People with bipolar disorder experience fluctuations in mood ranging from mania to major depression. Episodes can significantly impact quality of life and the ability to maintain relationships and employment. Bipolar disorder can also lead to high-risk behaviors like substance use, self harm, or even suicide. Treatments include medication, therapy, psychoeducation, risk reduction, and caregiver support with the goal being to manage acute symptoms and prevent recurrences of mania/hypomania and depression.
In today's side-by-side comparison, we look at the latest clinical practice guidelines from the Veterans Health Administration/Department of Defense (VA/DoD) and the National Institute for Health and Care Excellence (NICE) on bipolar disorder with a focus on pharmacotherapy. We encourage you to review the full guidelines which can be found at the links below for more information on this topic.
Guidelines for Comparison
| Item | Management of Bipolar Disorder | Bipolar Disorder: Assessment and Management |
|---|---|---|
| Authoring Organization | Veterans Health Administration/Department of Defense | National Institute for Health and Care Excellence |
| Publication Date | October 2023 | September 2025 |
| Graded Recommendations | Yes | Yes |
| Links | Summary / Full Text | Summary / Full Text |
Key Takeaways
General
- The clinical practice guideline from the VA/DoD is meant to help diagnose and treat bipolar disorder in US service members and their families. It is intended for adults 18 years of age or older.
- NICE is part of the United Kingdom National Health Services. It provides evidence-based guidance for patients in the UK and is recognized internationally. Pharmacologic interventions utilize the British National Formulary. Their clinical practice guideline provides recommendations for the diagnosis and management of bipolar disorder in children, young people, and adults.
Pharmacotherapy for Bipolar Disorder
Acute Mania:
- Monotherapy: Both societies are in agreement that quetiapine, olanzapine, risperidone, or haloperidol may be used as monotherapy for acute mania. The VA/DoD recommends additional medications that can be used as monotherapy for acute mania— lithium, cariprazine, paliperidone, aripiprazole, asenapine, carbamazepine, valproate, and ziprasidone.
- Combination Therapy: Both Societies agree with using quetiapine, olanzapine, haloperidol, or risperidone in combination with either lithium or valproate for acute mania. In addition, the VA/DoD recommends asenapine with either lithium or valproate as combination therapy for acute mania.
Acute Depression:
- Monotherapy: Both societies are in agreement with using quetiapine or olanzapine as monotherapy for acute bipolar depression.
- Combination Therapy: Both societies recommend the combination of lamotrigine with lithium for acute bipolar depression. Additional different combinations involving lamotrigine were recommended by each society: VA/DoD: lamotrigine combined with quetiapine; NICE: lamotrigine combined with valproate.
- Other recommended combination therapies for acute bipolar depression according to NICE include: Quetiapine or olanzapine with either lithium or valproate; Fluoxetine with olanzapine; Fluoxetine with olanzapine and either lithium or valproate.
Long-Term Management of Bipolar Disorder
When it comes to medications for long-term bipolar disorder the VA/DoD makes the distinction between medications used to prevent recurrence of depression versus medication that can prevent recurrence of mania. The NICE guideline just makes recommendations for long-term management of bipolar disorder without this distinction.
- Monotherapy: Both societies agree with using quetiapine, olanzapine, lithium, and risperidone as monotherapy for long-term treatment of bipolar. The VA/DoD specifically recommends risperidone for the prevention of mania and the other three drugs for the prevention of both mania and bipolar depression. The VA/DoD also recommends paliperidone monotherapy for the prevention of mania and lamotrigine monotherapy for the prevention of bipolar depression. NICE recommends two additional medications that can be used as monotherapy for long-term treatment of bipolar disorder—aripiprazole and asenapine.
- Combination Therapy: Both societies recommend quetiapine, olanzapine, or aripiprazole in combination with either lithium or valproate for long-term treatment of bipolar disorder. The VA/DoD specifically recommends quetiapine or olanzapine with lithium or valproate to prevent both mania and depression, while aripiprazole with lithium or valproate is recommended for the prevention of just mania. Both societies recommend additional combinations that may be used: VA/DoD—ziprasidone with lithium or valproate to prevent mania and lurasidone with lithium or valproate to prevent depression. NICE—asenapine or risperidone in combination with either lithium or valproate and the combination of valproate with lithium.
Monotherapies for Bipolar Disorder According to Society
| Medication | Treatment of Acute Mania | Treatment of Acute Bipolar Depression | Prevention of Mania | Prevention of Bipolar Depression | Long-Term Bipolar Treatment |
|---|---|---|---|---|---|
| quetiapine | VA/DoDNICE | Va/DoDNICE | Va/DoD | Va/DoD | NICE |
| olanzapine | VA/DoDNICE | Va/DoDNICE | Va/DoD | Va/DoD | NICE |
| lithium | VA/DoD | NICE | Va/DoD | Va/DoD | NICE |
| cariprazine | VA/DoD | VA/DoD | – | – | – |
| paliperidone | VA/DoD | – | VA/DoD | – | – |
| risperidone | VA/DoDNICE | – | VA/DoD | – | NICE |
| aripiprazole | VA/DoD | – | – | – | NICE |
| asenapine | VA/DoD | – | – | – | NICE |
| carbamazepine | VA/DoD | – | – | – | – |
| haloperidol | VA/DoDNICE | – | – | – | |
| valproate | VA/DoD | NICE | – | – | – |
| ziprasidone | VA/DoD | – | – | – | – |
| lumateperone | – | VA/DoD | – | – | – |
| lurasidone | – | VA/DoD | – | – | – |
| lamotrigine | – | NICE | – | VA/DoD | – |
Combination Therapies for Bipolar Disorder According to Society
| Medications | Acute Mania | Acute Bipolar Depression | Prevention of Mania | Prevention of Bipolar Depression | Long-Term Treatment of Bipolar Disorder |
|---|---|---|---|---|---|
| quetiapine + lithium or valproate | VA/DoD NICE | NICE | VA/DoD | VA/DoD | NICE |
| olanzapine + lithium or valproate | VA/DoD NICE | NICE | VA/DoD | VA/DoD | NICE |
| haloperidol + lithium or valproate | VA/DoD NICE | – | – | – | – |
| asenapine + lithium or valproate | VA/DoD | – | – | – | NICE |
| risperidone + lithium or valproate | VA/DoDNICE | – | – | – | NICE |
| aripiprazole + lithium or valproate | – | – | VA/DoD | – | NICE |
| ziprasidone + lithium or valproate | – | – | VA/DoD | – | – |
| lurasidone + lithium or valproate | – | – | – | VA/DoD | – |
| lamotrigine + lithium or valproate | – | NICE | – | – | – |
| lamotrigine + quetiapine or lithium | – | VA/DoD | – | – | – |
| fluoxetine + olanzapine | – | NICE | – | – | – |
| fluoxetine and olanzapine + lithium or valproate | – | NICE | – | – | – |
| valproate + lithium | – | – | – | – | NICE |
Comparison of Recommendations
| Type | VA/DoD | NICE |
|---|---|---|
| Acute Mania Treatment Options | We suggest lithium or quetiapine as monotherapy for acute mania. If lithium or quetiapine is not selected based on patient preference and characteristics, we suggest olanzapine, paliperidone, or risperidone as monotherapy for acute mania. If lithium, quetiapine, olanzapine, paliperidone, or risperidone is not selected based on patient preference and characteristics, we suggest aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone as monotherapy for acute mania. We suggest lithium or valproate in combination with haloperidol, asenapine, quetiapine, olanzapine, or risperidone for acute mania symptoms in individuals who had an unsatisfactory response or a breakthrough episode on monotherapy. We suggest against the addition of aripiprazole, paliperidone, or ziprasidone after an unsatisfactory response to lithium or valproate monotherapy for acute mania. We suggest against brexpiprazole, topiramate, or lamotrigine as a monotherapy for acute mania. There is insufficient evidence to recommend for or against other first-generation antipsychotics or second-generation antipsychotics, gabapentin, oxcarbazepine, or benzodiazepines as monotherapy or in combination for acute mania. | If a person develops mania or hypomania and is taking an antidepressant (as defined by the British National Formulary [BNF]) as monotherapy, consider stopping the antidepressant and offer an antipsychotic as set out in recommendation 1.5.3, regardless of whether the antidepressant is stopped. If a person develops mania or hypomania and is taking an antidepressant (as defined by the BNF) in combination with a mood stabiliser, consider stopping the antidepressant. If the person is already taking a mood stabiliser as prophylactic treatment, consider increasing the dose, up to the maximum level in the BNF if necessary, depending on clinical response. If there is no improvement, consider adding haloperidol, olanzapine, quetiapine or risperidone, depending on the person's preference and previous response to treatment. If the person is already taking lithium, check plasma lithium levels to optimize treatment (see the section on how to use medication). Consider adding haloperidol, olanzapine, quetiapine or risperidone, depending on the person's preference and previous response to treatment. If the person is already taking valproate and develops mania or hypomania, review their treatment including adherence and consider increasing the dose if tolerated, but be aware of the increased risk of side effects at higher doses, or consider changing to an alternative treatment. If a person develops mania or hypomania and is not taking an antipsychotic or mood stabiliser, offer haloperidol, olanzapine, quetiapine or risperidone, taking into account any advance statements, the person's preference and clinical context (including physical comorbidity, previous response to treatment and side effects). If the first antipsychotic is poorly tolerated at any dose (including rapid weight gain) or ineffective at the maximum licensed dose, offer an alternative antipsychotic from the drugs listed in recommendation 1.5.3, taking into account any advance statements, the person's preference and clinical context (including physical comorbidity, previous response to treatment and side effects). If an alternative antipsychotic is not sufficiently effective at the maximum licensed dose, consider adding lithium. If adding lithium is ineffective, or if lithium is not suitable (for example, because the person does not agree to routine blood monitoring), consider adding valproate instead. Do not offer lamotrigine to treat mania. |
| Acute Depression Treatment Options | We recommend quetiapine as monotherapy for acute bipolar depression. There is insufficient evidence to recommend for or against antidepressants or lamotrigine as monotherapy for acute bipolar depression. If quetiapine is not selected based on patient preference and characteristics, we suggest cariprazine, lumateperone, lurasidone, or olanzapine as monotherapy for acute bipolar depression. We suggest lamotrigine in combination with lithium or quetiapine for acute bipolar depression. There is insufficient evidence to recommend for or against ketamine or esketamine as either a monotherapy or an adjunctive therapy for acute bipolar depression. There is insufficient evidence to recommend for or against antidepressants to augment treatment with second-generation antipsychotics or mood stabilizers for acute bipolar depression. | If a person develops moderate or severe bipolar depression and is not taking a drug to treat their bipolar disorder, offer fluoxetine combined with olanzapine, or quetiapine on its own, depending on the person's preference and previous response to treatment. If the person prefers, consider either olanzapine (without fluoxetine) or lamotrigine on its own. If there is no response to fluoxetine combined with olanzapine, or quetiapine, consider lamotrigine on its own. If a person develops moderate or severe bipolar depression and is already taking lithium, check their plasma lithium level. If it is inadequate, increase the dose of lithium; if it is at maximum level, add either fluoxetine combined with olanzapine or add quetiapine. If the person prefers, consider adding olanzapine (without fluoxetine) or lamotrigine to lithium. If there is no response to adding fluoxetine combined with olanzapine, or adding quetiapine, stop the additional treatment and consider adding lamotrigine to lithium. If a person develops moderate or severe bipolar depression and is already taking valproate, review their treatment including adherence and consider increasing the dose if tolerated but be aware of the increased risk of side effects at higher doses. If the maximum tolerated dose, or the top of the therapeutic range for valproate, has been reached and there is a limited response, add either of the following options, depending on the person's preference and previous response to treatment: Fluoxetine combined with olanzapine or Quetiapine. If the person does not wish to try adding fluoxetine combined with olanzapine or adding quetiapine, consider: Adding olanzapine (without fluoxetine) or adding lamotrigine or changing from valproate to an alternative treatment. If there is no response to adding fluoxetine combined with olanzapine or adding quetiapine, consider stopping the additional medications and: Adding lamotrigine to valproate or changing from valproate to an alternative treatment. |
| Long-Term Treatment Options | We recommend lithium or quetiapine for the prevention of recurrence of mania. We suggest lithium or quetiapine as monotherapy for the prevention of recurrence of bipolar depressive episodes. We recommend lamotrigine for the prevention of recurrence of bipolar depressive episodes. If lithium or quetiapine is not selected based on patient preference and characteristics, we suggest oral olanzapine, oral paliperidone, or risperidone long acting injectable for the prevention of recurrence of mania. If lithium or quetiapine is not selected based on patient preference and characteristics, we suggest olanzapine as monotherapy for the prevention of recurrence of bipolar depressive episodes. We suggest aripiprazole, olanzapine, quetiapine, or ziprasidone in combination with lithium or valproate for the prevention of recurrence of mania. We suggest olanzapine, lurasidone, or quetiapine in combination with lithium or valproate for the prevention of recurrence of bipolar depressive episodes. We suggest against lamotrigine as monotherapy for the prevention of recurrence of mania. There is insufficient evidence to recommend for or against other first-generation antipsychotics, second-generation antipsychotics, and anticonvulsants (including valproate) for the prevention of recurrence of mania. (See Recommendations 18, 19, and 30). There is insufficient evidence to recommend for or against other first-generation antipsychotics, other second-generation antipsychotics, and anticonvulsants (including valproate) as monotherapies for the prevention of recurrence of bipolar depressive episodes. There is insufficient evidence to recommend for or against other first-generation antipsychotics, other second-generation antipsychotics, and anticonvulsants in combination with a mood stabilizer for the prevention of recurrence of bipolar depressive episodes. | When planning long‑term pharmacological treatment to prevent relapse, take into account drugs that have been effective during episodes of mania or bipolar depression. Discuss with the person whether they prefer to continue this treatment or switch to lithium, and explain that lithium is the most effective long‑term treatment for bipolar disorder. Offer lithium as a first‑line, long‑term pharmacological treatment for bipolar disorder. If lithium is ineffective, poorly tolerated, or is not suitable (for example, because the person does not agree to routine blood monitoring), consider an antipsychotic (for example, asenapine, aripiprazole, olanzapine, quetiapine or risperidone). If the first antipsychotic is poorly tolerated at any dose (including rapid weight gain) or ineffective at the maximum licensed dose, consider an alternative antipsychotic from the drugs listed in recommendation 1.7.8. If an alternative antipsychotic is ineffective, consider a combination of valproate (follow the MHRA safety measures and precautionary advice for valproate in box 1), with either: An antipsychotic or lithium. Do not offer gabapentin or topiramate to treat bipolar disorder. |
| Special Populations | For individuals with bipolar disorder who are or might become pregnant and are stabilized on lithium, we suggest continued treatment with lithium at the lowest effective dose in a framework that includes psychoeducation and shared decision making. | Advise people taking lithium to: Seek medical attention if they develop diarrhoea or vomiting or become acutely ill for any reason. Ensure they maintain their fluid intake, particularly after sweating (for example, after exercise, in hot climates or if they have a fever), if they are immobile for long periods or if they develop a chest infection or pneumonia. Talk to their doctor as soon as possible if they become pregnant or are planning a pregnancy. |
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