Treating Depression in Bipolar I Disorder

The following treatment guidelines are meant as a reference tool, but 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:  Getting started:

• Discuss Lifestyle Management principles
• Discontinue all Alcohol and illicit drugs
• Psychotherapy can be effective at any point (Steps 2-5) in the treatment of Bipolar Depression when combined with medications.
• Consider starting omega-3 fatty acids
  • although the evidence is not conclusive that omega-3 fatty acids help, they can also be beneficial for a number of other health reasons and are not associated with any significant health risks

Step 2:  Start with one of the following options:

• Quetiapine
• Lithium
  
• Lamotrigine
  • This medication takes up to 2 months to reach therapeutic levels. In cases of severe depression it may not be an appropriate first choice.
• Combine Bupropion or an SSRI antidepressant (except Paroxetine) with either Lithium, Valproic Acid, Olanzapine or Quetiapine.
  • Important controversies have been raised over the use of antidepressants in Bipolar Depression.
  • Antidepressants should be avoided if there are manic symptoms occurring during the Depressive Episode, or if the Depressive Episode is occurring in the context of Rapid Cycling.
  • The antidepressant should be tapered and discontinued 6-8 weeks after the Depressive Episode has resolved.
  • Bupropion may have less of a tendency to trigger manic symptoms than other antidepressants [ref].
  • The combination of Fluoxetine with Olanzapine has been well studied.
  • The combinations of Bupropion with Olanzapine or Quetiapine have not been well studied.
  • There is more evidence supporting the use of Olanzapine plus an SSRI than Quetiapine plus an SSRI.
  • If the individual already happens to be taking an Atypical Antipsychotic other than Olanzapine or Quetiapine, then this other Atypical can be used instead.
  • Paroxetine is not recommended because several studies have found it ineffective for Bipolar Depression.
  • Venlafaxine should be avoided because it comes with a high risk of triggering manic symptoms.
• Lurasdione
  • The amount of evidence supporting its use for Bipolar Depression is currently less than for the other treatments listed in Step 2.
• Valproic Acid
  • The amount of evidence supporting its use for Bipolar Depression is less than for the other treatments listed in Step 2, and its effectiveness may not be great. This option is not commonly used in clinical practice.
• ECT can be considered at this point if psychotic symptoms are present.
  
• The above medications usually require about 2-4 weeks at a therapeutic dose for improvements to take place, 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 4 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 repeat Step 2 with a different treatment option.
• On the other hand, if after 4 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 5.
• On the other hand, if after 2 weeks at the maximum tolerated dose the condition has not resolved completely, go to Step 3.

Step 3:  Choose one of the following options:

• Add one of the medications listed in Step 2 that was not yet tried
  • Note that there is no point in combining two Atypical Antipsychotics
• Avoid combining two antidepressants
• Note that if combining Valproic Acid with Lamotrigine, Valproic Acid blood concentrations can be lowered and Lamotrigine blood levels may double.
• The combination of Lurasdione with Lamotrigine has not been well studied.
• Add Modafinil
  
• 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 5.
  • 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 3 or go to Step 4.
  • If after 2 weeks at the maximum tolerated dose the symptoms have improved but not resolved completely, repeat Step 3 or go to Step 4 while continuing the current medications.

Step 4:  Choose one of the following options:

• Add Carbamazepine
• Add Olanzapine if not already tried
  
• Start a course of ECT
• Replace any antidepressant that was used in a previous step with another antidepressant, such as an SSRI, a novel antidepressant, a TCA or an MAOI.
  • Venlafaxine, TCAs and MAOIs all come with a substantial risk of triggering manic symptoms
  • Avoid Paroxetine because several studies have found it ineffective for Bipolar Depression.
  • MAOIs should not be combined with Atypical Antipsychotics
• Add Pramipexole
• Add Riluzole
• Add Topiramate
• 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. Regarding ECT, a full course should be given.
  • If with this approach the depressive symptoms resolve completely, go to Step 5.
  • 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 4.
  • If after 2 weeks at the maximum tolerated dose the symptoms have improved but not resolved completely, repeat Step 4 while continuing the current medications.

Step 5:  Maintenance treatment:

• Continue to focus on Lifestyle Managements skills.
• Consider starting psychotherapy if not already done. This can be especially important if
  • the individual is having difficulty with Lifestyle Managements skills
  • there are important ongoing life stressors that can be moderated
  • the person is experiencing some ongoing depressive symptoms
• If antidepressants were used, taper and discontinue them after 6-8 weeks.
• Continue all other effective medications for at least a year so as to prevent further episodes.  However, for individuals who have experienced multiple previous Bipolar mood episodes (Hypomania, Mania, Depressive or Mixed), or even just one severe episode, it is recommended that they remain on medications indefinitely.
• If a decision is taken to stop medications, this should be done very gradually, one medication at a time, over a period of at least a couple of months for each medication, and with close monitoring by a physician. Monitoring and follow-ups should continue even after the medications have been stopped.
  
• If the goal is to reduce the number of medications being used, Lithium, Olanzapine, Lamotrigine and Quetiapine have all been shown to be effective in preventing relapses to Depression and are thus the first choice in maintenance treatment. Lithium also has the added advantage of being the only agent with proven effect in reducing the risk of suicide when taken over a long term.
• If the successful treatment that was used was ECT, then once the course of ECT is completed any medications that were partially effective should be continued.

Unless otherwise indicated, the above treatments strategies are based on the CANMAT Guidelines for the Management of Patients with Bipolar Disorder [ref, ref, ref, ref] and the Texas Medical Algorithm Project.