Combination therapy for bipolar depression in adults and young people
See Overview of pharmacotherapy for bipolar depression in adults and young people for a discussion on the choice between monotherapy or combination therapy for bipolar depression, drug choice and use in specific populations (eg young people, females of childbearing potential, pregnant people, males of reproductive potential).
Combination therapy for bipolar depression involves short-term use of an antidepressant combined with one of the following drugs: cariprazineRANZCP 2020, lithium, lurasidone, olanzapine, quetiapine or sodium valproate.
When using an antipsychotic, slower dose escalation may be required for people who are antipsychotic naive, to reduce the likelihood of antipsychotic adverse effects.
For selective serotonin reuptake inhibitor (SSRI)–based combination therapy for bipolar depression, as a two-drug regimen, use:
1 citalopram 20 mg orally, in the morning. Assess the patient’s response to therapy after 2 to 4 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 10 mg no more often than every 2 weeks until an acceptable response is achieved or a daily dose of 40 mg is reached. Withdraw within 1 to 2 months after recovery from the depressive episode citalopram citalopram citalopram
OR
1 escitalopram 10 mg orally, in the morning. Assess the patient’s response to therapy after 2 to 4 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 5 mg no more often than every 2 weeks until an acceptable response is achieved or a daily dose of 20 mg is reached. Withdraw within 1 to 2 months after recovery from the depressive episode bipolar disorder, depressive episode escitalopram escitalopram escitalopram
OR
1 fluoxetine 20 mg orally, in the morning. Assess the patient’s response to therapy after 2 to 4 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 10 mg no more often than every 2 weeks until an acceptable response is achieved or a daily dose of 60 mg is reached. Withdraw within 1 to 2 months after recovery from the depressive episode bipolar disorder, depressive episode fluoxetine fluoxetine fluoxetine
OR
1 fluvoxamine 50 mg orally, at night. Assess the patient’s response to therapy after 2 to 4 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 25 mg no more often than every 2 weeks until an acceptable response is achieved or a daily dose of 300 mg is reached. Daily doses above 150 mg can be given in divided doses. Withdraw within 1 to 2 months after recovery from the depressive episode bipolar disorder, depressive episode fluvoxamine fluvoxamine fluvoxamine
OR
1 paroxetine 20 mg orally, in the morning1. Assess the patient’s response to therapy after 2 to 4 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 10 mg no more often than every 2 weeks until an acceptable response is achieved or a daily dose of 50 mg is reached. Withdraw within 1 to 2 months after recovery from the depressive episode bipolar disorder, depressive episode paroxetine paroxetine paroxetine
OR
1 sertraline 50 mg orally, in the morning. Assess the patient’s response to therapy after 2 to 4 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 25 mg no more often than every 2 weeks until an acceptable response is achieved or a daily dose of 200 mg is reached. Withdraw within 1 to 2 months after recovery from the depressive episode bipolar disorder, depressive episode sertraline sertraline sertraline
PLUS ONE OF THE FOLLOWING
1 cariprazine 1.5 mg orally, daily; depending on clinical response and tolerability, the dose may be increased after 2 weeks to 3 mg daily. Maximum daily dose of 3 mg daily. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required RANZCAP 2020 guidelines cariprazine cariprazine cariprazine
OR
1 lithium carbonate immediate-release 500 to 750 mg orally, daily, in 2 or 3 divided doses or as a single dose at night—divided doses may improve tolerability whereas once-daily dosing may improve adherence. After 5 to 7 days of treatment, determine lithium blood concentration. Target a concentration of 0.6 to 0.8 mmol/L, depending on clinical response and tolerability; concentrations of 0.4 to 1.0 mmol/L may be effective in some patients. A lower lithium concentration (0.4 to 0.6 mmol/L) may be required in patients 60 years or older because of poorer tolerability. Adjust daily dose in increments of 250 to 500 mg. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required2345 bipolar disorder, depressive episode, combination therapy lithium lithium lithium
OR
1 lithium carbonate modified-release 450 to 675 mg orally, daily, in 2 divided doses or as a single dose at night—divided doses may improve tolerability whereas once-daily dosing may improve adherence. After 5 to 7 days of treatment, determine lithium blood concentration. Target a concentration of 0.6 to 0.8 mmol/L, depending on clinical response and tolerability; concentrations of 0.4 to 1.0 mmol/L may be effective in some patients. A lower lithium concentration (0.4 to 0.6 mmol/L) may be required in patients 60 years or older because of poorer tolerability. Adjust daily dose in increments of 225 to 450 mg. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required2345lithium lithium lithium
OR
1 lurasidone 20 mg orally, daily; titrate to response and tolerability. Maximum daily dose of 120 mg. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required bipolar disorder, depressive episode, combination therapy lurasidone lurasidone lurasidone
OR
1 olanzapine 5 mg orally, daily; titrate to response and tolerability. Maximum daily dose of 20 mg. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required bipolar disorder, depressive episode, combination therapy olanzapine olanzapine olanzapine
OR
1 quetiapine immediate-release 50 mg orally, at night on the first day; increase to 100 mg at night on the second day; increase to 200 mg at night on the third day; increase to 300 mg at night on the fourth day; then titrate to response and tolerability. Maximum daily dose of 600 mg. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required bipolar disorder, depressive episode, combination therapy quetiapine quetiapine quetiapine
OR
1 quetiapine modified-release 50 mg orally, at night on the first day; increase to 100 mg at night on the second day; increase to 200 mg at night on the third day; increase to 300 mg at night on the fourth day; then titrate to response and tolerability. Maximum daily dose of 600 mg. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required quetiapine quetiapine quetiapine
OR
1 sodium valproate 200 to 400 mg orally, twice daily. After 3 days of treatment, determine sodium valproate blood concentration. Target a concentration between 660 and 875 micromol/L (94 and 125 mg/L). Adjust the daily dose in increments of 200 to 400 mg every 7 days. A daily dose of 1000 to 2000 mg is usually required; maximum daily dose 3000 mg. Continue for at least 6 to 12 months to prevent relapse, then assess if prophylaxis is required45. bipolar disorder, depressive episode sodium valproate sodium valproate sodium valproate
During treatment with an antidepressant, monitor patients closely for signs of emerging hypomania or mania—this occurs more commonly in young people.
Response to treatment usually becomes apparent after at least 1 week; full benefit may take 4 to 6 weeks, or even longer. If there is no response or an inadequate response to SSRI-based combination therapy within these timeframes, see Nonresponse to treatment for bipolar depression.
If there is an acceptable response, continue combination therapy for 1 to 2 months after recovery from the depressive episode, then gradually reduce the dose of and stop the antidepressant (see Stopping an antidepressant for more detail). Continue with the other drug as monotherapy for at least 6 to 12 months to prevent relapse, then assess if prophylaxis of bipolar disorder is required.
If the patient relapses when the antidepressant is withdrawn, they may be more prone to recurrent depressive episodes. Discontinuing the antidepressant is therefore not always possible—see Nonresponse to treatment for bipolar depression .