Bipolar disorder in adults

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

Management of bipolar disorder is complex because of the recurrent nature of the condition, with episodes of differing mood polarity (depressed vs. manic or hypomanic), as well as more complex presentations of mixed features, rapid cycling, psychotic bipolar disorder, and treatment-refractory bipolar disorder.

The best treatment approach goes beyond the resolution of acute episodes and considers the need to simultaneously design an individualised strategy that can prevent future episodes, or that results in reduction of episode frequency and improvement in functioning and quality of life. The fundamentals of management include access to services, ensuring the safety of the patient and others, and enhanced care efforts (therapeutic alliance, patient and family education, treatment adherence, and management of functional impairments).[103][104] Treatment of medical and psychiatric comorbidities, and suicide risk mitigation, are other important aspects of management.[84]

The recommendations within this topic are based primarily on guidance from the Canadian Network for Mood and Anxiety Treatments (CANMAT).[5][36] This is one of a number of recently published international guidelines guiding treatment selection for bipolar disorder.[29][36][103][105][106] Differences exist between guideline recommendations. As a general rule all guidelines allow for substantial choice amongst first-line options, given that effect sizes are modest and similar across classes of drugs. Many of the later-line treatment recommendations are based on expert opinion, reflecting a lack of evidence, particularly pertaining to management of more complex patients, for example, those with psychiatric comorbidities, and those requiring polypharmacy to control symptoms. Overall there is a relative lack of evidence on treatment of bipolar II compared to bipolar I, given that few RCTs have focused on bipolar II treatments.

In practice, given the above uncertainty, choice of pharmacotherapy depends on several factors, including local guidance, polarity and severity of symptoms, patient choice, treatment history, presence of comorbidities, and previous tolerability problems.[107] Consider both short and long-term side effect profiles of pharmacotherapy, and where possible select drugs with the safest tolerability profiles, given that adverse effects of bipolar medications are believed to account for much of the increased standardised mortality (approximately 2.6 times higher) in people with bipolar disorder, compared with the general population.[107][108]

Lithium remains the most effective drug in bipolar I disorder, demonstrating anti-manic, antidepressant and antisuicide effects. However it is associated with several serious tolerability and safety concerns, including tremor, polyuria, cognitive impairment, weight gain, renal toxicity, narrow therapeutic index, and high risk in overdose.[84] Atypical antipsychotics have demonstrated efficacy in both mania and depression, but as a class they are associated with weight gain, metabolic syndrome, raised prolactin, sedation, akathisia, QT prolongation and tardive dyskinesia. Of note, some atypical antipsychotics (e.g., olanzapine) have a more severe side effect burden than others.[84][109] As a newer class of drug, data is currently lacking on the long-term effects of atypical antipsychotics. Valproate semisodium is effective in mania, although the data on efficacy in depression and on long-term prevention of recurrence are less strong.[84] Adverse effects of valproate semisodium include severe teratogenicity if taken in pregnancy, polycystic ovarian syndrome, hepatotoxicity, and pancreatitis.[84]

Diminished insight may impede patients’ willingness to accept treatment; where possible, encourage shared decision-making about the treatment plan as this may improve treatment adherence. Close collaboration with patients and families can help identify periods where the risk of relapse is high, allowing timely treatment adjustments.[110] Smartphone technology represents a promising method of enhancing symptom monitoring and patient-clinician collaboration, although it has to date not been demonstrated to improve outcomes, and is not yet part of routine care for bipolar disorder.[111][112][113][114]

Treatment response time varies between patients and according to the nature of the acute episode (e.g., whether manic or depressive symptoms are present). As a general guide, pharmacological treatment for acute mania should result in a response within 2 weeks, after which time patients should be considered non-responders to specific medication(s) at the specific dosage(s).[36] For acute bipolar depression and acutely mixed episodes, response to treatment may take longer, and improvements may be more subtle.[105]

Definitions vary and compound data lacks consistency, but treatment-resistant bipolar disorder has been defined in one study as 'failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment'.[115] If there is treatment non-response, clinicians should sensitively explore the possibility of non-adherence, substance or alcohol use problems, or other comorbidities, as potential contributing factors.[84] 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]

It is essential to note that there is substantial international variation with the approach to management of bipolar disorder and clinicians should be familiar with their local guidelines.

The table below summarises commonly used medications for bipolar disorder and incorporates evidence on efficacy for different subtypes and stages of bipolar treatment.

Note that since the original table was produced in 2018, other drugs have been approved for bipolar disorder, although their use is not currently part of routine clinical practice (see Emerging treatments section for examples).

[Figure caption and citation for the preceding image starts]: FDA-approved medications for bipolar disorderAdapted from Butler M, et al. Treatment for Bipolar Disorder in Adults: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Aug. (Comparative Effectiveness Review, No. 208.) Table 1, FDA-approved medications for bipolar disorder. Available from: https://www.ncbi.nlm.nih.gov/sites/books/NBK532193/table/ch2.tab1; used with permission [Citation ends]. com.bmj.content.model.Caption@2099bf5f

Acute management of mania or hypomania

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] Although a number of differences exist between international guideline recommendations, many prioritise the use of atypical antipsychotics (e.g., aripiprazole, asenapine, cariprazine) for those with more severe manic symptoms requiring rapid treatment, based on their efficacy and rapid onset of action.[116] Lithium, valproate semisodium, and carbamazepine are also frequently recommended, given their demonstrated efficacy in mania. Lithium is typically recommended as a first-line option for those not requiring rapid symptom resolution.[84][107][117]

It should be noted that guidance on first-line treatment options varies internationally. The approach to patients with mania with agitation and mania without agitation outlined in the bullets below generally aligns with CANMAT guidance; clinicians should also be aware of their local guidance.[36] In the UK, the National Institute for Health and Care Excellence (NICE) recommends haloperidol, olanzapine, quetiapine, or risperidone as potential first-line options for mania, considering patient preference, previous response to treatment, and comorbidities. If the first antipsychotic drug is ineffective or poorly tolerated, offer an alternative antipsychotic from these listed. NICE recommends that if the alternative antipsychotic is not effective at maximum dose, then clinicians should consider adding lithium.[29]

Before starting 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]

Mania with agitation

Severely affected patients and/or those without insight into their illness may require urgent psychiatric hospitalisation to assure their safety and that of others.[29][36]
For an agitated patient with mania, provide initial management in a tranquil environment with reduced stimuli, and attempt verbal de-escalation.[110]
The first step in managing agitation is to try to prevent or at least mitigate its severity by rapidly treating the causative manic episode (see below).
Therapy includes pharmacotherapy to rapidly reduce manic symptoms, while minimising adverse effects. Management of the causative manic episode is generally the same as for patients with acute mania without agitation; however, note that in specific circumstances, for example, when there is severe mania with agitation and a rapid response to treatment is required, combination treatment from the start with a mood stabiliser plus an antipsychotic may be considered.[36]
When agitation persists or worsens despite aggressive management of acute mania, administration of a rapidly acting non-oral antipsychotic or benzodiazepine may be necessary. Suggested 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, risperidone orally dissolving tablet, intramuscular ziprasidone, intramuscular haloperidol, and intramuscular haloperidol plus promethazine.[36]
Note that international differences in recommendations for rapidly-acting non-oral drugs to manage agitation apply. 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 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).

Mania without agitation

Monotherapy is a reasonable starting point for many patients, especially those without complex illness; however, combination treatment may be eventually required to adequately manage symptoms. Some international guidelines (e.g., from the Canadian Network for Mood and Anxiety Treatments) recommend combination treatment with a mood stabiliser and antipsychotic as a first-line option.[36] However, other guidelines and many clinicians prefer monotherapy before combination therapy due to the potential risks of polypharmacy.[29] In specific cases, combination treatment may be considered. 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 treatment, tolerability concerns with combination therapy, and patient preference. Patients often prefer monotherapy, but most experts and clinical experience suggest a combination is more effective.[119][120][121][122]
For patients with acute mania, lithium is effective and should be considered first line monotherapy unless there are specific reasons not to, for example, when 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.
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]
If the initial anti-manic treatment is effective, expect some response to treatment within 1 to 2 weeks.[36] For patients who do not respond during this time, optimise the dose and check medication adherence. If response remains inadequate, the next step is either switching to an alternative choice of monotherapy with a mood stabiliser or antipsychotic, or using 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 unwell and has not responded to initial treatment, the quickest and most effective option is usually to proceed to combination therapy. Recommended combination regimens to consider first include lithium or valproate semisodium plus an atypical antipsychotic (e.g., risperidone, quetiapine, aripiprazole, or asenapine).[36] If there is no response to the second choice of therapy after 2 weeks, optimise the dose and check medication adherence.
Consider adjunctive electroconvulsive therapy (ECT) for people with bipolar disorder who are severely ill, catatonic, or not responding to several trials of medication.[29][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]
Third-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]
Evidence for brain stimulation techniques is expanding and, in patients resistant to pharmacotherapy, a trial of transcranial magnetic stimulation (rTMS) may be considered as an adjunct.[36][110]

Hypomania

For some patients, hypomania might be short and results in minimal functional impairment; if so, treatment might not be recommended. However, treatment is required if symptoms are prolonged, severe, and/or associated with significant functional impairment. Treatment is typically the same as for mania, with mood stabilisers such as lithium or valproate semisodium and/or atypical antipsychotics frequently used.[36]

Acute management of bipolar depression

Episodes of depression are common, and often represent the primary reason for people with bipolar disorder to seek treatment.[107] 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] Patients with bipolar II depression must have experienced at least one episode of hypomania previously.[1]

Before starting pharmacological treatment for a bipolar depressive episode, it is important to 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]

Suicide risk management is imperative given the high risk of suicide for people with bipolar disorder during a depressive episode, with over 70% of the suicidal attempts or deaths occurring during the depressive phase of a bipolar disorder.[34][36]

It is important to note international differences in approach. The approach to patients with bipolar I depression and bipolar II depression outlined in the bullets below generally aligns with CANMAT guideline recommendations; clinicians should consult local guidance. NICE guidance in the UK does not distinguish between bipolar I or bipolar II depression in terms of management.[29][36] According to NICE, first-line management in someone who is not taking a drug to treat their bipolar depression is to offer 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 lithium is at maximal level, add either quetiapine (or olanzapine/fluoxetine), olanzapine monotherapy, or lamotrigine, depending on the person's preference and previous response to treatment. NICE also recommend that people with bipolar depression are offered concurrent psychological therapy.[29]

Bipolar I depression

Note that international differences in treatment approach exist, and some treatment guidelines (e.g., NICE in the UK) do not distinguish between bipolar I and bipolar II in terms of treatment recommendations (see above).[29]
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 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. 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 patients do not respond adequately to the first choice of treatment, optimise dosing and explore adherence before changing treatment. If there continues to be a poor response to initial treatment, consider 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 due to the risks associated with polypharmacy; however, in selected cases, careful polypharmacy may be required to adequately control symptoms, as a single drug may be effective against some but not all components of the person’s illness. 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 ineffective 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. If switching of medication is required, it should be done as an overlap and taper rather than stopping abruptly, unless there is a compelling rationale for abrupt discontinuation.[36]
If a patient does not improve adequately from multiple trials of first-line agents, other drugs to consider either as add-on or switch therapy include olanzapine/fluoxetine and cariprazine.[36][133][135][136] Alternatively, 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 as an add-on treatment.[36][130][137]
Antidepressants should be avoided in patients with mixed features (see below) and in those with a history of antidepressant-induced mania or hypomania, or recent rapid cycling (see below). Patients 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 the treatment of bipolar I depression.[36]
Consider ECT as an adjunctive treatment for patients with a bipolar I depressive episode that has not responded to several adequate trials of medication.[36] 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]
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]
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][139]
These treatments may be considered by a specialist in secondary care, taking into account individual patient factors.[36]
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]
Patients 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]

Bipolar II depression

Note that international differences in treatment approach exist, and some treatment guidelines (e.g., NICE in the UK) do not distinguish between bipolar I and bipolar II in terms of treatment recommendations (see above).[29]
There is less evidence on the acute management of bipolar II depression compared with bipolar I depression; in general terms, acute treatment of bipolar II depression is similar to acute treatment of bipolar I depression, with mood stabilisers and antipsychotics typically being used. While antidepressants may have a more favourable 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]
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 assess adherence before adjusting treatment strategies.
Lithium and lamotrigine are second-line options. 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] Adjunctive ECT is another second-line option, and may be suitable for patients with treatment-refractory symptoms and those in need of a rapid response.
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]
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]

Acute management of mixed features

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

Initial management when a patient presents with mixed features is to 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] Clinicians should 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] Be aware that antipsychotics, lithium, and 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 medications.[5]

For patients with mixed features, most treatment guidelines favour addressing the manic symptoms while at the same time tapering and discontinuing any current antidepressants.[36][150] Studies suggest mixed features indicate a more severe course of illness, and combination treatment is often required to adequately control symptoms.[36][151] International differences in approach exist, and clinicians should consult local treatment guidelines regarding management of mixed features.

Although recommendations presented in this topic in the bullets below generally align with CANMAT, 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]

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

Mixed features: important note on treatment selection

Evolving diagnostic criteria for mixed features in bipolar disorder present a challenge for evidence-based treatment selection, given that most trial data is based on studies using previous (stricter) DSM-IV mixed episode criteria, rather than the newer (more permissive) DSM-5-TR mixed features specifier.

CANMAT guidance, with which this topic generally aligns, divides recommendations on acute treatment of mixed presentations into 3 sections, and recommends 3 separate treatment approaches for each.

The separate treatment groups are as follows:[5]

DSM-5 manic or hypomanic episodes with mixed features (presentations consisting of predominantly manic or hypomanic symptoms with some depressive features)
DSM-5 depressive episodes with mixed features (presentations consisting of predominantly depressive symptoms with some manic or hypomanic features)
DSM-IV mixed episodes (concurrent syndromal manic and depressive episodes)

To determine which treatment approach is most appropriate, CANMAT advises that when assessing a person experiencing a mixed presentation of bipolar disorder, clinicians should use their global impression of the patient to determine the most appropriate treatment.[5]

This approach is reflected in the topic as follows:

For a patient experiencing a predominantly manic or hypomanic episode with some associated depressive symptoms, see: ‘Acute management of DSM-5-TR mania or hypomania with mixed features’.
For a patient experiencing a predominantly depressive episode with some associated manic or hypomanic symptoms, see: ‘Acute management of DSM-5-TR depression with mixed features’.
For a patient in whom manic and depressive symptoms are equally prominent, see: ‘Acute management of DSM-IV mixed episodes (fully syndromal concurrent manic and depressive episodes)’.

DSM-5-TR mania or hypomania with mixed features

Mania (or hypomania) 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 most days of the current or most recent episode of mania (or hypomania).[1]
The evidence base on pharmacologic treatment in DSM-5-TR mixed presentations is limited.[5]
First-line options recommended by CANMAT include asenapine, cariprazine, valproate semisodium, or aripiprazole.[152][153][154][155][156][157]
Secondary options include monotherapy with ziprasidone, olanzapine, quetiapine, or carbamazepine.[5][158][159][160][161]
Combination treatment is often 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]
ECT is a possible adjunctive or standalone option; although it has not been specifically studied in people with DSM-5-TR mania with mixed features, it is recommended by CANMAT based on expert opinion, for patients who are severely unwell and who have not responded to recommended pharmacotherapy with first and second-line options.[5] It may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail patients), or if the patient prefers this option.[127]
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 who are already stabilised on lithium, lithium is typically continued (the rationale being long-term prevention of mood episodes).
For patients with mania plus mixed features and worsening agitation despite use of an oral anti-manic or antipsychotic drugs, 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 patients with ‘pure’ mania.[5]
Note that international differences apply, and clinicians should consult local guidance. Administration of rapidly-acting non oral medication for agitation 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 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]
For acutely mixed episodes, response to treatment may take longer than 2 weeks (in contrast to mania).

DSM-5-TR depression with mixed features

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 the majority of days of the current or most recent episode of depression.[1]
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]
Secondary pharmacological options include olanzapine, olanzapine/fluoxetine, quetiapine, valproate semisodium, lamotrigine, or ziprasidone.[166][167][168][169][170][171][172]
ECT is a possible adjunctive or standalone option; although it has not been specifically studied in people with DSM-5-TR depression with mixed features, it is recommended based on expert opinion, for patients who are severely unwell and who have not responded to recommended pharmacotherapy with first and second-line options.[5] It may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail patients), or if the patient prefers this option.[127]
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]
Note that international differences in treatment approach exist, and clinicians should consult local guidance (see above).

DSM-IV mixed episodes (fully syndromal concurrent manic and depressive episodes)

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] For people with fully syndromal concurrent manic and depressive episodes, there is significantly more data to inform treatment decisions compared to those who meet DSM-5-TR definitions of mixed features.[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.[177][121][178][179][180]
Further-line options include ziprasidone, valproate semisodium plus carbamazepine, cariprazine, and lithium plus valproate semisodium.[181][182]
ECT is a possible adjunctive or standalone option.[127][183][184][185][186] It may also be considered when the medication risks outweigh ECT risks (e.g., in older or medically frail patients), or if the patient prefers this option.[127]
Note that international differences in treatment approach exist, and clinicians should consult local guidance (see above).

Acute management of rapid cycling

The treatment approach to a patient who is 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 for patients with rapid cycling as they could destabilise the mood, even if used concurrently with a mood stabiliser.[36]

When managing a person with rapid-cycling bipolar disorder, remove any factors that may destabilise mood. These include antidepressant and psychostimulant medications, alcohol or illicit drugs, excessive caffeine intake, unnecessary hormonal treatments, diet pills or over-the-counter 'remedies', or untreated hypothyroidism.

Pharmacotherapy should focus on mood-stabilising drugs. Generally these are the anti-manic therapies or agents approved for bipolar mania. 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. Lithium, valproate semisodium, olanzapine, and quetiapine have all demonstrated efficacy as maintenance treatment for patients with rapid cycling.[187]

Rapid-cycling bipolar disorder presents with resistance to most monotherapies, usually requiring combinations of mood stabilisers. Adding a second or third mood stabiliser may be necessary.

Rapid cycling has been introduced as a potential variant or course specifier for bipolar disorder and this highlights 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] While there are short and long-term tolerability concerns associated with its use lithium is an effective and cost-effective intervention; and when bipolar disorder requires lifelong treatment, lithium remains the recommended maintenance therapy.[124] Furthermore, bipolar disorder carries a high risk for suicide, and lithium may confer some degree of protection.[124][189] Lithium has an unknown yet probably unique mechanism of action, making it an attractive option to complement other mood stabilisers for rapid-cycling patients. The addition of lithium to address residual, particularly manic or subsyndromal symptoms in rapid cycling may help stabilise mood and improve functioning.

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]

Management of mental health comorbidities

Comorbidity with other mental health conditions is common, and as a general guide, comorbidities are associated with more severe symptomatology and greater functional impairment.[190] Data on management of comorbidities are limited, and clinical judgment is required.[107][191][192]

One approach is to treat the primary bipolar disorder as fully as possible before considering additional treatment for comorbidities.[107] Of note, caution is required when treating comorbid anxiety or ADHD with antidepressants or stimulants respectively, due to the associated risk of mood instability/switching with these classes of drugs.[107]

Older adults with bipolar disorder

Although prevalence appears to decline in late life, older patients with new onset or persistence of lifelong bipolar disorder present treatment challenges. Psychiatric and medical comorbidities are observed in older people with bipolar disorder as least as frequently as in younger patients, with higher rates of medical comorbidities in older people with bipolar disorder.

Onset of mania after 60 years of age is more likely to be associated with a general medical condition (such as stroke or other brain lesion) than with bipolar disorder.

Limited data exist on treatment for older people with bipolar disorder. However, medications with efficacy in younger adults appear to be effective in late-life bipolar disorder. 'Start low and go slow' with the dosing, because of increased risk of reduced renal clearance, drug interactions, and pharmacokinetic issues (such as reduced protein binding) in an older person.[193]

Preconception considerations in women and men

For women who may become pregnant, the most effective management during pregnancy ideally starts prior to conception as part of a planned pregnancy. This allows the patient and her family to consult with the psychiatrist and obstetrician and receive education on the heritability of bipolar disorder, the risks (known, including teratogenicity, and unknown) of medication exposure during pregnancy, and the risks of drug discontinuation. A plan can also be established for intervention should recurrence occur during pregnancy or in the postnatal period.

Preconception recommendations in both males and females include:

Routinely ask all women of child-bearing age and potential about contraception, particularly prior to prescription of any psychotropic medication.
Women of childbearing age with bipolar disorder should be referred for specialist preconception advice.[194]
Maternal antenatal vitamins including high-dose folic acid are recommended prior to conception and throughout pregnancy.[36]
Because lithium has a narrow therapeutic window, ideally, lithium levels in women planning a pregnancy should be stabilised prior to conception, and a therapeutic goal level established.[195]
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] Valproic acid and its derivatives are not recommended for use in girls and women of childbearing potential by the World Health Organization (WHO).[197] Both European and the US guidelines recommend against using valproic acid in female patients of childbearing potential unless other drugs are unsuitable, and there is a pregnancy prevention program in place, and certain conditions are met.[29][198][199]
Precautionary measures may also be required in male patients taking valproic acid and its derivatives 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 regarding valproic acid and its derivatives 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 these agents 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]

Patients who are pregnant

The peripartum period is considered a time of high risk for episodes of mood disturbance, particularly depressive and psychotic episodes.[200][201][202][203][204] Women with a history of postnatal psychosis have a particularly high risk of recurrence following future deliveries; for women with a history of postnatal psychosis, speciality psychiatric care during pregnancy and postnatal is key, including multidisciplinary pre-birth care planning.[195]

Reviews on medication during pregnancy demonstrate the difficulty of managing pregnant women with bipolar disorder.[205] Some reviews include emerging data on the more common mood stabilisers used in bipolar disorder.[206] Recommendations for management during pregnancy, and in the immediate postnatal period, include the following.

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 postnatal 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]
During pregnancy, when medications are required, prescribe the lowest effective doses of monotherapy.[207][208]
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 effective, or if the patient has responded only to valproic acid in the past. 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]
Lithium use in pregnancy is associated with a small increased risk of congenital malformations.[209] The risk for Ebstein's 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.[210][124][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.[212] 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 of lithium is required to prevent toxicity.[195] 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]
Animal reproduction studies have failed to demonstrate a risk to the fetus associated with lurasidone, and no adequate, well-controlled studies have been conducted in pregnant women.
If pharmacotherapy is initiated during lactation, passage through breast milk should be considered alongside the likelihood of drug efficacy.[195]
As a general guide, women taking pharmacotherapy for bipolar disorder should not typically be discouraged from breastfeeding due to 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
Mixed presentations are common in pregnancy and in the postnatal period, particularly when mood stabilisers are discontinued prior to or in early pregnancy.[214] As in the non-pregnant population, mixed presentations are associated with an increased risk of self-harm and suicide, requiring careful assessment and mitigation.[26]
Women with postnatal psychosis are at elevated risk of suicide and infanticide, and require immediate emergency psychiatric admission, evaluation, intensive monitoring and treatment, in order to assure their safety and the safety of their infant, and to optimise pharmacological treatment.[195] The woman should not be left alone, or left unattended with the infant.[195]
ECT may be considered for bipolar depression in pregnancy if the medication risks outweigh ECT risks.[215]

Duration of acute phase treatment

Available treatment guidelines are primarily based on expert opinion given the absence of evidence.[103][105] For manic symptoms, treat the acute phase with the same medication and at the same dosage for a minimum of 2 months after full resolution of symptoms.[105] Full recovery from mania may take longer, and treatment may be continued for 3 to 6 months to achieve mood stability.[103] For depressive symptoms, one set of international consensus guidelines recommends continuing treatment for 6 months following full resolution of symptoms; after this period, either continue treatment or gradually switch to the recommended maintenance treatment.[105] The British Association for Psychopharmacology recommends tapering down and ultimately discontinuing antidepressants from 3 months of recovery onwards. However, it advises that longer treatment periods are required if patients relapse when treatment is withdrawn.[103]

Maintenance treatment

Treatment guidelines from CANMAT endorse initiation of maintenance pharmacological therapy after a single manic episode and suggest discussing maintenance options collaboratively with all patients stabilised after an acute episode.[36]

Most patients may continue maintenance therapy with medications used to stabilise an acute episode, particularly if the therapy has demonstrated efficacy as a maintenance agent. 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 rapid cycling.[36] UK guidance from NICE recommends that when considering long-term treatment, clinicians should discuss with the person whether they prefer to continue this treatment or switch to lithium; lithium is recommended by NICE as the first-line maintenance treatment for bipolar disorder.[29]

For all patients taking long-term (maintenance) treatment for bipolar disorder, closely monitor for relapse or recurrence as well as for any treatment-emergent adverse effects, particularly neurological (extrapyramidal side effects, tardive dyskinesia) or 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]

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]

Monitoring and enhancing adherence is a routine part of long-term bipolar disease management, because non-adherence is associated with recurrence.[216] Effective strategies that maximise adherence include: education, self-monitoring, recurrence prevention, managing adverse effects, identifying and managing stressors, and addressing belief systems and attitudes to illness.[217]

There are no controlled trials in bipolar disorder to support ECT to prevent recurrence of bipolar mood episodes, but uncontrolled studies and retrospective data analysis provide some support for its use.[218]

Mounting evidence supports the efficacy of the following psychosocial interventions for maintenance therapy of bipolar disorder.[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 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. Reasons to consider adjunctive psychosocial therapy include interpersonal or relationship dysfunction, employment difficulties, trauma, suicidality and/or the presence of psychiatric comorbidities.[84] Group psychosocial therapy has also been shown to reduce relapse and hospitalisation rates.[223]

It is important to note international differences in approach; clinicians should consult local guidance. The approach to maintenance treatment in patients with bipolar I, bipolar II and those with mixed features outlined in the bullets below generally aligns with CANMAT guideline recommendations, but note that other treatment guidelines do not distinguish between bipolar I, bipolar II, or mixed features in terms of long-term management.[29] According to guidance from 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 semisodium with either an antipsychotic or lithium.[29]

Bipolar I: maintenance pharmacotherapy

Lithium has the strongest evidence for prevention of recurrence in bipolar disorder compared with other agents and 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] One large Finnish nationwide cohort study found that maintenance treatment with lithium was associated with the lowest risk of hospitalisation due to a mental or somatic disorder of all the treatments studied.[227]
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 parenteral preparation).[171][228][229][230]
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, but is also indicated for prevention of recurrence for any mood disorder.[232]
Most people with bipolar I require short- or long-term combination treatment at some point during their lifetime to adequately control 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. For patients stabilised with quetiapine, there is evidence to suggest that continuation of quetiapine or switching to lithium is effective in delaying recurrence of manic and depressive events compared with placebo.[171]
Consider long-acting injections as an alternative to oral medication if available and if you are concerned 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.
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. For patients who have not responded adequately to multiple trials of first-line drugs, options include olanzapine or carbamazepine monotherapy, oral risperidone or risperidone long-acting injection (as either a monotherapy or an adjunctive treatment), paliperidone, 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 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]
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]

Bipolar II: maintenance pharmacotherapy

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 disorder, and is supported by research demonstrating that it reduces the frequency and severity of hypomania and depression in bipolar II.[241][244] Lithium 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%.[245]
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 switch to an alternative first-line drug. If therapy is not tolerated or results are suboptimal following multiple trials of first-line drugs, consider a time-limited trial of treatment with venlafaxine.[246] 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]

Mixed presentations: maintenance pharmacotherapy

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 people whose acute presentation was with a predominantly manic or hypomanic episode with some associated depressive symptoms (i.e., when the diagnosis is DSM-5-TR mania with mixed features), CANMAT recommends the following maintenance treatments supported by expert opinion (owing to a lack of evidence): asenapine, cariprazine, valproate semisodium, olanzapine monotherapy (or combination therapy with olanzapine plus lithium or valproate semisodium), quetiapine, carbamazepine, or lithium.[5] ECT may also be considered as a further-line option, for patients 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 patients), or if the patient prefers this option.[127]
For people whose acute presentation was with a predominantly depressive episode with some associated manic or hypomanic symptoms (i.e., when the diagnosis is 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] ECT may also be considered as a further-line option.[5]
For people with equally prominent manic and depressive symptoms (i.e., when the diagnosis is a DSM-IV mixed episode), 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.[226][236][247][171]
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] ECT may also be considered as a further-line option.[5]

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