Bipolar disorder in adults

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

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

not rapid cycling and without mixed features (with acute mania or hypomania): non-pregnant

1st line – mood stabiliser or antipsychotic

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1st line –

mood stabiliser or antipsychotic

Treatment of mania is a psychiatric emergency and often requires inpatient admission, given that risk-taking in mania can have substantially negative personal, occupational and financial consequences.[107]

Monotherapy is a reasonable starting point for many patients with acute mania, especially those without complex illness, although combination treatment with a mood stabiliser plus antipsychotic may eventually be required. Some international guidelines (e.g., The Canadian Network for Mood and Anxiety Treatments) recommend combination therapy as a first-line option.[36] However, other guidelines and many physicians prefer monotherapy initially before combination therapy due to the potential for an increased risk of adverse effects with combination therapy.[29] This is a clinical decision and depends on the severity of the patient’s illness, the rapidity of response to treatment needed (combination treatments tend to work faster), previous response to monotherapy, tolerability concerns with combination therapy, and patient preference.

For patients with acute mania, lithium is effective and it should be considered first-line monotherapy unless there are specific reasons not to, for example, where rapid symptom resolution is required. A key advantage of lithium is its robust effect on preventing future mood episodes.[36][123][124] [ ] [Evidence B] Other first-line initial options for monotherapy are valproate semisodium or an atypical antipsychotic including aripiprazole, asenapine, cariprazine, paliperidone, risperidone, or quetiapine.[36] [ ] [Evidence A] [ ] [Evidence B] Use of paliperidone for bipolar disorder is ‘off-label’ and it has not received approval for this indication. International guideline recommendations for acute mania differ, but many prioritise the use of atypical antipsychotics for those with more severe manic symptoms requiring rapid treatment, based on their efficacy and rapid onset of action.[116]

Carbamazepine, olanzapine, ziprasidone, and haloperidol are recommended as secondary options for monotherapy due to their associated adverse effects; typically clinicians should consider the primary options before considering any of the secondary options, unless there are other relevant factors such as a history of adverse effects or non-response to a particular first-line drug, or patient preference.[36]

It should be noted that guidance on first-line options varies internationally, and clinicians should consult local guidance. In the UK, the National Institute for Health and Care Excellence guidance recommends haloperidol, olanzapine, quetiapine, or risperidone as potential first-line options, considering patient preference, previous response to treatment, and comorbidities. If this is ineffective or poorly tolerated, offer an alternative antipsychotic from these listed. If the alternative antipsychotic is not effective at maximum dose, then consider adding lithium.[29]

For patients with hypomania, treatment is required only if symptoms are prolonged, severe, and/or associated with significant functional impairment; typically treatment is with mood stabilisers such as lithium or valproate semisodium and/or an atypical antipsychotic.[36]

Valproic acid and its derivatives (including valproate semisodium) may cause major congenital malformations, including neurodevelopmental disorders and neural tube defects, after in utero exposure. These agents 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. Precautionary measures may also be required in male patients owing to a potential risk that use in the three months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children. Regulations and precautionary measures for female and male patients may vary between countries and you should consult your local guidance for more information. UK guidance from the National Institute for Health and Care Excellence (NICE) takes a heightened precautionary stance, and recommends that valproate must not be started for the first time in any people (male or female) younger than 55 years, unless two specialists independently agree that other options are unsuitable, or that there are compelling reasons that the reproductive risks do not apply.[29]

Primary options

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

risperidone: 2-3 mg orally once daily initially, adjust dose according to response, maximum 6 mg/day

quetiapine: 50 mg orally (immediate-release) twice daily initially, adjust dose according to response, maximum 800 mg/day; 300 mg orally (extended-release) once daily initially, adjust dose according to response, maximum 800 mg/day

aripiprazole: 15 mg orally once daily initially, adjust dose according to response, maximum 30 mg/day

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 6 mg/day

asenapine: 5-10 mg sublingually twice daily

paliperidone: 3-6 mg orally once daily initially, adjust dose according to response, maximum 12 mg/day

Secondary options

carbamazepine: 200 mg orally (immediate-release or extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

ziprasidone: 40 mg orally twice daily initially, adjust dose according to response, maximum 160 mg/day

haloperidol: consult specialist for guidance on dose

Plus – removal of exacerbating factors

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Plus –

removal of exacerbating factors

Treatment recommended for ALL patients in selected patient group

Before starting pharmacological treatment, rule out symptoms secondary to substance use disorders, drugs, or medical comorbidities (although, if these are present, anti-manic drugs may still be considered on a short-term basis).[36] Consider whether referral to services to assist with substance use disorders is required. Discontinue antidepressants; if this is the first appearance of manic symptoms in a patient taking antidepressants, confirm the diagnosis of bipolar disorder prior to starting anti-manic treatment by observing the patient for a period of time after antidepressant discontinuation to check whether symptoms persist.[29][36]

Consider – management of agitation

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Consider –

management of agitation

Additional treatment recommended for SOME patients in selected patient group

Severely affected patients and/or those without insight into their illness may require urgent psychiatric hospitalisation to assure their safety and that of others. The aim is to provide a tranquil environment with reduced stimuli; if the person with bipolar disorder is experiencing severe psychomotor agitation, attempt verbal de-escalation.[110]

The first step in managing agitation is to prevent or at least mitigate its severity by rapidly treating the causative manic episode. Therapy includes pharmacotherapy to prevent or rapidly reduce manic symptoms, while minimising adverse effects.

International guideline recommendations for acute mania differ, but many prioritise the use of atypical antipsychotics for those with more severe manic symptoms requiring rapid treatment, based on their efficacy and rapid onset of action.[116] Combination treatment from the start with a mood stabiliser plus antipsychotic may be required for selected patients, for example, those with severe mania with agitation necessitating a rapid response to treatment.[36] This is a clinical decision and depends on the severity of the patient’s illness, the rapidity of response to treatment needed (combination treatments tend to work faster), previous response to monotherapy, tolerability concerns with combination therapy, and patient preference.

For patients with mania and worsening agitation despite aggressive management of acute mania, administration of a rapidly-acting non-oral antipsychotic or benzodiazepine, including inhaled loxapine, intramuscular olanzapine, or intramuscular lorazepam, may be necessary.[36] Lorazepam can be used as an adjunct or as monotherapy.[36] Second-line options include sublingual asenapine, intramuscular haloperidol, intramuscular haloperidol plus promethazine, risperidone orally dissolving tablet, and intramuscular ziprasidone.

Recommendations within this topic generally align with CANMAT guidance, but note that international differences exist in recommendations for rapidly-acting non-oral drugs to manage agitation, and clinicians should consult local guidance. This is sometimes termed ‘rapid tranquilisation’. UK guidance from NICE recommends either monotherapy with intramuscular lorazepam, or combination therapy with intramuscular haloperidol combined with intramuscular promethazine, for rapid tranquilisation in adults.[118] Of note, NICE recommends the use of intramuscular lorazepam rather than combination treatment with intramuscular haloperidol plus promethazine when there is evidence of cardiovascular disease, including a prolonged QT interval, or when no ECG has been carried out.[118]

In some cases, patient co-operation may not be readily obtained and forced or involuntary administration may be required (e.g., where the health and life of the patient or of others may otherwise be at risk).

Primary options

olanzapine: 2.5 to 10 mg intramuscularly as a single dose, may repeat after 2 hours and then again after 4 hours if required, maximum 30 mg/day

loxapine inhaled: 10 mg (1 puff) inhaled once daily when required

lorazepam: 2 mg intramuscularly as a single dose

Secondary options

asenapine: 5-10 mg sublingually twice daily

risperidone: 2 mg orally (orally disintegrating tablet) as a single dose, may repeat if necessary, maximum 4 mg/day

ziprasidone: 10 mg intramuscularly every 2 hours when required, or 20 mg intramuscularly every 4 hours when required, maximum 40 mg/day

haloperidol lactate: 0.5 to 10 mg intramuscularly every 1-4 hours when required, maximum 20 mg/day

and

promethazine: 25-50 mg intramuscularly as a single dose

2nd line – switch to alternative first-line drug or combination therapy

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2nd line –

switch to alternative first-line drug or combination therapy

If anti-manic treatment is effective, some response to treatment is expected within 1-2 weeks.[105] If there is a suboptimal treatment response, optimise the dose and check medication adherence. If response remains inadequate, either switch to an alternative choice of monotherapy with a mood stabiliser or antipsychotic that has not yet been tried, or use combination treatment with a mood stabiliser and antipsychotic (typically by adding on an additional drug).

In the author’s experience, switching to another form of monotherapy is preferred if there are tolerability concerns with the initial choice of monotherapy; in acute mania, when a patient is acutely unwell and has not responded to the initial choice of treatment, then typically the quickest and most effective option is to proceed to combination therapy with a mood stabiliser plus antipsychotic.

First-line combination therapies with good evidence include combinations of lithium or valproate semisodium plus an atypical antipsychotic (e.g., risperidone, quetiapine, aripiprazole, asenapine).[36]

Consult a specialist for guidance on choice of drug regimen and dose. The dose of some drugs requires adjustment when used as part of a combination drug regimen; consult your local drug formulary for more information.

Consider – electroconvulsive therapy

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Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[36][125][126] ECT may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail people), or if the person prefers this option.[127]

3rd line – alternative pharmacotherapy

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3rd line –

alternative pharmacotherapy

Third-line treatment options have a limited evidence base and most are used off-label, and they should be considered by a specialist when patients have not responded to multiple adequate trials of first- and second-line options alone or in combination.

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider – brain stimulation techniques

Back

Consider –

brain stimulation techniques

Additional treatment recommended for SOME patients in selected patient group

Evidence for brain stimulation techniques is expanding and, in patients resistant to pharmacotherapy, a trial of transcranial magnetic stimulation (rTMS) may be considered.[36][248]

not rapid cycling and without mixed features (with acute bipolar I depression): non-pregnant

1st line – mood stabiliser and/or atypical antipsychotic

Back

1st line –

mood stabiliser and/or atypical antipsychotic

Patients with bipolar I depression must have had at least one manic or mixed episode at some point in the course of their illness.[1] Episodes of depression are common, and often represent the primary reason for people with bipolar disorder to seek treatment.[107]

Suicide risk management is imperative given the high risk of suicide for people with bipolar disorder during a depressive episode.[34][36]

The use of antidepressants may cause emergence of a mania or mixed episode or rapid cycling; furthermore, antidepressants have not been associated with durable remission or recovery from bipolar depression.[129][130]

First-line options for the acute management of bipolar I depression include quetiapine, lamotrigine, lithium, or lurasidone.[36][131][132][133] Lurasidone may be used either alone or in combination with lithium or valproate semisodium.[36][132]

The initial choice of treatment is influenced by factors such as past and current response to medication, the safety and tolerability of the drug(s), and patient preference. For example, if a patient is already established on a particular drug (e.g., lithium) and experiences a breakthrough episode of depression, consider adding on a first-line antipsychotic (e.g., quetiapine, lamotrigine, or lurasidone) or switching to quetiapine or lamotrigine monotherapy.

It is important to note international differences in approach; clinicians should be familiar with local guidance. In the UK, the National Institute for Health and Care Excellence (NICE) guidance does not distinguish between acute bipolar I or bipolar II depression in terms of management. First-line management for bipolar depression is quetiapine monotherapy (or olanzapine/fluoxetine, which is third-line in other countries), depending on the person's preference and previous response to treatment. Alternatively, consider olanzapine or lamotrigine monotherapy. If a person develops moderate or severe bipolar depression and is already taking lithium, NICE recommends checking plasma lithium levels and increasing the dose if inadequate. If it is at maximum level, add quetiapine (or olanzapine/fluoxetine), olanzapine monotherapy, or lamotrigine, depending on the person's preference and previous response to treatment.[29]

Valproic acid and its derivatives (including valproate semisodium) may cause major congenital malformations, including neurodevelopmental disorders and neural tube defects, after in utero exposure. These agents must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention programme in place, and certain conditions are met. Precautionary measures may also be required in male patients owing to a potential risk that use in the 3 months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children. Regulations and precautionary measures for female and male patients may vary between countries and you should consult your local guidance for more information. UK guidance from the National Institute for Health and Care Excellence (NICE) takes a heightened precautionary stance, and recommends that valproate must not be started for the first time in any people (male or female) younger than 55 years, unless two specialists independently agree that other options are unsuitable, or that there are compelling reasons that the reproductive risks do not apply.[29]

Primary options

quetiapine: 50 mg orally (immediate-release or extended-release) once daily initially, adjust dose according to response, maximum 300 mg/day

lamotrigine: dose depends on any concomitant drugs; consult specialist for guidance on dose

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

lurasidone: 20 mg orally once daily initially, adjust dose according to response, maximum 120 mg/day

-- AND --

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Plus – removal of exacerbating factors

Back

Plus –

removal of exacerbating factors

Treatment recommended for ALL patients in selected patient group

Before starting pharmacological treatment, rule out symptoms secondary to alcohol/drug use, medications, other treatments, or general medical conditions. Use a technique such as motivational interviewing to support patients to discontinue stimulant use and to limit nicotine, caffeine, drug and alcohol use; consider whether referral to services to assist with substance use disorders is required.[36][128]

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

The addition of psychosocial interventions for bipolar depression has been associated with higher recovery rates at 1 year, as well as shorter times to recovery, and is supported by guidelines internationally.[29][36][140][141] People with bipolar depression who received any 1 of 3 intensive psychotherapies (family-focused therapy, interpersonal social rhythm therapy, or cognitive behavioural therapy) reported better total functioning, relationship functioning, and life satisfaction over a 9-month follow-up period.[140][141] Suicide risk management is imperative given the high risk of suicide for people with bipolar disorder during depressive episodes.

2nd line – switch to alternative first-line drug or combination therapy

Back

2nd line –

switch to alternative first-line drug or combination therapy

When assessing response to treatment, lack of early improvement (at 2 weeks) is a robust predictor of non-response.[134] Lamotrigine is an exception to this, given the need for slow titration when starting this drug.

If there is inadequate response to initial treatment, the next step is switching to an alternative first-line drug, or adding on another first-line drug (e.g., by adding on lithium or valproate semisodium to an atypical antipsychotic).

In general, a switch of treatment is preferred to adding on additional treatment, although in selected cases, careful polypharmacy via add-on treatments may be required to control symptoms. When deciding whether to switch or add on a drug, take into account the effect a particular drug has on the management of the patient’s bipolar disorder as a whole; for example, consider retaining lithium or an atypical antipsychotic even if they are inadequately effective in managing a patient’s depression, given their role in anti-manic prophylaxis, and adding on an additional drug in the event of an initial treatment failure rather than switching.[36]

Switch of medications should be done in an overlap and taper manner unless there is a medical need for abrupt discontinuation.[36]

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

3rd line – mood stabiliser or atypical antipsychotic plus antidepressant or cariprazine monotherapy

Back

3rd line –

mood stabiliser or atypical antipsychotic plus antidepressant or cariprazine monotherapy

An adjunctive antidepressant (e.g., a selective serotonin-reuptake inhibitor such as escitalopram, or bupropion) may be considered in combination with lithium or valproate semisodium or an atypical antipsychotic (e.g., quetiapine) as an add-on treatment for people who have not responded adequately to multiple trials of first-line drugs for bipolar depression.[130][137]

Other drugs to consider either as add-on or switch therapy include olanzapine/fluoxetine and cariprazine.[36][133][135][136] It is important to note international differences in approach; clinicians should follow local guidance. In the UK, the National Institute for Health and Care Excellence guidance recommends olanzapine/fluoxetine as a first-line option for bipolar depression.[29]

There is much debate about traditional antidepressant medications for bipolar depression. The limited efficacy of antidepressants in the acute treatment of bipolar depression reduce their clinical utility.[129] Furthermore, antidepressants may cause emergence of mania or rapid cycling, and have not been associated with durable remission or recovery.[249][250] However, a 2016 meta-analysis supports the efficacy of adjunctive antidepressants for acute bipolar depression when combined with a mood stabiliser or atypical antipsychotic, although the effect size appears small.[130]

Antidepressants should be avoided, or used cautiously if necessary, in patients with a history of antidepressant-induced mania or hypomania, current or predominant mixed features, or recent rapid cycling. People and carers should be warned about early warning symptoms of switch to mania or cycle acceleration, and antidepressants should be stopped if these emerge. Antidepressant monotherapy is unsuitable for bipolar depression.[36]

Drug regimens here are examples only. Consult specialist for guidance on choice of drug regimen.

Primary options

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

quetiapine: 50 mg orally (immediate-release or extended-release) once daily initially, adjust dose according to response, maximum 300 mg/day

-- AND --

escitalopram: 10 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

bupropion: 100 mg orally (immediate-release) twice daily initially, adjust dose according to response, maximum 450 mg/day given in 2-3 divided doses

olanzapine/fluoxetine: 6 mg (olanzapine)/25 mg (fluoxetine) orally once daily initially, adjust dose according to response, maximum 12 mg (olanzapine)/50 mg (fluoxetine) once daily

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 3 mg/day

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider electroconvulsive therapy (ECT) as an adjunctive treatment for people with a bipolar I depressive episode that has not responded to several adequate trials of medication. ECT is also indicated for bipolar depression with acute suicidality/high risk of suicide; with catatonic or psychotic features; with a rapidly deteriorating physical condition brought on by the depression, such as anorexia; when the medication risks outweigh ECT risks (e.g., in older or medically frail people); in an individual with a prior history of good response to ECT; or if there is a patient preference for ECT.[127]

4th line – alternative pharmacotherapy

Back

4th line –

alternative pharmacotherapy

Further-line treatment options have a limited evidence base and most are used off-label, and so should be considered by a specialist when patients have not responded to multiple adequate trials of first- and second-line options alone and in combination.[36]

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider electroconvulsive therapy (ECT) as an adjunctive treatment for people with a bipolar I depressive episode that has not responded to several adequate trials of medication. ECT is also indicated for bipolar depression with acute suicidality/high risk of suicide; with catatonic or psychotic features; with a rapidly deteriorating physical condition brought on by the depression, such as anorexia; when the medication risks outweigh ECT risks (e.g., in older or medically frail people); in a person with a prior history of good response to ECT; or if there is a patient preference for ECT.[127]

Consider – light therapy or brain stimulation techniques

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Consider –

light therapy or brain stimulation techniques

Additional treatment recommended for SOME patients in selected patient group

Adjunctive procedures that may be of benefit in addition to medication are light therapy with or without total sleep deprivation, or repetitive transcranial magnetic stimulation (rTMS).[138] These treatments have a very limited evidence base and should only be considered by a specialist after multiple unsuccessful trials of first-, second-, and third-line drugs (with or without electroconvulsive therapy).[36][139] These treatments may be considered by a specialist in secondary care, taking into account individual patient factors.[36]

not rapid cycling and without mixed features (with acute bipolar II depression): non-pregnant

1st line – quetiapine

Back

1st line –

quetiapine

To meet the diagnostic criteria for bipolar II, patients must have never had a full manic episode; they must have had at least one hypomanic episode and at least one major depressive episode during the course of their illness.[1]

Suicide risk management is imperative given the high risk of suicide for people with bipolar disorder during a depressive episode.[34][36]

There is less evidence on the acute management of bipolar II depression compared with bipolar I depression.

Quetiapine monotherapy is recommended first line unless there are specific reasons not to use it (e.g., previous non-response or tolerability concerns).[133][142][143] Quetiapine has also demonstrated efficacy as an adjunctive treatment for bipolar II depression.[144][145]

Assess response after 2 weeks of treatment; in the case of limited and non-response to initial treatment, optimise dosing and explore assess adherence before adjusting treatment strategies.

It is important to note international differences in approach; clinicians should follow local guidance. In the UK, National Institute for Health and Care Excellence guidance does not distinguish between bipolar I and bipolar II in management approach, although it does support the use of quetiapine as a first-line option. Clinicians should be aware of differences in prescribing practices and follow local guidance.[29]

Primary options

quetiapine: 50 mg orally (immediate-release or extended-release) once daily initially, adjust dose according to response, maximum 300 mg/day

Plus – removal of exacerbating factors

Back

Plus –

removal of exacerbating factors

Treatment recommended for ALL patients in selected patient group

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

The addition of psychosocial interventions for bipolar depression has been associated with higher recovery rates at 1 year, as well as shorter times to recovery, and is supported by guidelines internationally.[29][36][140][141] People with bipolar depression who received any 1 of 3 intensive psychotherapies (family-focused therapy, interpersonal social rhythm therapy, or cognitive behavioural therapy) reported better total functioning, relationship functioning, and life satisfaction over a 9-month follow-up period.[140][141] The results of a small 12-week pilot study suggest that interpersonal social rhythm therapy and quetiapine treatment are equally effective in the acute treatment of people with bipolar II depression.[149] Suicide risk management is imperative given the high risk of suicide for people with bipolar disorder during depressive episodes.

2nd line – mood stabiliser or antidepressant

Back

2nd line –

mood stabiliser or antidepressant

When assessing response to treatment, lack of early improvement (at 2 weeks) is a robust predictor of non-response.[134]

For patients who do not respond to initial treatment, second-line options include monotherapy with lithium or lamotrigine. Short-term monotherapy with the antidepressants sertraline or venlafaxine is also a second-line option, but is suitable only for patients with pure depression (without mixed features).[146][147][148] While antidepressants may have a more favorable risk-benefit ratio than in bipolar I depression, their use remains controversial due to the risk of a switch into hypomania/mania, mixed state, or rapid cycling.[36]

Primary options

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

lamotrigine: dose depends on any concomitant drugs; consult specialist for guidance on dose

sertraline: 50 mg orally once daily initially, adjust dose according to response, maximum 200 mg/day

venlafaxine: 75 mg/day orally (immediate-release) given in 2-3 divided doses initially, adjust dose according to response, maximum 225 mg/day (outpatients) or 375 mg/day (hospitalised patients)

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

The addition of psychosocial interventions for bipolar depression has been associated with higher recovery rates at 1 year, as well as shorter times to recovery, and is supported by guidelines internationally.[29][36][140][141] People with bipolar depression who received any 1 of 3 intensive psychotherapies (family-focused therapy, interpersonal social rhythm therapy, or cognitive behavioural therapy) reported better total functioning, relationship functioning, and life satisfaction over a 9-month follow-up period.[140][141] The results of a small 12-week pilot study suggest that interpersonal social rhythm therapy and quetiapine treatment are equally effective in the acute treatment of people with bipolar II depression.[149] Suicide risk management is imperative given the high risk of suicide for people with bipolar disorder during depressive episodes.

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Electroconvulsive therapy (ECT) is another second-line option, and may be a good option as an adjunctive treatment for people with treatment-refractory symptoms and those requiring a rapid response to treatment.

ECT may also be indicated for bipolar depression marked by acute suicidality/high risk of suicide; with catatonic or psychotic features; with a rapidly deteriorating physical condition brought on by the depression, such as anorexia; when the medication risks outweigh ECT risks (e.g., in older or medically frail people); in a person with a prior history of good response to ECT; or if there is a patient preference for ECT.[127]

3rd line – alternative pharmacotherapy

Back

3rd line –

alternative pharmacotherapy

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

The addition of psychosocial interventions for bipolar depression has been associated with higher recovery rates at 1 year, as well as shorter times to recovery, and is supported by guidelines internationally.[29][36][140][141] People with bipolar depression who received any 1 of 3 intensive psychotherapies (family-focused therapy, interpersonal social rhythm therapy, or cognitive behavioural therapy) reported better total functioning, relationship functioning, and life satisfaction over a 9-month follow-up period.[140][141] The results of a small 12-week pilot study suggest that interpersonal social rhythm therapy and quetiapine treatment are equally effective in the acute treatment of people with bipolar II depression.[149] Suicide risk management is imperative given the high risk of suicide for people with bipolar disorder during depressive episodes.

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Electroconvulsive therapy (ECT) is another second-line option, and may be a good option as an adjunctive treatment for patients with treatment-refractory symptoms and those requiring a rapid response to treatment.

not rapid cycling and with mixed features (with acute mania or hypomania predominant): non-pregnant

1st line – mood stabiliser and/or atypical antipsychotic

Back

1st line –

mood stabiliser and/or atypical antipsychotic

Mania with mixed features, as defined by DSM-5-TR, occurs where full criteria for a manic (or hypomanic) episode are met, and at least 3 symptoms of depression are present during most days of the current or most recent episode of mania (or hypomania).[1]

Mixed presentations may represent a more difficult-to-treat state, and are associated with an increased risk of suicide attempts; careful suicide risk mitigation including determination of the most appropriate treatment setting is imperative.[4][5]

The evidence base on pharmacological treatment in DSM-5-TR mixed presentations is limited.[5] First-line options include aripiprazole, asenapine, cariprazine, or valproate semisodium.[152][153][154][155][156][157]

Secondary options include monotherapy with ziprasidone, olanzapine, quetiapine, or carbamazepine.[5][158][159][160][161]

Studies suggest mixed features indicate a more severe course of illness, and combination treatment may be required to adequately control symptoms.[36][151] Combination treatment with olanzapine plus lithium or valproate semisodium is another secondary option according to CANMAT.[5][162][163]

The efficacy of lithium in mixed states is questionable.[5][151] Some international treatment guidelines recommend against it as an initial treatment option in mixed bipolar disorder.[5][36] However, in practice, for patients who develop mixed features and are already stabilised on lithium, lithium is typically continued (the rationale being long-term prevention of mood episodes).

It is important to highlight international differences in approach; clinicians should consult local treatment guidelines. The recommendations presented in this topic generally align with CANMAT, but other international guidelines (including NICE guidance in the UK) do not recommend a specific course of management for patients with mixed features.[29] Instead, NICE recommends treating for mania, with close monitoring for the emergence of depression.[29]

For acutely mixed episodes, response to treatment may take longer than 2 weeks (in contrast to mania without mixed features) and improvements may be more subtle.[105]

Primary options

aripiprazole: 15 mg orally once daily initially, adjust dose according to response, maximum 30 mg/day

asenapine: 5-10 mg sublingually twice daily

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 6 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Secondary options

carbamazepine: 200 mg orally (extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

ziprasidone: 40 mg orally twice daily initially, adjust dose according to response, maximum 160 mg/day

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

-- AND --

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Plus – removal of exacerbating factors

Back

Plus –

removal of exacerbating factors

Treatment recommended for ALL patients in selected patient group

Before starting pharmacological treatment, rule out symptoms secondary to substance use (both prescribed and illicit), other treatments and general medical (e.g., endocrine disorder) or neurological conditions, but note that, even where the above are present, symptomatic treatment may be given on a short-term basis.[36] Consider whether referral to services to assist with substance use disorders is required.

Determine whether the mixed presentation may have been iatrogenically induced, for example, with antidepressants or stimulants; in this scenario, consider a dose taper or discontinuation.[5]

It is important to note that antipsychotics, lithium or valproate semisodium may cause sedation, emotional blunting or psychomotor slowing which could mimic depressive symptoms within a mixed presentation; therefore, clinicians should compare the onset of mixed-type symptoms against the timing of any introduction or changes in drugs.[5]

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

Although there are no studies which specifically examine the role of non-pharmacological interventions on mixed presentations, CANMAT notes that expert opinion supports the use of psychoeducation and/or other evidence-based psychosocial interventions with evidence in bipolar mood states.[5]

Consider – management of agitation

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Consider –

management of agitation

Additional treatment recommended for SOME patients in selected patient group

The first step in managing agitation is to prevent or at least mitigate its severity by rapidly treating the causative manic episode. Therapy includes medication to prevent or rapidly reduce manic symptoms, while minimising adverse effects.

Studies suggest mixed features indicate a more severe course of illness, and combination treatment is often required to adequately control symptoms.[36][151] Combination treatment from the start with a mood stabiliser plus antipsychotic may be required for selected patients, for example, those with severe mania with agitation necessitating a rapid response to treatment.[36] This is a clinical decision and depends on the severity of the patient’s illness, the rapidity of response to treatment needed (combination treatments tend to work faster), previous response to monotherapy, tolerability concerns with combination therapy, and patient preference.

For patients with mania with mixed features and worsening agitation despite aggressive management of acute mania, administration of a rapidly acting non-oral antipsychotic or benzodiazepine may be necessary. First-line options include intramuscular olanzapine, inhaled loxapine, or intramuscular lorazepam.[36] Lorazepam can be used as an adjunct or as monotherapy.[36] Recommended second-line options include sublingual asenapine or intramuscular ziprasidone.[36] Haloperidol and risperidone are not recommended by CANMAT for the management of mixed features, unlike in the management of agitation in patients with ‘pure’ mania.[5]

Recommendations within this topic generally align with CANMAT guidance, but note that international differences in recommendations for rapidly-acting non-oral drugs to manage agitation apply, and clinicians should consult local guidance. This is sometimes termed ‘rapid tranquilisation’. UK guidance from NICE recommends either monotherapy with intramuscular lorazepam, or combination therapy with intramuscular haloperidol combined with intramuscular promethazine, for rapid tranquilisation in adults.[118] Of note, NICE recommends the use of intramuscular lorazepam rather than combination treatment with intramuscular haloperidol plus promethazine when there is evidence of cardiovascular disease, including a prolonged QT interval, or when no ECG has been carried out.[118]

In some cases, patient cooperation may not be readily obtained and forced or involuntary administration may be required (e.g., where the health and life of the patient or of others may otherwise be at risk).

Primary options

olanzapine: 2.5 to 10 mg intramuscularly as a single dose, may repeat after 2 hours and then again after 4 hours if required, maximum 30 mg/day

loxapine inhaled: 10 mg (1 puff) inhaled once daily when required

lorazepam: 2 mg intramuscularly as a single dose

Secondary options

asenapine: 5-10 mg sublingually twice daily

ziprasidone: 10 mg intramuscularly every 2 hours when required, or 20 mg intramuscularly every 4 hours when required, maximum 40 mg/day

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[5][36][125][126] ECT may also be considered when the medication risks outweigh ECT risks (e.g., in older or people frail patients), or if the person prefers this option.[127]

not rapid cycling and with mixed features (with acute depression predominant): non-pregnant

1st line – mood stabiliser and/or atypical antipsychotic

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1st line –

mood stabiliser and/or atypical antipsychotic

Depression with mixed features, as defined by DSM-5-TR, occurs where full criteria for a depressive episode are met, and at least 3 symptoms of mania or hypomania are present during most days of the current or most recent episode of depression.[1]

Careful suicide risk mitigation including determination of the most appropriate treatment setting is imperative.[4][5]

The evidence base on pharmacological treatment is limited.[5] CANMAT suggests that the most suitable initial pharmacological options to consider are monotherapy with cariprazine or lurasidone.[164][165]

Second-line pharmacological options include olanzapine, olanzapine/fluoxetine, quetiapine, valproate semisodium, lamotrigine, or ziprasidone.[166][167][168][169][170][171][172]

Antidepressant monotherapy or adjunctive antidepressant therapy is not recommended for people with bipolar depression and mixed features, owing to an increased risk of manic switch.[5][173]

It is important to highlight international differences in approach; clinicians should consult local treatment guidelines. The recommendations presented in this topic generally align with CANMAT, but other international guidelines (including NICE guidance in the UK) do not recommend a specific course of management for patients with mixed episodes.[29] Instead, NICE recommends treating for mania, with close monitoring for the emergence of depression.[29]

Primary options

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 3 mg/day

lurasidone: 20 mg orally once daily initially, adjust dose according to response, maximum 120 mg/day

Secondary options

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

olanzapine/fluoxetine: 6 mg (olanzapine)/25 mg (fluoxetine) orally once daily initially, adjust dose according to response, maximum 12 mg (olanzapine)/50 mg (fluoxetine) once daily

quetiapine: 50 mg orally (immediate-release or extended-release) once daily initially, adjust dose according to response, maximum 300 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

lamotrigine: dose depends on any concomitant drugs; consult specialist for guidance on dose

ziprasidone: 40 mg orally twice daily initially, adjust dose according to response, maximum 160 mg/day

Plus – removal of exacerbating factors

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Plus –

removal of exacerbating factors

Treatment recommended for ALL patients in selected patient group

First, assess for potential contributors and alternative conditions (e.g., endocrine disturbance, personality disorders, ADHD, substance use disorders and iatrogenic induction of symptoms (e.g., with antidepressants or stimulants).[5]

Use a technique such as motivational interviewing to support patients to discontinue stimulant use and to limit nicotine, caffeine, drug and alcohol use; consider whether referral to services to assist with substance use disorders is required.[36][128]

Strongly consider careful tapering and/or discontinuation of antidepressants in patients already taking them, based on an assessment of the individual risks versus benefits of reducing or stopping the antidepressant; tapering and/or discontinuation should always be accompanied by careful monitoring for worsening of depressive symptoms.[5]

Plus – psychosocial interventions

Back

Plus –

psychosocial interventions

Treatment recommended for ALL patients in selected patient group

Adjunctive psychoeducation and/or other evidence-based psychosocial interventions with evidence in bipolar mood states is recommended.[5]

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[5][36][125][126] It may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail people), or if the person prefers this option.[127]

not rapid cycling and with mixed features (with equally prominent concurrent manic and depressive symptoms): non-pregnant

1st line – mood stabiliser and/or atypical antipsychotic

Back

1st line –

mood stabiliser and/or atypical antipsychotic

DSM-IV criteria for mixed episodes requires fully syndromal concurrent manic and depressive episodes (although with depression lasting ≥1 week rather than 2 weeks); this represents the most restrictive criteria for a mixed presentation.[174] Although DSM-IV has been superseded by DSM-5-TR, for people with fully syndromal concurrent manic and depressive episodes, there is significantly more data to inform treatment decisions compared to those who meet more permissive DSM-5-TR definitions of mixed features.[5]

Careful suicide risk mitigation including determination of the most appropriate treatment setting is paramount.[5]

First-line treatment is with aripiprazole or asenapine, given that there is evidence that both improve both manic and depressive symptoms based on post-hoc/subgroup RCT analysis.[153][156][157][175][176]

Secondary options include olanzapine monotherapy, olanzapine plus lithium or valproate semisodium, or carbamazepine or valproate semisodium monotherapy.[121][177][178][179][180]

Further-line options include ziprasidone, valproate semisodium plus carbamazepine, cariprazine, and lithium plus valproate semisodium.[181][182]

It is important to highlight that clinicians should consult local treatment guidelines regarding management of mixed features. The recommendations presented in this topic generally align with CANMAT, but note that other international guidelines (including NICE guidance in the UK) do not recommend a specific course of management for patients with mixed episodes.[29] Instead, NICE recommends treating for mania, with close monitoring for the emergence of depression.[29]

Primary options

aripiprazole: 15 mg orally once daily initially, adjust dose according to response, maximum 30 mg/day

asenapine: 5-10 mg sublingually twice daily

Secondary options

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

carbamazepine: 200 mg orally (extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

-- AND --

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Tertiary options

ziprasidone: 40 mg orally twice daily initially, adjust dose according to response, maximum 160 mg/day

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 6 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

-- AND --

carbamazepine: 200 mg orally (extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

Plus – removal of exacerbating factors

Back

Plus –

removal of exacerbating factors

Treatment recommended for ALL patients in selected patient group

Plus – psychosocial therapies

Back

Plus –

psychosocial therapies

Treatment recommended for ALL patients in selected patient group

Adjunctive psychoeducation and/or other evidence-based psychosocial interventions with evidence in bipolar mood states is recommended.[5]

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[5][36][125][126] ECT may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail people), or if the person prefers this option.[127]

rapid cycling: non-pregnant

1st line – mood stabiliser or atypical antipsychotic

Back

1st line –

mood stabiliser or atypical antipsychotic

The treatment approach to patients experiencing rapid cycling (4 or more mood episodes in a 1-year period) requires planning and patience. Shifts in mood states may occur suddenly, and treatment of the current individual episode may be counterproductive. For example, the addition of, or increase in dose of, an antidepressant to a person who is rapid cycling who is depressed may precipitate a switch to mania or acceleration of cycles; as a result, antidepressants are not recommended as they destabilise the mood, even if used concurrently with a mood stabiliser.[36]

There is no evidence to support any specific agent to treat acute depression during a rapid-cycling phase, so treatment should be chosen based on effectiveness in the acute and maintenance phases, if known. Pharmacotherapy should focus on medications that can act as mood stabilisers. Generally these are the anti-manic therapies or agents approved for use in bipolar mania.

Rapid cycling has been introduced as a potential variant or course specifier for bipolar disorder, highlighting the failure of lithium prophylaxis in its treatment; however, lithium should not be avoided in such patients, given the noted benefits of lithium on the overall course of illness.[124][188] An argument can be made to include lithium as part of the pharmacotherapeutic treatment plan, or to use it in combination with other psychotropic drugs such as atypical antipsychotics, in most people with rapid cycling.[124][188]

Rapid-cycling bipolar disorder is well known for its resistance to most monotherapies, usually requiring combinations of mood stabilisers. Adding a second or third mood stabiliser may be necessary.

Lithium, valproate semisodium, olanzapine, and quetiapine have all demonstrated efficacy as maintenance treatment for patients with rapid cycling and are therefore reasonable to consider as first-line options.[187]

Note that international differences in treatment approach exist, and clinicians should consult local guidance. UK-based guidance from NICE recommends that clinicians offer people with rapid cycling bipolar disorder the same interventions as people with other types of bipolar disorder, citing a lack of strong evidence to guide differences in treatment.[29]

Primary options

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

Plus – removal of exacerbating factors

Back

Plus –

removal of exacerbating factors

Treatment recommended for ALL patients in selected patient group

Remove any factors that may destabilise mood including antidepressant and psychostimulant medication, alcohol or illicit drugs, excessive caffeine intake, unnecessary hormonal treatments, diet pills or over-the-counter 'remedies', or untreated hypothyroidism. Consider whether referral to services to assist with substance use disorders is required.[36][128]

2nd line – combination therapy

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2nd line –

combination therapy

Rapid-cycling bipolar disorder is well known for its resistance to most monotherapies, generally requiring combinations of mood stabilisers. However, starting with monotherapy may be advisable, then re-assessing mood control and cycle frequency after a 3- to 4-month period. Adding a second or third mood stabiliser may be necessary.

pregnant

1st line – consult psychiatrist and obstetrician

Back

1st line –

consult psychiatrist and obstetrician

The patient’s care should be overseen by a psychiatrist who is familiar and comfortable with managing mood disorders during pregnancy. In the US, Perinatal Psychiatry Access Programs may aid and support the obstetric care clinician in their management of patients with bipolar disorder.[195]

Care planning in consideration of the early postnatal period is important, given the high risk of serious illness during this time, including risk of postnatal psychosis, which is a psychiatric emergency.[195]

Reviews on medication during pregnancy include emerging data on some of the most common mood stabilisers used in bipolar disorder.[206]

The American College of Obstetricians and Gynecologists (ACOG) recommends continuation of pharmacotherapy (excluding valproic acid and its derivatives) for pregnant women with bipolar disorder.[195] Discontinuation of pharmacotherapy for bipolar disorder in pregnancy and in the postnatal period is associated with a threefold higher risk of relapse compared with discontinuation in non-perinatal women.[200] If discontinuation is considered, it requires careful assessment and shared decision-making with the woman regarding the risk of recurrence.[195]

When medications are required during pregnancy, prescribe the lowest effective doses of monotherapy.[207][208]

Valproic acid and its derivatives (including valproate semisodium) carry a high risk of birth defects and developmental disorders in children born to mothers who take the drug during pregnancy; up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects (including neural tube defects).[196] They are not recommended for use in girls and women of childbearing potential by the World Health Organization (WHO).[197] In the US, standard practice is that valproic acid and its derivatives 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, or if the patient has responded only to valproic acid in the past.[198]

The European Medicines Agency recommends that valproic acid and its derivatives are contraindicated in bipolar disorder during pregnancy due to the risk of congenital malformations and developmental problems in the infant/child.[199] Both European and US guidelines recommend against using valproic acid in female patients of childbearing potential, unless other drugs are unsuitable, there is a pregnancy prevention programme in place, and certain conditions are met.[29][198][199]

Lithium use in pregnancy is associated with a small increased risk of congenital malformations.[209] The risk for Ebstein anomaly is 20-fold according to some studies, although more recent data suggest a lower risk, with an odds ratio of 1.81 for congenital abnormalities overall, and an odds ratio of 1.86 for cardiac anomalies.[124][210][211] The risk is higher for first-trimester and higher-dose exposure.[210] Careful monitoring of dose and serum lithium levels throughout pregnancy, at delivery, and immediately postnatal is crucial given the significant volume of distribution changes that take place.[195][212] Because lithium has a narrow therapeutic window, ideally, lithium levels should be stabilised prior to pregnancy, and a therapeutic goal level established.[195] ACOG recommends that pregnant patients taking lithium in the first trimester are offered a detailed ultrasound examination in the second trimester. Fetal echocardiography may also be considered.[195] After delivery, careful but rapid down-titration is required to prevent toxicity. Close monitoring and lithium dose adjustments may also be required in several common scenarios, including pre-eclampsia, renal impairment, postnatal use of non-steroidal anti-inflammatory drugs, hyperemesis, and acute blood loss.[195] Initiation of high-dose lithium immediately after delivery has the strongest evidence for prevention of postnatal psychosis.[213]

For lurasidone, animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Electroconvulsive therapy (ECT) may be indicated for bipolar depression if the medication risks outweigh ECT risks.[215]

If pharmacotherapy is initiated during lactation, passage through breast milk should be considered alongside the likelihood of drug efficacy.[195] Women taking pharmacotherapy for bipolar disorder should not typically be discouraged from breastfeeding due concerns about transmission through breast milk, if that is their desired choice of feeding. However, recommendations regarding breastfeeding with maternal lithium use are mixed, and there is a risk of lithium toxicity in the newborn for babies exposed via breast milk.[195] Coordination between obstetrics, paediatrics, and psychiatry is required if a woman taking lithium is considering breastfeeding.[195] In general, the decision on whether to breastfeed should be an individual one, taking into account factors such as the impact of maternal sleep deprivation and stress, which may be destabilising in bipolar disorder.[85] Depending on the individual circumstances, foregoing breastfeeding overnight may be considered, at least initially.[195]

Consult a specialist for guidance on pharmacotherapy during pregnancy and lactation. Updated information about potential harms from medications during pregnancy and breastfeeding can be found at resources such as LactMed and UKTIS. Drugs and Lactation Database (LactMed®) Opens in new window UKTIS Opens in new window

ONGOING

bipolar I after stabilisation of acute episode (including rapid cycling but without mixed features): non-pregnant

1st line – mood stabiliser and/or atypical antipsychotic

Back

1st line –

mood stabiliser and/or atypical antipsychotic

Treatment guidelines from CANMAT endorse initiation of maintenance treatment after a single manic episode.[36] Discuss maintenance options collaboratively with the patient once stabilised. Preventing early relapse after a single manic episode may be associated with a more benign course of illness; advise patients who have been stable on treatment for several years to remain on maintenance indefinitely, as recurrence risk remains high.[103]

For patients with rapid cycling, discontinue stimulants and antidepressants and treat hypothyroidism if present; patients with rapid cycling will often require a combination of mood stabilisers.

Medications used to stabilise an acute episode may be continued as maintenance therapy for most people. An exception to this is that long-term antidepressant therapy is not typically recommended, due to concerns about potential risk of manic-hypomanic switch and worsening of rapid cycling.[36]

Monitor for relapse or recurrence and for treatment-emergent adverse effects, particularly neurological (extrapyramidal side effects, tardive dyskinesia), metabolic (obesity, diabetes, dyslipidaemias) effects, or toxicity (renal, hepatic, haematological, thyroid). It may be necessary to lower the dose once in maintenance treatment as patients often experience greater side effects at this stage. Early integration between mental and physical health services is important for people experiencing metabolic adverse effects or toxicity secondary to bipolar medications.[84]

Lithium has the strongest evidence for prevention of recurrence in bipolar disorder compared with other agents, remains the treatment of choice for long-term maintenance therapy, and is supported by guidelines internationally.[29][36][124][224] Lithium is effective against relapse of both manic and depressive symptoms and appears to have an anti-suicidal effect.[225][226]

Other first-line options include quetiapine (as an adjunct to lithium or valproate semisodium, or as monotherapy), valproate semisodium, lamotrigine, asenapine, and aripiprazole (as an adjunct to lithium or valproate semisodium, or as monotherapy as an oral or injectable preparation).[171][228][229]

Quetiapine is effective in preventing manic, depressive, and mixed episodes.[231]

Monotherapy with asenapine or aripiprazole is more effective in preventing mania than depression. Lamotrigine is more effective in preventing depression than mania, and it is also indicated for prevention of recurrence for any mood disorder.[232]

It is important to note international differences in approach; clinicians should consult local guidance. The approach to maintenance treatment in patients with bipolar I disorder outlined here generally aligns with CANMAT guideline recommendations, but note that NICE guidance in the UK does not distinguish between bipolar I, bipolar II, or mixed features in terms of long-term management.[5][29][36] According to NICE, clinicians should recommend lithium as the first-line, long-term pharmacological treatment for all subtypes of bipolar disorder. If lithium is ineffective, poorly tolerated, or is not suitable, consider an antipsychotic. If the first antipsychotic is poorly tolerated at any dose, or ineffective at the maximum dose, consider an alternative antipsychotic. If an alternative antipsychotic is ineffective, consider a combination of valproate with either an antipsychotic or lithium.[29]

Consider long-acting injections as an alternative to oral medication if available and if there is a concern about non-adherence resulting in frequent relapse and/or if the patient would prefer intramuscular administration.[234][235] Before prescribing a long-acting injectable preparation, ensure that the patient has been stabilised on (and had a good response to) the oral preparation of the same medication.

Most people with bipolar I require short- or long-term combination treatment at some point during their lifetime to adequately control their symptoms and reduce rates of recurrence. There is evidence that the risk of recurrence is reduced when an atypical antipsychotic is combined with lithium or valproate semisodium; when an atypical antipsychotic is combined with lithium or valproate semisodium, there is evidence to suggest a benefit in continuing this treatment for the first 6 months following response to treatment.[233] The risks versus benefits beyond this period are currently unclear. For patients with both mania and depression, lithium or valproate semisodium in combination with quetiapine is protective against relapse.

Primary options

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

lamotrigine: dose depends on any concomitant drugs; consult specialist for guidance on dose

asenapine: 5-10 mg sublingually twice daily

aripiprazole: 15 mg orally once daily initially, adjust dose according to response, maximum 30 mg/day; 300-400 mg intramuscularly once monthly

aripiprazole bimonthly injection: 720-960 mg intramuscularly every 2 months

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

-- AND --

aripiprazole: 15 mg orally once daily initially, adjust dose according to response, maximum 30 mg/day

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Monitoring and enhancing adherence is a routine part of long-term bipolar disease management, because non-adherence is associated with recurrence.[216] Education, self-monitoring, recurrence prevention, managing adverse effects, identifying and managing stressors, and addressing belief systems and attitudes to illness are all helpful to enhance adherence.[217]

Mounting evidence supports the efficacy of specific psychosocial interventions for maintenance therapy of bipolar disorder as advocated in the Canadian Network for Mood and Anxiety Treatments guidelines and National Institute for Health and Care Excellence guidance in the UK.[29][36][219] Offer psychoeducation to recognise and manage early warning symptoms first line to all patients. Psychoeducation has been shown to reduce relapse rates, improve long-term treatment adherence, and help improve overall social functioning in patients.[220] A systematic review showed that psychoeducation increased time to any mood recurrence, reduced hospitalisation rates, and improved functioning.[221] Adjunctive cognitive behavioural therapy reduced depression scores, lengthened time to depressive recurrence, and improved dysfunctional attitudes.[222]

Offer adjunctive cognitive therapy, family-focused therapy, interpersonal social rhythm therapy, and peer support as second-line options based on individual strengths and needs. Group psychosocial therapy has also been shown to reduce relapse and hospitalisation rates.[223]

2nd line – switch to (or add on) alternative first-line drug

Back

2nd line –

switch to (or add on) alternative first-line drug

For patients whose symptoms recur or who remain symptomatic with first-line monotherapy or combination therapy, optimise dosage and check medication adherence. If therapy is not tolerated or results are suboptimal at a therapeutic dose, switch to, or add on, an alternative first-line drug.

Most people with bipolar I will require short- or long-term combination treatment at some point during their lifetime to adequately address their symptoms and reduce rates of recurrence. There is evidence that the risk of recurrence is reduced when an antipsychotic is combined with lithium or valproate semisodium; when an atypical antipsychotic is combined with lithium or valproate semisodium, there is evidence to suggest a benefit in continuing this treatment for the first 6 months following response to treatment.[233] The risks versus benefits beyond this period are currently unclear.

Note that international differences in recommendations on maintenance therapy apply, and clinicians should be familiar with local guidance.

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

3rd line – alternative mood stabiliser and/or atypical antipsychotic

Back

3rd line –

alternative mood stabiliser and/or atypical antipsychotic

For patients who have not responded adequately to multiple trials of first-line drugs, options include olanzapine or carbamazepine monotherapy, oral or long-acting intramuscular risperidone (as either a monotherapy or an adjunctive treatment), paliperidone, or lurasidone or ziprasidone in combination with either lithium or valproate semisodium.[36] Use of paliperidone for bipolar disorder is ‘off-label’ and it has not received approval for this indication.

Olanzapine is effective against manic and depressive episodes, but it is considered a second-line drug due to its adverse effects (particularly metabolic syndrome).[235][236] Risperidone appears to be effective against mania but not depression.[233][237][238] Paliperidone appears to be more effective than placebo but less effective than olanzapine in preventing any mood episode.[239]

Most people with bipolar I will require short- or long-term combination treatment at some point during their lifetime to adequately address their symptoms and reduce rates of recurrence. There is evidence that the risk of recurrence is reduced when an atypical antipsychotic is combined with lithium or valproate semisodium; when an atypical antipsychotic is combined with lithium or valproate semisodium, there is evidence to suggest a benefit in continuing this treatment for the first 6 months following response to treatment.[233] The risks versus benefits beyond this period are currently unclear.

Consider long-acting injections as an alternative to oral medication if available and if there is a concern about adherence resulting in frequent relapse and/or if the patient would prefer intramuscular administration.[234][235] Before prescribing a long-acting injectable preparation, ensure that the patient has been stabilised on (and had a good response to) the oral preparation of the same medication.

Note that international differences in recommendations on maintenance therapy apply, and clinicians should be familiar with local guidance.

Primary options

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

carbamazepine: 200 mg orally (immediate-release or extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

risperidone: 2-3 mg orally once daily initially, adjust dose according to response, maximum 6 mg/day; 25-50 mg intramuscularly every 2 weeks

paliperidone: 3-6 mg orally once daily initially, adjust dose according to response, maximum 12 mg/day

lurasidone: 20 mg orally once daily initially, adjust dose according to response, maximum 120 mg/day

ziprasidone: 40 mg orally twice daily initially, adjust dose according to response, maximum 160 mg/day

-- AND --

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

There are no controlled trials in bipolar disorder to support electroconvulsive therapy (ECT) to prevent recurrence of bipolar mood episodes, but some uncontrolled studies and retrospective data analysis provide some support for its use.[218] Consider ECT for a bipolar depressive episode that has not responded to several adequate medication trials. ECT may also be indicated for bipolar depression marked by acute suicidality/high risk of suicide; with catatonic or psychotic features; with a rapidly deteriorating physical condition brought on by the depression, such as anorexia; when the medication risks outweigh ECT risks (e.g., in older or medically frail people); in a person with a prior history of good response to ECT; or if there is a patient preference for ECT.[127]

4th line – alternative pharmacotherapy

Back

4th line –

alternative pharmacotherapy

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

bipolar II after stabilisation of acute episode (including rapid cycling but without mixed features): non-pregnant

1st line – mood stabiliser or antipsychotic

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1st line –

mood stabiliser or antipsychotic

As a rule, if a patient has responded to a particular medication in the acute phase of treatment, continued treatment with that drug is recommended.

Monotherapy with quetiapine, lithium, or lamotrigine is recommended as first-line treatment, supported by guidelines internationally.[29][36][229][240][241][242][243]

Quetiapine is particularly protective against relapse into depression.[240]

Lithium is another good option for maintenance treatment in bipolar II, and is supported by research demonstrating that it reduces the frequency and severity of hypomania and depression.[241][244] It is also supported by long-term naturalistic studies, which show that it reduces the time spent in episodes of both hypomania and depression by over 50%, and is supported by guidelines internationally.[29][36][245]

For people with rapid cycling, discontinue stimulants and antidepressants and treat hypothyroidism if present; patients with rapid cycling will often require a combination of mood stabilisers.

It is important to note international differences in approach; clinicians should be familiar with local guidance. The approach to maintenance treatment in patients with bipolar II disorder outlined here generally aligns with CANMAT guideline recommendations, but note that NICE guidance in the UK does not distinguish between bipolar I, bipolar II, or mixed features in terms of long-term management.[5][29][36] According to NICE, clinicians should recommend lithium as the first-line, long-term pharmacological treatment for all subtypes of bipolar disorder. If lithium is ineffective, poorly tolerated, or is not suitable, consider an antipsychotic. If the first antipsychotic is poorly tolerated at any dose, or ineffective at the maximum dose, consider an alternative antipsychotic. If an alternative antipsychotic is ineffective, consider a combination of valproate with either an antipsychotic or lithium.[29]

Primary options

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

lamotrigine: dose depends on any concomitant drugs; consult specialist for guidance on dose

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

2nd line – switch to alternative first-line drug

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2nd line –

switch to alternative first-line drug

For patients whose symptoms recur or who remain symptomatic with first-line monotherapy, optimise dosage and check medication adherence. If therapy is not tolerated or results are suboptimal at a therapeutic dose, the next step is to switch to an alternative first-line drug that has not yet been tried.

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

3rd line – venlafaxine

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3rd line –

venlafaxine

For patients whose symptoms recur or who remain symptomatic, optimise dosage and check medication adherence. If therapy is not tolerated or results are suboptimal following multiple trials of first- or second-line drugs, consider a time-limited trial of treatment with venlafaxine.[246]

Note that antidepressants including venlafaxine are not recommended for rapid cycling bipolar disorder due to the potential risk of manic-hypomanic switch and worsening of rapid cycling.[36]

Primary options

venlafaxine: 75 mg/day orally (immediate-release) given in 2-3 divided doses initially, adjust dose according to response, maximum 225 mg/day (outpatients) or 375 mg/day (hospitalised patients)

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

4th line – alternative pharmacotherapy

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4th line –

alternative pharmacotherapy

Further-line treatment options have a limited evidence base and some are used off-label, and so should be considered by a specialist when patients have not responded to multiple adequate trials of first- and second-line options alone and in combination.[36]

Consult a specialist for guidance on choice of drug regimen and dose.

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

not rapid cycling and with mixed features (with mania or hypomania predominant) after stabilisation of acute episode: non-pregnant

1st line – antipsychotic and/or mood stabiliser

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1st line –

antipsychotic and/or mood stabiliser

Mania with mixed features occurs where full criteria for a manic (or hypomanic) episode are met, and at least 3 symptoms of depression are present during the majority of days of the current or most recent episode of mania (or hypomania).[1]

Regardless of the polarity of the index mood episode, CANMAT recommends continuation of successful initial treatment into the maintenance phase, except for antidepressants.[5]

For DSM-5-TR mania with mixed features, due to a lack of evidence, CANMAT recommends the following maintenance treatments supported by expert opinion: asenapine, cariprazine, valproate semisodium, olanzapine monotherapy (or combination therapy with olanzapine plus lithium or valproate semisodium), quetiapine, carbamazepine, or lithium.[5]

It is important to note international differences in approach; clinicians should be familiar with local guidance. The approach to maintenance treatment in patients with mixed features aligns with CANMAT guideline recommendations, but note that NICE guidance in the UK does not distinguish between bipolar I, bipolar II, or mixed features in terms of long-term management.[5][29][36] According to NICE, clinicians should recommend lithium as the first-line, long-term pharmacological treatment for all subtypes of bipolar disorder. If lithium is ineffective, poorly tolerated, or is not suitable, consider an antipsychotic. If the first antipsychotic is poorly tolerated at any dose, or ineffective at the maximum dose, consider an alternative antipsychotic. If an alternative antipsychotic is ineffective, consider a combination of valproate with either an antipsychotic or lithium.[29]

Primary options

asenapine: 5-10 mg sublingually twice daily

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 6 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

carbamazepine: 200 mg orally (extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

-- AND --

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Mounting evidence supports the efficacy of specific psychosocial interventions for maintenance therapy of bipolar disorder as advocated in the Canadian Network for Mood and Anxiety Treatments guidelines and National Institute for Health and Care Excellence guidance in the UK.[36][29][219] Offer psychoeducation to recognise and manage early warning symptoms first line to all patients. Psychoeducation has been shown to reduce relapse rates, improve long-term treatment adherence, and help improve overall social functioning in patients.[220] A systematic review showed that psychoeducation increased time to any mood recurrence, reduced hospitalisation rates, and improved functioning.[221] Adjunctive cognitive behavioural therapy reduced depression scores, lengthened time to depressive recurrence, and improved dysfunctional attitudes.[222]

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[5][36][125][126] It may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail people), or if the person prefers this option.[127]

not rapid cycling and with mixed features (with depression predominant) after stabilisation of acute episode: non-pregnant

1st line – mood stabiliser or antipsychotic

Back

1st line –

mood stabiliser or antipsychotic

Depression with mixed features occurs where full criteria for a depressive episode are met, and at least 3 symptoms of mania/hypomania are present during most days of the current or most recent episode of depression.[1]

Regardless of the polarity of the index mood episode, CANMAT recommends continuation of successful initial treatment into the maintenance phase, except for antidepressants.[5]

For DSM-5-TR depression with mixed features, CANMAT notes that expert opinion supports the following as maintenance treatments options: cariprazine, lurasidone, olanzapine, quetiapine, valproate semisodium, asenapine, or lithium.[5]

It is important to note international differences in approach; clinicians should be familiar with local guidance. The approach to maintenance treatment in patients with mixed features aligns with CANMAT guideline recommendations, but note that NICE guidance in the UK does not distinguish between bipolar I, bipolar II, or mixed features in terms of long-term management.[36][5][29] According to NICE, clinicians should recommend lithium as the first-line, long-term pharmacological treatment for all subtypes of bipolar disorder. If lithium is ineffective, poorly tolerated, or is not suitable, consider an antipsychotic. If the first antipsychotic is poorly tolerated at any dose, or ineffective at the maximum dose, consider an alternative antipsychotic. If an alternative antipsychotic is ineffective, consider a combination of valproate with either an antipsychotic or lithium.[29]

Primary options

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 3 mg/day

lurasidone: 20 mg orally once daily initially, adjust dose according to response, maximum 120 mg/day

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

quetiapine: 50 mg orally (immediate-release or extended-release) once daily initially, adjust dose according to response, maximum 300 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

asenapine: 5-10 mg sublingually twice daily

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Monitoring and enhancing adherence is a routine part of long-term bipolar disease management, because nonadherence is associated with recurrence.[216] Education, self-monitoring, recurrence prevention, managing adverse effects, identifying and managing stressors, and addressing belief systems and attitudes to illness are all helpful to enhance adherence.[217]

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[5][36][125][126] It may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail people), or if the person prefers this option.[127]

not rapid cycling and with mixed features (with equally prominent concurrent manic and depressive symptoms) after stabilisation of acute episode: non-pregnant

1st line – mood stabiliser and/or atypical antipsychotic

Back

1st line –

mood stabiliser and/or atypical antipsychotic

Regardless of the polarity of the index mood episode, CANMAT recommends continuation of successful initial treatment into the maintenance phase, except for antidepressants.[5]

For DSM-IV mixed episodes, quetiapine monotherapy or combination therapy (with lithium or valproate semisodium) are recommended first-line options for maintenance treatment.[171][231]

Recommended secondary maintenance options for DSM-IV mixed episodes include lithium and olanzapine.[171][226][236][247]

Recommended further-line maintenance options for DSM-IV mixed episodes (based on expert opinion) include asenapine, carbamazepine, valproate semisodium, valproate semisodium plus carbamazepine, cariprazine, or lithium plus valproate semisodium.[5]

Primary options

-- AND --

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Secondary options

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

olanzapine: 10-15 mg orally once daily initially, adjust dose according to response, maximum 20 mg/day

Tertiary options

asenapine: 5-10 mg sublingually twice daily

carbamazepine: 200 mg orally (extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

and

carbamazepine: 200 mg orally (extended-release) twice daily initially, adjust dose according to response and serum drug level, maximum 1600 mg/day

cariprazine: 1.5 mg orally once daily initially, adjust dose according to response, maximum 6 mg/day

lithium: 300 mg orally (immediate-release) three times daily initially, adjust dose according to response and serum drug level, maximum 1800 mg/day

and

valproate semisodium: 750 mg/day orally given in 2-3 divided doses initially, adjust dose according to response and serum drug level, doses greater than 45 mg/kg/day require careful monitoring

Plus – psychosocial interventions and monitoring

Back

Plus –

psychosocial interventions and monitoring

Treatment recommended for ALL patients in selected patient group

Consider – electroconvulsive therapy

Back

Consider –

electroconvulsive therapy

Additional treatment recommended for SOME patients in selected patient group

Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[5][36][125][126] It may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail people ), or if the person prefers this option.[127]

after stabilisation of acute episode: pregnant

1st line – consult psychiatrist and obstetrician

Back

1st line –

consult psychiatrist and obstetrician

Reviews on medication during pregnancy include emerging data on some of the most common mood stabilisers used in bipolar disorder.[206]

When medications are required, prescribe the lowest effective doses of monotherapy.[207][208][210]

Valproic acid and its derivatives carry a high risk of birth defects and developmental disorders in children born to mothers who take the drug during pregnancy; up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects (including neural tube defects).[196] They are not recommended for use in girls and women of childbearing potential by the World Health Organization (WHO).[197] In the US, standard practice is that valproic acid and its derivatives 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, or if the patient has responded only to valproic acid in the past.[198] The European Medicines Agency recommends that valproic acid and its derivatives are contraindicated in bipolar disorder during pregnancy due to the risk of congenital malformations and developmental problems in the infant/child.[199] Both European and US guidelines recommend against using valproic acid in female patients of childbearing potential unless other drugs are unsuitable, there is a pregnancy prevention programme in place, and certain conditions are met.[29][198][199]

Lithium use in pregnancy is associated with a small increased risk of congenital malformations.[209] The risk for Ebstein anomaly 20-fold according to some studies, although more recent data suggest a lower risk, with an odds ratio of 1.81 for congenital abnormalities overall, and an odds ratio of 1.86 for cardiac anomalies.[124][210][211] The risk is higher for first-trimester and higher-dose exposure.[210] Careful monitoring of dose and serum lithium levels throughout pregnancy, at delivery, and immediately postnatal is crucial given the significant volume of distribution changes that take place.[195][212] Because lithium has a narrow therapeutic window, ideally, lithium levels should be stabilised prior to pregnancy, and a therapeutic goal level established.[195] ACOG recommends that pregnant patients taking lithium in the first trimester are offered a detailed ultrasound examination in the second trimester. Fetal echocardiography may also be considered.[195] After delivery, careful but rapid down-titration is required to prevent toxicity. Close monitoring and lithium dose adjustments may also be required in several common scenarios, including pre-eclampsia, renal impairment, postnatal use of non-steroidal anti-inflammatory drugs, hyperemesis, and acute blood loss.[195] Initiation of high-dose lithium immediately after delivery has the strongest evidence for prevention of postnatal psychosis.[213]

For lurasidone, animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Electroconvulsive therapy (ECT) may be indicated for bipolar depression if the medication risks outweigh ECT risks.[215]

If pharmacotherapy is initiated during lactation, passage through breast milk should be considered alongside the likelihood of drug efficacy.[195] Women taking pharmacotherapy for bipolar disorder should not typically be discouraged from breastfeeding due concerns about transmission through breast milk, if that is their desired choice of feeding. However recommendations regarding breastfeeding with maternal lithium use are mixed, and there is a risk of lithium toxicity in the newborn for babies exposed via breast milk.[195] Coordination between obstetrics, paediatrics, and psychiatry is required if a woman taking lithium is considering breastfeeding.[195] In general, the decision on whether to breastfeed should be an individual one, taking into account factors such as the impact of maternal sleep deprivation and stress, which may be destabilising in bipolar disorder.[85] Depending on the individual circumstances, foregoing breastfeeding overnight may be considered, at least initially.[195]

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Bipolar disorder in adults

Treatment algorithm

not rapid cycling and without mixed features (with acute mania or hypomania): non-pregnant

mood stabiliser or antipsychotic

Primary options

Secondary options

removal of exacerbating factors

management of agitation

Primary options

Secondary options

switch to alternative first-line drug or combination therapy

electroconvulsive therapy

alternative pharmacotherapy

electroconvulsive therapy

brain stimulation techniques

not rapid cycling and without mixed features (with acute bipolar I depression): non-pregnant

mood stabiliser and/or atypical antipsychotic

Primary options

removal of exacerbating factors

psychosocial interventions

switch to alternative first-line drug or combination therapy

psychosocial interventions

mood stabiliser or atypical antipsychotic plus antidepressant or cariprazine monotherapy

Primary options

psychosocial interventions

electroconvulsive therapy

alternative pharmacotherapy

psychosocial interventions

electroconvulsive therapy

light therapy or brain stimulation techniques

not rapid cycling and without mixed features (with acute bipolar II depression): non-pregnant

quetiapine

Primary options

removal of exacerbating factors

psychosocial interventions

mood stabiliser or antidepressant

Primary options

psychosocial interventions

electroconvulsive therapy

alternative pharmacotherapy

psychosocial interventions

electroconvulsive therapy

not rapid cycling and with mixed features (with acute mania or hypomania predominant): non-pregnant

mood stabiliser and/or atypical antipsychotic

Primary options

Secondary options

removal of exacerbating factors

psychosocial interventions

management of agitation

Primary options

Secondary options

electroconvulsive therapy

not rapid cycling and with mixed features (with acute depression predominant): non-pregnant

mood stabiliser and/or atypical antipsychotic

Primary options

Secondary options

removal of exacerbating factors

psychosocial interventions

electroconvulsive therapy

not rapid cycling and with mixed features (with equally prominent concurrent manic and depressive symptoms): non-pregnant

mood stabiliser and/or atypical antipsychotic

Primary options

Secondary options

Tertiary options

removal of exacerbating factors

psychosocial therapies

electroconvulsive therapy

rapid cycling: non-pregnant

mood stabiliser or atypical antipsychotic

Primary options

removal of exacerbating factors

combination therapy

pregnant

consult psychiatrist and obstetrician

bipolar I after stabilisation of acute episode (including rapid cycling but without mixed features): non-pregnant

mood stabiliser and/or atypical antipsychotic

Primary options

psychosocial interventions and monitoring

switch to (or add on) alternative first-line drug

psychosocial interventions and monitoring

electroconvulsive therapy