Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

acute mania/mixed mania

1st line – second-generation antipsychotic or mood stabilizer

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ACUTE
|
acute mania/mixed mania
1st line – 

second-generation antipsychotic or mood stabilizer

Recommendations in line with Food and Drug Administration indication for initial treatment include risperidone, aripiprazole, olanzapine, lithium, or quetiapine.[130][131][132][133][134][136][139][140][141][143][144]​ The adverse-effect profile usually governs which medication is most likely to be used.

Data from controlled trials for divalproex is unclear. One meta-analysis demonstrated no significant difference in response rates to divalproex, compared with placebo, for treatment of acute mania in children and adolescents, although the quality of evidence was very low.[155] Some therapeutic response is expected within 1-2 weeks.[156]

For children and adolescents with first onset of psychosis, there is a lack of trial data to guide the choice of treatment. One head-to-head randomized controlled trial comparing quetiapine (extended release) versus aripiprazole in children and adolescents with a first episode of psychosis showed no significant differences between the treatment groups in severity of psychotic symptoms after 12 weeks of treatment, with only a modest improvement in symptoms for both groups. Quetiapine was associated with more metabolic adverse events and aripiprazole was associated with more initial akathisia and, unexpectedly, with more sedation.[165]

In the US, standard practice is that valproate and its analogs are only prescribed for the treatment of manic episodes associated with bipolar disorder during pregnancy, if other alternative medications are not acceptable or not effective.[125]Divalproex is not recommended for use in girls and women of childbearing potential by the World Health Organization (WHO).[126]​ Other international guidelines stipulate that valproate and its analogs must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention program in place, and certain conditions are met.[118]​[127]​​

For patients failing to respond to one of the initial approaches, consideration of dose optimization and medication adherence is recommended before moving on to alternative pharmacotherapy options.[117][157]​ If there is no response, or the drug is not tolerated due to adverse effects, it is recommended that a different drug among the recommended initial treatments is tried.

Primary options

risperidone: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 0.5 mg orally once daily initially, increase according to response, maximum 2.5 mg/day

OR

aripiprazole: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 2.5 mg orally once daily initially, increase according to response, maximum 30 mg/day

More

OR

olanzapine: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 2.5 mg orally once daily initially, increase according to response, maximum 20 mg/day

OR

quetiapine: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 25 mg orally (immediate-release) twice daily initially, titrate slowly in first 5 days according to response, maximum 400-600 mg/day

OR

lithium: children ≥7 years of age and adolescents: consult specialist for guidance on dose

More

Secondary options

divalproex sodium: children ≥7 years of age and adolescents: 15-20 mg/kg/day orally, adjust dose according to response and serum valproic acid level

Plus – psychosocial intervention

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ACUTE
|
acute mania/mixed mania
Plus – 

psychosocial intervention

Treatment recommended for ALL patients in selected patient group

The aims of psychosocial interventions are to enable recognition of future episodes before they progress too far, enhance treatment adherence, and address environmental stressors that act as possible precipitants to further episodes. Treatment options include multifamily and individual family psychoeducation, family-focused therapy for adolescents, child- and family-focused cognitive behavioral therapy for younger children, and collaborative problem-solving.

There is evidence that psychoeducation produces improvements in the longer term over routine care, and one meta-analysis demonstrated that psychotherapy in combination with pharmacotherapy was associated with a 44% reduction in relapse of symptoms at 1-year follow-up compared to pharmacotherapy alone.[156][195][197]

Plus – maintenance pharmacotherapy

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ACUTE
|
acute mania/mixed mania
Plus – 

maintenance pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Medications utilized to stabilize an acute episode may be continued as maintenance therapy for most patients, although it is necessary to remain vigilant for relapse or recurrence as well as any treatment-emergent adverse effects, particularly neurologic (extrapyramidal adverse effects, tardive dyskinesia), metabolic (obesity, diabetes mellitus, dyslipidemias), or toxic effects (renal, hepatic, hematologic, thyroid).[138][145][148][157][188][189][190][191]

In adults, lithium and aripiprazole, when used as monotherapy, are more effective in preventing mania than depression. There is evidence for both the antimanic and antidepressant effects of olanzapine and quetiapine.[174] Divalproex is more effective as a maintenance treatment when combined with lithium in people with bipolar disorder.[119][146][194]

2nd line – addition of mood stabilizer to second-generation antipsychotic

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ACUTE
|
acute mania/mixed mania
2nd line – 

addition of mood stabilizer to second-generation antipsychotic

If the first drug that was tried was a second-generation antipsychotic and proved to be only partially effective, lithium or divalproex can be added.

Divalproex has been found to reduce levels of aripiprazole and olanzapine when given as combination treatment in adults.[158]

In the US, standard practice is that valproate and its analogs are only prescribed for the treatment of manic episodes associated with bipolar disorder during pregnancy, if other alternative medications are not acceptable or not effective. [125]​ Divalproex is not recommended for use in girls and women of childbearing potential by the WHO.​[126]​ Other international guidelines stipulate that valproate and its analogs must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention program in place, and certain conditions are met.[118]​[127]​​

Primary options

lithium: children ≥7 years of age and adolescents: consult specialist for guidance on dose

More

or

divalproex sodium: children ≥7 years of age and adolescents: 15-20 mg/kg/day orally, adjust dose according to response and serum valproic acid levels.

-- AND --

risperidone: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 0.5 mg orally once daily initially, increase according to response, maximum 2.5 mg/day

or

aripiprazole: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 2.5 mg orally once daily initially, increase according to response, maximum 30 mg/day

More

or

olanzapine: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 2.5 mg orally once daily initially, increase according to response, maximum 20 mg/day

or

quetiapine: children <10 years of age: consult specialist for guidance on dose; children ≥10 years of age and adolescents: 25 mg orally (immediate-release) twice daily initially, titrate slowly in first 5 days according to response, maximum 400-600 mg/day

Plus – psychosocial intervention

Back
ACUTE
|
acute mania/mixed mania
Plus – 

psychosocial intervention

Treatment recommended for ALL patients in selected patient group

The aims of psychosocial interventions are to enable recognition of future episodes before they progress too far, enhance treatment adherence, and address environmental stressors that act as possible precipitants to further episodes. Treatment options include multifamily and individual family psychoeducation, family-focused therapy for adolescents, child- and family-focused cognitive behavioral therapy for younger children, and collaborative problem-solving.

There is evidence that psychoeducation produces improvements in the longer term over routine care, and one meta-analysis demonstrated that psychotherapy in combination with pharmacotherapy was associated with a 44% reduction in relapse of symptoms at 1-year follow-up compared to pharmacotherapy alone.[156][195][197]

Plus – maintenance pharmacotherapy

Back
ACUTE
|
acute mania/mixed mania
Plus – 

maintenance pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Medications utilized to stabilize an acute episode may be continued as maintenance therapy for most patients, although it is necessary to remain vigilant for relapse or recurrence as well as any treatment-emergent adverse effects, particularly neurologic (extrapyramidal adverse effects, tardive dyskinesia), metabolic (obesity, diabetes mellitus, dyslipidemias), or toxic effects (renal, hepatic, hematologic, thyroid).[138][145][148][157][188][189][190][191]

In adults, lithium and aripiprazole, when used as monotherapy, are more effective in preventing mania than depression. There is evidence for both the antimanic and antidepressant effects of olanzapine and quetiapine.[174] Divalproex is more effective as a maintenance treatment when combined with lithium in people with bipolar disorder.[119][146][194]

3rd line – alternative pharmacotherapy options

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ACUTE
|
acute mania/mixed mania
3rd line – 

alternative pharmacotherapy options

Other pharmacotherapy options include substituting a first-generation antipsychotic agent such as haloperidol (although this should be avoided in very young children due to the possibility of tardive dyskinesia) or a second-generation antipsychotic (e.g., paliperidone), adding a benzodiazepine such as lorazepam (useful in cases of agitated mania), and/or adding a mood stabilizer (e.g., carbamazepine). There is no evidence that oxcarbazepine is effective for acute bipolar disorder and its use is not recommended.[86][162] Gabapentin can be useful for children and adolescents with sleeping problems.

These off-label treatments appear in many treatment guidelines, but data supporting their efficacy in mania are largely absent.

A specialist should be consulted for guidance on suitable drug combinations using the drugs below (possibly with drugs the patient may already be on) and the doses for these treatments.

Primary options

haloperidol: children and adolescents: consult specialist for guidance on dose

Secondary options

lorazepam: children and adolescents: consult specialist for guidance on dose

Tertiary options

paliperidone: children and adolescents: consult specialist for guidance on dose

OR

carbamazepine: children and adolescents: consult specialist for guidance on dose

OR

gabapentin: children and adolescents: consult specialist for guidance on dose

Plus – psychosocial intervention

Back
ACUTE
|
acute mania/mixed mania
Plus – 

psychosocial intervention

Treatment recommended for ALL patients in selected patient group

The aims of psychosocial interventions are to enable recognition of future episodes before they progress too far, enhance treatment adherence, and address environmental stressors that act as possible precipitants to further episodes. Treatment options include multifamily and individual family psychoeducation, family-focused therapy for adolescents, child- and family-focused cognitive behavioral therapy for younger children, and collaborative problem-solving.

There is evidence that multifamily psychoeducation produces improvements in the longer term over routine care, and one meta-analysis demonstrated that psychotherapy in combination with pharmacotherapy was associated with a 44% reduction in relapse of symptoms at 1-year follow-up compared to pharmacotherapy alone.[156][195][197]

Plus – maintenance pharmacotherapy

Back
ACUTE
|
acute mania/mixed mania
Plus – 

maintenance pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Medications utilized to stabilize an acute episode may be continued as maintenance therapy for most patients, although it is necessary to remain vigilant for relapse or recurrence as well as any treatment-emergent adverse effects, particularly neurologic (extrapyramidal adverse effects, tardive dyskinesia), metabolic (obesity, diabetes mellitus, dyslipidemias), or toxic effects (renal, hepatic, hematologic, thyroid).[138][145][148][157][188][189][190][191]

In adults, lithium and aripiprazole, when used as monotherapy, are more effective in preventing mania than depression. There is evidence for both the antimanic and antidepressant effects of olanzapine and quetiapine.[174] Divalproex is more effective as a maintenance treatment when combined with lithium in people with bipolar disorder.[119][146][194]

Adult data suggest that lamotrigine is more effective in preventing depression than mania.

acute depressive episode

1st line – olanzapine/fluoxetine or lurasidone

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ACUTE
|
acute depressive episode
1st line – 

olanzapine/fluoxetine or lurasidone

The depressive phase of the illness remains understudied in both children and adults, and many frequently used treatments, such as lithium, divalproex, and lamotrigine, have limited or no evidence to support their use for the acute treatment of bipolar depression.[166][167][168]

The olanzapine/fluoxetine combination and lurasidone have both been shown to be superior to placebo, and have both been approved by the Food and Drug Administration for the acute treatment of bipolar I depression in patients 10 to 17 years of age. However, benefits should be weighed against the risk of adverse events, particularly weight gain and hyperlipidemia.[171]

There has been considerable debate regarding the increased risk of suicidality with selective serotonin-reuptake inhibitors (SSRIs). Use of the olanzapine/fluoxetine combination should be carefully monitored.[179][180]

The risk of "switching" or developing mood elevation as a result of most drug therapies used to improve mood is a contentious topic.[183] Extrapolating from information about activation in studies of SSRIs, activation rates are higher in children, averaging about 10%, than in adolescents and adults.[185][186] Activation is a form of behavioral toxicity in which a drug makes a child more excited and irritable.

Rates of antidepressant-induced mania in depressed children and adolescents generally appear to be low, but may be greater in children and adolescents at risk of developing bipolar disorder, such as those with some manic symptoms, or a family history of bipolar disorder.[187]

Primary options

olanzapine/fluoxetine: children and adolescents 10-17 years of age: 3 mg (olanzapine)/25 mg (fluoxetine) orally once daily in the evening initially, increase gradually according to response, maximum 12 mg (olanzapine)/50 mg (fluoxetine) per day

OR

lurasidone: children and adolescents 10-17 years of age: 20 mg orally once daily initially, increase gradually according to response, maximum 80 mg/day

Plus – psychosocial intervention

Back
ACUTE
|
acute depressive episode
Plus – 

psychosocial intervention

Treatment recommended for ALL patients in selected patient group

The aims of psychosocial interventions are to enable recognition of future episodes before they progress too far, enhance treatment adherence, and address environmental stressors that act as possible precipitants to further episodes. Treatment options include multifamily and individual family psychoeducation, family-focused therapy for adolescents, child- and family-focused cognitive behavioral therapy for younger children, and collaborative problem-solving.

There is evidence that multifamily psychoeducation produces improvements in the longer term over routine care, and one meta-analysis demonstrated that psychotherapy in combination with pharmacotherapy was associated with a 44% reduction in relapse of symptoms at 1-year follow-up compared to pharmacotherapy alone.[156][195][197]

Plus – maintenance pharmacotherapy

Back
ACUTE
|
acute depressive episode
Plus – 

maintenance pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Medications utilized to stabilize an acute episode may be continued as maintenance therapy for most patients, although it is necessary to remain vigilant for relapse or recurrence as well as any treatment-emergent adverse effects, particularly neurologic (extrapyramidal adverse effects, tardive dyskinesia), metabolic (obesity, diabetes mellitus, dyslipidemias), or toxic effects (renal, hepatic, hematologic, thyroid).[138][145][148][157][188][189][190][191]

In adults, lithium and aripiprazole, when used as monotherapy, are more effective in preventing mania than depression. There is evidence for both the antimanic and antidepressant effects of olanzapine and quetiapine.[174] Divalproex is more effective as a maintenance treatment when combined with lithium in people with bipolar disorder.[119][146][194]

Adult data suggest that lamotrigine is more effective in preventing depression than mania.

ONGOING

mania or depression: not responsive to all previous treatment

1st line – electroconvulsive therapy

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ONGOING
|
mania or depression: not responsive to all previous treatment
1st line – 

electroconvulsive therapy

Electroconvulsive therapy (ECT) has been used in adolescents with depression and mania only when all other treatments have failed. There is evidence that ECT significantly improves clinical outcomes for adolescents in acute phase treatment, especially for those diagnosed with a comorbid substance use disorder.[163] Adult guidelines can be followed in cases where the depression or mania resembles those conditions in an adult.[156][164]

Plus – psychosocial intervention

Back
ONGOING
|
mania or depression: not responsive to all previous treatment
Plus – 

psychosocial intervention

Treatment recommended for ALL patients in selected patient group

The aims of psychosocial interventions are to enable recognition of future episodes before they progress too far, enhance treatment adherence, and address environmental stressors that act as possible precipitants to further episodes. Treatment options include multifamily and individual family psychoeducation, family-focused therapy for adolescents, child- and family-focused cognitive behavioral therapy for younger children, and collaborative problem-solving.

There is evidence that multifamily psychoeducation produces improvements in the longer term over routine care, and one meta-analysis demonstrated that psychotherapy in combination with pharmacotherapy was associated with a 44% reduction in relapse of symptoms at 1-year follow-up compared to pharmacotherapy alone.[156][195][197]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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