of the following conditions are met [level 3]:
   
   • The episode of Depression had been severe, chronic, or difficult to treat.
     
   • The person has had 3 or more Depressive Episodes in their lifetime.
     
   • The person is elderly.
   • The person suffers from other concurrent and signficant psychiatric or medical conditions.
   • The person is experiencing ongoing residual depressive symptoms.
   • In the past, the person relapsed back into Depressive Episodes when they stopped their medications.
 
2. If psychotherapy had been useful, then follow-up booster sessions should be given every month for a year.
 
3. If ECT was what helped to resolve the episode, then a maintenance treatment should be used for 2 years. A treatment from Step 1b or any other treatments that been helpful previously should be used, but avoid using treatments that had failed.  Alternatively, monthly ECT sessions can be used as a maintenance treatment to prevent relapse.

Evidence Base for the Above Strategies

Except where otherwise indicated, the above treatments strategies are based on the CANMAT 2009 Clinical Guidelines for the Management of Major Depression in Adults [ref, ref, ref, ref, ref]. These guidelines define levels of evidence to support the various recommendations. The better the level of evidence, the more certain we can be that a given conclusion is correct.

• Level 1 evidence: This is the highest level of evidence. It requires that a given conclusion is supported by at least two randomized controlled trials with adequate sample sizes, and/or a meta-analysis with narrow confidence intervals.
• Level 2 evidence: This requires that a given conclusion is supported by at least one randomized controlled trials with adequate sample sizes, and/or a meta-analysis with wide confidence intervals.
• Level 3 evidence: This requires non-randomized, controlled prospective studies, case series, or high-quality retrospective studies.
• Level 4 evidence: This is based on the opinions or consensus of experts in the field.