Bipolar disorder in adults: symptoms, diagnosis and management

Bipolar disorder, also known as bipolar affective disorder, is a chronic psychiatric condition. It is characterised by episodic extremes of mood, where people may feel persistently high or low for several days or weeks at a time^​1​. Approximately 2% of the UK population are estimated to be living with bipolar disorder, with over 40 million people thought to currently live with the condition worldwide^​2,3​. Diagnosing bipolar disorder is challenging owing to the range of symptoms that people may exhibit. Some symptoms of bipolar disorder are shared with other conditions, which has been shown to delay a correct diagnosis of bipolar disorder by six to eight years^​4​. 

Bipolar disorder is associated with impaired cognition and functioning. These symptoms can impact a person’s education or work^​5​ and has financial implications. In terms of the UK economy, bipolar disorder is estimated to cost around £6bn per year^​6​. 

People living with bipolar disorder have a decreased quality of life, with mortality rates widening when compared with the general population^​7​. The increased mortality rate is driven by several factors, including cardiovascular mortality and suicide. Around 15–20% of people with bipolar disorder eventually take their own lives^​7,8​. The burden of bipolar disorder is also significant for carers. Caregivers have been shown to have increased objective burdens, which include money and emotional burdens, such as grief^​9​. Consequently, correct diagnosis and treatment are important.

Pharmacy professionals have a vital role in ensuring patients receive optimal treatment for bipolar disorder. Where possible, pharmacy professionals should ensure that treatment choice is suitable, that patients are adherent with medication, that medications are monitored appropriately and that patients are counselled effectively on their medication. Mental health pharmacist prescribers have an additional role in reviewing a person’s response to medication and optimising prescriptions according to tolerability, efficacy and serum levels, where applicable. 

Aetiology

There appear to be several factors that contribute to the development of bipolar disorder. Genetics seem to have a large role, with family and twin studies showing a heritability of 85%^​10,11​. Identical twins have a 40–70% chance of developing bipolar disorder if their twin has the condition, while the risk for first-degree relatives is 5–10%. In addition, the risk for unrelated people is 0.5–1.5%^​12​. Genes affecting ion channels, neurotransmitter signalling and synaptic signalling pathways have been linked with bipolar disorder, and new potential therapeutic targets have even been identified^​13​. Epigenetics — where gene expression is affected as opposed to the genes themselves — also plays a part^​14​.

There are also environmental factors involved, such as emotional abuse, physical abuse and neglect in childhood^​15,16​. Psychological stress and significant life events, such as losing a family member, losing a job or becoming disabled, have been shown to contribute to the risk of developing bipolar disorder^​17​. Illicit substance use is often comorbid with bipolar disorder — although the causality of the relationship is still in question^​18​. 

Since medications can trigger mood disturbances, it is important to be aware of medications that could contribute to an acute episode. Steroids, including anabolic steroids, have been shown to contribute to both mania and depression^​19,20​, while levodopa^​21​ and antidepressants^​22,23​ have been shown to contribute to mania. Many medicines, such as beta blockers, have depression listed as a side effect^​24​. While that specific relationship is still being discussed^​25​, several drugs, such as hormonal contraceptives^​26​ and mefloquine^​27​, have demonstrated a causative relationship with depression.

Diagnosis

Bipolar disorder is diagnosed according to symptoms reported by the patient, their family and their friends. The condition is separated into two main subtypes: bipolar type 1 and bipolar type 2. 

For a diagnosis of bipolar type 1, patients must have experienced at least one episode of mania that has lasted for at least one week. Mania is characterised by^​28​:

• Elation or euphoria (i.e. feelings of intense happiness);
• Irritability;
• Increased energy and activity.

Several symptoms may accompany this, including^​28​: 

• Pressure of speech (i.e. talking excessively and rapidly, which is often impossible to interrupt);
• Flight of ideas (i.e. thoughts quickly shift to loosely associated topics);
• Grandiosity (i.e. an inflated sense of self-importance);
• Decreased amount of sleep;
• Distractibility;
• Impulsivity;
• Mood lability (i.e. rapid and excessive mood changes);
• Psychotic symptoms^​29,30​:
  • Delusions are false beliefs held firmly despite evidence of the contrary, separate from cultural and religious views. In bipolar disorder, these may be delusions of grandeur/grandiose delusions, where people may believe they have special powers, identity or wealth^​31​;
  • Hallucinations are perceptions in absence of a true external stimulus. These are often auditory but can also be visual, tactile, olfactory and gustatory.

For a diagnosis of bipolar type 2, both a hypomanic and a depressive episode must have occurred. Hypomania shares the symptoms of mania, but differs by the level of impairment in occupational or social functioning (i.e. patients experiencing hypomania may still be able to work, and relationships may not be strained, whereas those experiencing mania will have significant impairment to functioning) by the fact that it does not require hospital admission and the absence of psychotic symptoms^​28,32​. To be considered to have had a depressive episode, a person must present with a two-week history of^​28​:

• Depressed mood;
• Anhedonia (i.e. lack of interest or pleasure in activities).

In addition, the depressive episode may be accompanied by:

• Changes in appetite;
• Changes in sleep;
• Fatigue;
• Feelings of worthlessness or hopelessness;
• Inappropriate or excessive guilt, where someone believes a small misdemeanour should result in an objectively disproportionate punishment, such as stealing a chocolate bar as a child means they now deserve to be jailed);
• Poor concentration;
• Suicidality.

It is worth noting that the International Classification of Diseases, 11^th revision (ICD-11) does not mandate a minimum number of symptoms to satisfy the diagnosis of mania or hypomania. This differs from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), which requires at least three symptoms to reach a diagnosis^​33,34​. The ICD-11 and DSM-5 differ further on hypomania. The ICD-11 is less prescriptive on the minimum number of days required for the diagnosis, which simply states that symptoms must be present for “several” days, whereas the DSM-5 specifies that four days of symptoms are required. These subtle differences have been shown to have an effect on clinical practice. Using the ICD-11 criteria leads to a greater number of diagnoses for bipolar type 2 compared with the DSM-5^​35​.

Closely linked with bipolar disorder is cyclothymia, where patients still experience a fluctuation in mood but not to the extent that they meet the diagnostic criteria for a bipolar disorder^​28​. Within each of the bipolar disorders, the conditions can be divided further into rapid-cycling bipolar disorder^​36​ and mixed states^​37​. 

Differential diagnosis

Differential diagnosis is a challenge in bipolar disorder. An important element of the bipolar disorders, particularly bipolar type 2, is the depressive element. Depending on the order of the onset of symptoms, it could mean that patients are diagnosed with unipolar depression before bipolar disorder is recognised. A diagnosis of unipolar depression could lead to inappropriate treatment, with an antidepressant as monotherapy increasing the risk of a manic switch^​22​, where ‘switch’ refers to a sudden change from one mood episode (i.e. bipolar depression) to another of the opposite pole (i.e. mania or hypomania)^​38​.

If psychotic symptoms are present, schizophrenia is a differential diagnosis that can overlap with bipolar disorder. As well as presenting with hallucinations and delusions, schizophrenia can present with irritability, disordered thinking, distractibility, poor sleep and negative symptoms. Negative symptoms share similarities with depression, including flat mood, anhedonia and low energy^​39​. Schizoaffective disorder, if the criteria for both schizophrenia and a mood disorder (i.e. mania, mixed state or moderate-to-severe depression) are met within the same episode, could also be considered^​19​. There are subtle ways to differentiate the conditions. In bipolar disorder, psychotic symptoms are more likely to be mood congruent, while psychotic symptoms would not be expected to continue when mood is euthymic^​40​.

Non-pharmacological treatment options for bipolar disorder

Psychological interventions have a complementary role alongside medication and should be offered to patients with bipolar disorder. Psychological interventions include:

• Cognitive behavioural therapy (CBT): a therapy that teaches people to identify and challenge thoughts that cause psychological distress, negatively impacting behaviour and emotions^​41​;
• Interpersonal therapy: a time-limited therapy that looks at the impact of stressful life events on mental health, focusing on improving the relationships of the social supports around this^​42​;
• Behavioural couples therapy: a therapy that is aimed at improving relationships between partners^​43​.

People with bipolar disorder can experience significant guilt, shame and self-stigma owing to their actions when unwell. Third-wave psychological therapies, such as compassion-focused therapy (CFT) and acceptance and commitment therapy (ACT), emphasise emotions, mindfulness and acceptance, as well as improve the way patients view themselves, improve their relationships and reduce suicidal ideation^{​44–47​}. 

In addition, case formulations are a useful tool. A case formulation looks at the underlying causes that contribute to a person’s illness. It can benefit the patient by improving their understanding of themselves and their condition. Case formulations also benefit clinicians by providing further information, leading to more individualised and holistic care^​48,49​. There are many different formulation models used. 

The ‘5 Ps’ formulation model used in CBT focuses on^​48​:

• Presenting issues: the problems that someone is experiencing as a result of their mental health, including social, interpersonal and occupational problems;
• Predisposing factors: factors that increase a person’s vulnerability to developing a mental health condition, such as genetics, environmental factors and their personality;
• Precipitating factors: significant events that trigger the mental health condition, such as psychological stress or illicit substance use;
• Perpetuating factors: factors that maintain the current mental health problem, such as ongoing illicit substance use;
• Protective factors: strengths or supports that reduce the severity of the mental health condition, such as coping skills and social networks.

The ACT formulation model has six elements^​50​:

• Experiential acceptance: non-judgemental awareness of private experiences, such as thoughts, feelings and memories;
• The present moment: focusing on sensory experiences in the current situation;
• Values: defining important goals and views to help drive direction and decisions;
• Committed action: actions that move the person towards achieving their values;
• Self as context: viewing yourself externally and understanding that thoughts and feelings do not define or change core beliefs;
• Cognitive defusion: being aware of the process of thinking, rather than the content of the thoughts, to reduce emotional burden.

The CFT formulation model focuses on^​51​:

• Emotional memories (e.g. in bipolar disorder, this could be someone having an affair during a manic episode);
• Key fears (e.g. a fear that a person may become unwell and have another affair, losing their family as a result);
• Safety strategies (e.g. avoiding leaving the house, sticking to routine, doing anything to keep family happy);
• Unintended consequences (e.g. social isolation, lack of autonomy and control);
• Self-to-self relating (e.g. worthlessness, guilt and shame).

As well as psychological interventions, a healthy lifestyle can also help maintain good mental health. Disturbed sleep can often be a precursor, or symptom, of both bipolar mania and depression. With that in mind, patients should be encouraged to regulate their sleep cycle^​52​. A routine that includes exercise should be promoted^​53​ — although evidence for the benefits of exercise in bipolar disorder is scarce^​54​. Dietary intake has an important role in bipolar disorder. In terms of physical health, people with bipolar disorder are more likely to develop cardiovascular disease and should be encouraged to have a healthy diet^​7,55​. In terms of mental health, supplementation with omega-3, folic acid and zinc has been associated with improved depressive symptoms but may not impact mania^​55,56​. Bipolar disorder has a strong correlation with alcohol and illicit substance use. Substances should be avoided, where possible, and monitored carefully if being used^​18,57​.

Pharmacological options in bipolar disorder

The choice of treatment depends on several factors:

• The state of bipolar disorder (i.e. manic or depressive);
• Whether it is for prophylactic or acute treatment, medication used in prophylaxis, such as lithium or lamotrigine, may take time to titrate to an effective dose and delay effective treatment. An acute episode is often treated with antipsychotics owing to their quick action^​52​;
• Whether someone is already taking medication for bipolar disorders, where possible, treatment should always be optimised first before introducing new medication in order to reduce polypharmacy. 

The usual medicines used in bipolar disorder are antipsychotics, mood stabilisers and antidepressants.

Antipsychotics

Antipsychotics mainly exert their effect through dopamine D₂ antagonism. First-generation antipsychotics, or ‘typical’ antipsychotics (e.g. haloperidol), act solely as dopamine D₂ antagonists, although they may still bind to other receptors, such as muscarinic M₁ and adrenergic α₂, causing unintended side effects. Second-generation antipsychotics, or ‘atypical’ antipsychotics (e.g. olanzapine), comprise those that are not solely dopamine D₂ antagonists. The current second-generation antipsychotics are predominantly dual-mechanism dopamine D₂ and serotonin 5-HT_2A antagonists^​58​. 

However, there are outliers that do not fit either category. Although often labelled as a second-generation antipsychotic, aripiprazole — the third-most-prescribed antipsychotic drug in the UK in 2023^​59​ — acts as a dopamine D₂ partial agonist^​58​.

Mood stabilisers

‘Mood stabilisers’ refer to lithium and certain antiepileptics used in bipolar disorder, which are mainly valproate and lamotrigine. The mechanism of action for these medicines in bipolar disorder has not been definitively confirmed but is likely to involve glutamate antagonism and gamma-aminobutyric acid enhancement^{​60–63​}. 

Lithium requires regular haematological monitoring, as it has a narrow therapeutic window. The usual range is 0.4–1.0 mmol/L^​52,64​:

• Lower lithium levels (0.4–0.6 mmol/L) are often reserved for older patients;
• Mid-range lithium levels (0.6–0.8 mmol/L) are used for acute treatment and long-term prophylaxis;
• Higher lithium levels (0.8–1.0 mmol/L) are reserved for patients who have relapsed while taking lithium, or for those who did not respond adequately to lower levels. 

While the levels are a useful indicator of therapeutic effect, it is important to treat the patient and not the level — for example, someone requiring acute treatment may respond well to a level of 0.4mmol/L, and there would be no need to increase the dose and the level to the 0.6mmol/L– 0.8mmol/L range.  

Levels above 1.5 mmol/L indicate toxicity^​65​. Dehydration is a risk factor for lithium toxicity, so it is important that patients maintain adequate fluid intake^​66,67​. Lithium is primarily renally excreted. Medicines that impair renal function also increase the risk of toxicity^​68​. Common medicines that interact with lithium include non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors and diuretics^​24​. Regular monitoring of renal function is recommended because of lithium’s nephrotoxic properties^​69​. In addition, regular monitoring of thyroid function and calcium are also advised because of lithium’s propensity to cause hypothyroidism, hyperthyroidism and hyperparathyroidism^​65​. The lithium therapy information pack and record book, also known as the purple book, are useful tools to help patients keep track of when their blood tests are due, monitor the results and remain informed about lithium’s general side effects, as well as symptoms of toxicity^​70​. 

There are two main forms of valproate available in the UK^​71​: sodium valproate (e.g Epilim; Sanofi), which is only licensed for epilepsy,^​72​ and semi-sodium valproate (e.g. Depakote), which is only licensed for use in bipolar disorder^​73​. Sodium valproate and semi-sodium valproate are both metabolised into valproic acid, which is responsible for the therapeutic effect^​74​. As semi-sodium valproate contains a higher equivalence of valproic acid than sodium valproate does, a 10% dose adjustment is recommended if changing from one to the other (i.e. semi-sodium valproate 1,000mg daily would be roughly equivalent to sodium valproate 1,100mg daily)^​74,75​.

Although valproate remains a useful medicine for bipolar disorder, its use is declining as we understand more about its risks. Valproate use in women who are pregnant has been shown to significantly increase the risk of congenital malformations and neurodevelopmental issues in the unborn child^​76​. A link has also been seen in men, who are now advised to use contraception if they have taken valproate within the past three months^​77​. Owing to these risks, Medicines and Healthcare products Regulatory Agency (MHRA) guidance on valproate safety measures, published in 2024, states that all female patients aged under 55 years who are still of childbearing potential must complete an annual risk acknowledgement form and be enrolled into the pregnancy prevention programme^​78​. Men must also complete a risk acknowledgement form, although this is currently on initiation only. To provide further assurance, both risk acknowledgement forms require two specialists to independently review the case and agree on valproate’s use^​78​. 

Although lithium, valproate and lamotrigine are known collectively as ‘mood stabilisers’, they each play a different role in bipolar disorder. Lithium is known to work for both mania and bipolar depression; valproate is predominantly used as an anti-manic medication; and lamotrigine use is limited to bipolar depression^{​52,58,74,79​}.

Antidepressants

The evidence for antidepressant use in bipolar depression is largely lacking, with only fluoxetine — specifically in combination with olanzapine — having good evidence for its use^​52​. Non-fluoxetine antidepressants can still be used in bipolar depression; however, it is worth noting that data for an antidepressant’s efficacy in bipolar depression is extrapolated from the evidence for unipolar depression^​74​. 

Antidepressants should be used carefully in bipolar disorder — particularly when used as monotherapy —  owing to the risk of causing a manic switch^​22​. If an antidepressant is required, it is advised that it is accompanied by a treatment for mania^​52​.

All antipsychotics, mood stabilisers and antidepressants for bipolar disorder should be initiated by secondary care services. Once a patient has been established on treatment, primary care can take over prescribing from secondary care, in accordance with local guidance. If the patient remains open to secondary care services, then secondary care should hold responsibility for optimising medication. If the patient has been discharged back to primary care, then primary care may amend medication doses according to tolerability and response, if the prescriber is comfortable doing so. If not, advice from secondary care should be sought. Referrals on how to optimise medications should be sent to the community mental health teams, according to local pathways.

Pharmacological management of mania and hypomania 

Despite the difference in severity, the treatment for mania and hypomania is the same. If a patient experiences mania or hypomania, it is important to review any antidepressants, particularly those that are being used as monotherapy. Dual-action antidepressants (i.e. serotonin–noradrenaline reuptake inhibitors and tricyclic antidepressants) have a greater associated risk of inducing a manic switch compared with selective serotonin reuptake inhibitors^​52​.

Treatment decisions will differ according to whether or not the patient is already receiving any pharmacological treatment for bipolar disorder.

If the risks are high and acute, then patients should be referred to the local crisis resolution and home treatment teams. These teams provide intensive community support and act as gatekeepers who can further assess the acuity of the situation and request for an acute inpatient bed, if required. If the risks are low, patients should be referred to the community mental health team for further assessment, treatment and review. Referral pathways differ depending on the locality, so pharmacists should be aware of their local procedures around who can refer and how to do so.

Patients not already receiving treatment

For those experiencing an acute manic or hypomanic episode and not already receiving medication for bipolar disorder, an antipsychotic is recommended as a first-line treatment. The National Institute for Health and Care Excellence (NICE) guidelines on bipolar disorder, published in 2014, recommends the first-generation antipsychotic haloperidol and the second-generation antipsychotics olanzapine, quetiapine and risperidone^​79​. 

The choice of antipsychotic is determined by several factors, including patient preference and side-effect profile. Compared with second-generation antipsychotics, first-generation antipsychotics are more likely to induce extrapyramidal side-effects (EPSEs). A patient may present with^​24,74​:

• Akathisia – feelings of restlessness;
• Dystonia – muscle spasms, leading to abnormal movements and posture. Torticollis and oculogyric crisis are acute, while severe forms of dystonia require urgent medical attention^​80​;
• Parkinsonism – symptoms mirroring those of Parkinson’s disease, including slowed movement, stiffness and rigidity;
• Tardive dyskinesia – involuntary and repetitive muscle movements, which are often orofacial (i.e. grimacing, lip-smacking, tongue protrusions)^​81​.

It is worth noting that second-generation antipsychotics may still cause EPSEs. In addition, second-generation antipsychotics are associated with a greater risk of cardiometabolic side effects, including weight gain, diabetes, dyslipidemia and hypertension^​82​.

If the initial antipsychotic is ineffective or intolerable, a trial with an alternative antipsychotic is advised. If the second antipsychotic trial is unsuccessful, a mood stabiliser should be considered. Lithium should be considered as the first option; however, its use relies on regular haematological monitoring. In addition, patients who have impaired renal function at baseline, such as elderly patients, may not be suitable. Valproate is an alternative to lithium; however, as described previously, MHRA guidance must be followed^​79​. 

Patients already receiving treatment

Patients who are already receiving treatment may experience an acute episode for several reasons, such as social, occupational or economic stress, illicit substance use and non-adherence with medication, which require further medication intervention. 

For patients having an acute episode who are already receiving treatment, current medications should be optimised up to the maximum licensed doses, according to tolerability and response. For those on lithium, the levels should be checked first to ascertain whether there is any scope to increase the dose further^​79​.

If optimisation of the current treatment is insufficient, the guidance for patients not receiving treatment should be followed.

Pharmacological management of bipolar depression

Patients not already receiving treatment

For patients who are experiencing a moderate–severe episode of bipolar depression and not receiving treatment, first-line options are the combination of fluoxetine and olanzapine, or a combination of olanzapine, quetiapine or lamotrigine as monotherapy^​79​.

If an antipsychotic is indicated, the choice should again be directed by patient preference and side-effect profile. However, quetiapine and olanzapine are structurally similar antipsychotics^​58​ and have similar propensity for causing most side effects, including weight gain, akathisia, sedation and QTc interval prolongation^​83​. 

If lamotrigine is chosen, a careful titration, which may take several weeks, is required upon initiation, owing to its potential for causing serious skin reactions, such as Stevens–Johnson syndrome^​24,84​.

Patients already receiving treatment

For patients who are receiving treatment, current medications should be optimised up to the maximum licensed doses, according to response and tolerability. For those on lithium, the levels should be checked first to ascertain whether there is any scope to increase the dose further^​79​.

If optimisation of current treatment is insufficient, the guidance for patients not on treatment should be followed.

Ongoing management

It is not uncommon for patients to remain on treatment for bipolar disorder as long-term prophylaxis. The medication and doses used depend on patient preference and the nature of their illness — for example, how often the patient experiences an acute episode, how many relapses have occurred in the past, whether the patient is at risk of relapsing and what doses have been successful as prophylaxis^​79​. If medication is stopped, then it must be reduced gradually over a minimum of four weeks but preferably three months^​24​, owing to the risk of relapse following abrupt cessation^​85,86​.

For prophylaxis, lithium is considered a gold standard, owing to strong evidence for its efficacy against both manic and depressive relapse^​52​. If lithium was not used during the acute episode, it should be offered as an option for long-term treatment. 

If lithium is not suitable, an antipsychotic is advised. Often, this will be the antipsychotic that was used during the acute episode. However, antipsychotic choice for prophylaxis is not limited to the four antipsychotic options advised for a manic/hypomanic episode, nor the two antipsychotic options advised for a bipolar depressive episode^​79​. With more options, further consideration can be given towards side-effect profile and tolerability. Aripiprazole is often a suitable long-term option, owing to its low risk of metabolic side effects and EPSEs^​83​. However, aripiprazole presents with a high rate of akathisia, with up to 25% of patients experiencing this side effect^​87​.

Should neither lithium nor antipsychotics be effective, valproate can be used in conjunction with either treatment. Valproate can also be considered as monotherapy^​52​.

Physical health monitoring 

People living with severe mental illness, which includes schizophrenia, psychosis and bipolar disorder, have a significant gap in health quality when compared with the general population. Life expectancy is significantly reduced, which has been mostly attributed to preventable physical illness^​88​. All people living with severe mental illness are entitled to an annual physical health check^​89​. In addition, long-term treatment with antipsychotics or mood stabilisers may increase the risk of physical issues. Patients on these medications should be monitored in accordance with licensing, NICE guidelines and the British National Formulary^{​24,79,90​}.

While physical health monitoring is important, be aware that acutely unwell patients may not be able to comply with baseline monitoring. In these situations, the risks and benefits towards the patient must be carefully weighed up.

Table 1: Antipsychotic physical health monitoring^​79,91​

Table 2: Lithium physical health monitoring^​65,79​

*’Stable’ refers to at least two consecutive levels within range at the same dose.

Table 3: Valproate physical monitoring^​79​

Summary

• Bipolar disorder is treated differently depending on the current state (i.e. mania/hypomania or bipolar depression);
• If a patient is experiencing an acute episode, review medications to see whether they could be contributing. Be particularly alert for antidepressant monotherapy in someone experiencing mania or hypomania;
• Ensure patients are adherent with medication and are monitored appropriately. Be aware that acutely unwell patients may not be able to comply with baseline monitoring;
• Counsel patients effectively on their medications, including potential side effects, interactions with common medications and the need for long-term monitoring, to ensure that patients can make an informed decision about their treatment;
• If valproate is used, ensure that the relevant risk acknowledgement forms have been completed.