Clinical Assessment and Management of Bipolar Disorder – Summary of RANZCP and BAP Guidelines

DSM-5 CLASSIFICATION OF BIPOLAR DISORDER

Bipolar disorders are defined by the presence or history of mania/hypomania, which distinguishes them from depressive disorders.

Not all patients experience mania/hypomania and hence the DSM-5 has attempted to subtype the various presentations.

Please see the criteria and diagnostic interview questions for a manic episode. 

The critical difference between a hypomanic episode and manic episode is the duration (see below), and that hypomania is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalisation.

If psychotic features are present, the episode is considered to be a manic episode.

A hypomanic episode is defined in DSM-5 as persisting for at least four consecutive days, whereas a manic episode lasts for one week.

According to the DSM-5 definitions:

1. Bipolar I disorder – at least one manic episode must be presented, although major depressive episodes are typical but not needed for diagnosis.
2. Bipolar II disorder – at least one hypomanic episode and one major depressive episode needed for diagnosis.
3. Cyclothymic disorder – hypomanic and depressive periods that do not fulfill criteria for hypomania or major depression for at least two years.

Other specified bipolar and related disorders include:

• Short duration hypomanic episodes and major depressive episode.
• Hypomanic episodes with insufficient symptoms and major depressive disorder.
• Hypomanic episode without prior major depressive disorder and short duration cyclothymia.

Rapid cycling disorder – the presence of at least four mood episodes that meet criteria for mania, hypomania or major depression within 12 months.

The mixed features specifier diagnosis – either manic, hypomanic or depressive comingled with 3 symptoms of the opposite pole. The mixed state clinical features and guidelines for management were summarised in this interactive CPD module.

KEY FACTS OF BIPOLAR I AND BIPOLAR II DISORDER

Bipolar I disorder (BD-I):

• Lifetime prevalence of bipolar disorder is 0.06%.
• It affects both genders equally.
• Mean age at diagnosis is late twenties.
• Mean age of onset is late teens.
• The ratio of manic to depressive episodes is 1:3, indicating a higher preponderance of depressive episodes.
• 50% of Bipolar disorder I patients experience a recurrence in two years.
• Bipolar I is associated with a significant risk of suicide.
• Bipolar disorders also have ADHD as a comorbidity more often.

Bipolar II disorder (BD-II):

• Bipolar II disorder has a lower lifetime prevalence and is more common in females than males.
• The primary age of onset is 29 years.
• Risk of suicide is as high as in BD-I.

DIFFERENTIATING BETWEEN UNIPOLAR AND BIPOLAR DISORDER

Since many patients with a bipolar disorder initially present with a depressive episode, differentiating bipolar depression from unipolar depression is challenging. This distinction, however, is vital as undetected bipolarity has a high degree of morbidity.

Approximately 20% of individuals with bipolar disorder having a depressive episode are diagnosed as bipolar disorder within the first year of treatment.

Individuals who only ever experience depression are usually described as having a major depressive disorder. However, there are patients who may experience depression who may still have a bipolar trait present.

In the majority of cases, individuals with bipolar disorder experience several episodes of depression before developing hypomania, and for most people with bipolar disorder, the predominance of depressive episodes continues through the course of the illness.

Bipolar depression is the predominant and most disabling component of both BD-I and BD-II with patients spending a considerable proportion of their lives with syndromal or subsyndromal depressive symptoms.

Although there are no definitive diagnostic criteria that distinguish bipolar and unipolar depression, Pies provided a mnemonic checklist (WHIPLASHED), that can be clinically useful in detecting bipolar disorder when patients present with depression. [4]

 

Furthermore, we also summarised the recent guidelines on major depressive disorder with mixed features, providing guidance on the management of depressive mixed states; a condition that is more likely to lie along a bipolar trait than along the lines of a unipolar depressive disorder.

CLINICAL MANAGEMENT OF BIPOLAR DISORDER

Broadly treatment modalities can be divided into:

Biological

The main biological treatments used are:

• Antipsychotic medications (AP)
• Mood stabilising agents (MSA)
• GABA agonists (e.g., benzodiazepines)
• Antidepressants
• Neurostimulation
• Complimentary therapies

Psychological

The main psychological treatments used are:

• Cognitive Behavioural Therapy (CBT): Focuses on the relationship between thoughts, behaviours, and emotions to reduce symptoms and manage relapses.
• Psychoeducation: Aims at empowering patients in becoming experts in managing their disorder by enhancing compliance with medication and stabilising moods.
• Family-focused therapy (FFT): Improve communication and problem-solving skills in the family. Also addresses high expressed emotion (EE) which is a risk factor for relapse.
• Interpersonal Social Rhythm Therapy (IPSRT): A combination of interpersonal therapy (addressing losses, role conflicts, role disputes and other interpersonal problems) with behaviours aimed at stabilising circadian rhythms via stabilising social rhythms (e.g., regular sleep-wake times through the week).

Phases of treatment

1. Acute manic phase.
2. Acute depressive episodes.
3. Long-term treatment – continuation and maintenance phase.

 

 

MANAGEMENT OF ACUTE MANIC EPISODE

Acute mania can be a medical emergency and may need the use of mental health legislation.

The types of  treatments that are used in acute manic episodes include:

1. Dopamine antagonists/partial agonists.
2. Mood stabilisers – Lithium, Carbamazepine, and Valproate.
3. Combination of a Dopamine antagonist drug with Lithium or Valproate in acute mania.
4. GABA Modulators.
5. Electroconvulsive therapy (ECT) in refractory mania.

General Principles

1. Taper and cease any agents with mood elevating properties. E.g., antidepressants, stimulants.
2. Institute general measures such as reducing stimulation, lowering activity level, delaying the individual from making important decisions and maintaining a structured routine.
3. Dopamine antagonists and partial agonists have been shown to be superior to Lithium or Valproate alone when combined with Lithium or Valproate. Combination treatment can thus be considered, especially when patients show breakthrough mania with the first agent.
4. Psychosis occurs in approximately 60% of episodes of acute mania. Antipsychotics may be used as an adjunctive treatment for acute psychotic symptoms if not already being administered as an antimanic agent (second generation APs preferred).
5. Dopamine antagonists and partial agonists, such as Aripiprazole, Haloperidol, Olanzapine, Risperidone, and Quetiapine are effective in the short term reduction of symptoms.
6. GABA modulators such as Benzodiazepines are useful adjunctive agents to assist with agitation or to induce sedation or sleep.
7. For patients who suffer a manic episode while taking long-term treatment, the first step is to optimise the current medication, for example: with Lithium, check the serum concentrations. These should be within the target range of 0.6-0.8 mmol/L.  Concentrations of 0.8-1.0 may be more effective but carry a greater risk of harm if continued long term.
8. If the patient is taking Lithium, consider adding a Dopamine antagonist, a partial agonist or Valproate. If the symptoms are inadequately controlled with optimised doses of first-line medication, and their mania is very severe, then consider adding another medication.
9. ECT is an important treatment option in case of delirious mania (medical emergency) and severe treatment-resistant mania.

 

TREATMENT OF ACUTE DEPRESSIVE EPISODES

Acute depressive episodes can be divided into De Novo (New onset) or Breakthrough Depression

De Novo Depression:

• Medication naïve
• To commence treatment for the first time
• Stopped taking prescribed treatment

Breakthrough Depression:

• Become unwell while taking treatment
• Recently commenced treatment, which is still being titrated and they are yet to respond

The main choices of medications include:

1. Antipsychotic medication (APs)
2. Mood stabilisers (MSAs)

The approach that can be considered is either

1. Monotherapy
2. Combination

Monotherapy:

There can be considered to be a total of six options:

1. APs: Quetiapine, Lurasidone, and Olanzapine
2. MSAs: Lithium, Lamotrigine, and Valproate

The specific combination of Olanzapine/Fluoxetine is also evidence-based but is not classified as monotherapy, as it is not available as a single agent in some countries.

ECT

ECT is indicated for patients with high suicidal risk, treatment-resistant psychosis, severe depression during pregnancy or life-threatening illness associated with not eating or drinking.

Psychological Treatments

Family-focused therapy, cognitive behavioural therapy, and interpersonal social rhythm therapy can shorten the acute depressive episode.

Combination Therapy:

• The second generation antipsychotics are an effective monotherapy option when added to other mood stabiliser or antidepressants.
• Lithium can be combined with all other monotherapy options.
• Valproate, similarly, can be combined with other options but caution should be exercised when combining with Lamotrigine and should be cautioned in women of child bearing age.

Antidepressants in Bipolar Depression

Antidepressants can be added to all effective monotherapy options, with the exception of Lamotrigine. According to the RANZCP guidelines-

Regarding the prescription of antidepressants in the treatment of Bipolar I depression, these should be avoided if there has been 1 – 2 manic symptoms as part of the depressive episode, or of psychomotor agitation or rapid cycling is a feature of the illness, or if there is a history of antidepressant use, mood elevation or ongoing active substance use.

Thus antidepressants should be avoided in the presence of following variables:

• Bipolar I Disorder
• History of rapid cycling and/or a
• High level of mood instability
• Mixed States

 

 

The evidence of the use of Antidepressants in Bipolar Depression was summarised by Gitlin; [Gitlin, 2018]

• The efficacy of antidepressants in bipolar depression remains unproven.
• When added to mood stabilisers, antidepressants are not associated with increased treatment-emergent affective switch (TEAS).
• No consistent evidence has demonstrated cycle acceleration in bipolar patients on modern antidepressants (especially with mood stabiliser co-treatment).
• Bipolar II patients may be treated safely (at least in the short term) with antidepressants.
• A subset of bipolar patients, both bipolar I and II, will need a maintenance regimen of mood stabilizers plus antidepressants and will not show mood instability with this regimen.

TREATMENT OPTIONS FOR BIPOLAR II DEPRESSION

The evidence base for treatments in Bipolar II disorder is still emerging, and most of the data is extrapolated from Bipolar I disorders.

In clinical practice, Quetiapine and Lamotrigine are the most commonly used medications.

The mood stabilising agent, Lamotrigine, seems to have greater efficacy for Bipolar II depression than Bipolar I.

Use of antidepressants in Bipolar II depression:

According to RANZCP guidelines:

Antidepressants should be used with caution in bipolar depression.  Always co-prescribe with a mood stabilising agent and with very close mental state review, given the risk of destabilisation in some patients.

However, this potential hazard needs to be balanced against the reality that in clinical practice many bipolar patients appear to benefit from antidepressants and the risk associated with refractory depression. 

Mood stabiliser monotherapy is therefore preferable if it provides adequate control of the depressive phase, the short and long term risks of iatrogenic elevated states are averted.

In relation to the antidepressant-induced switch, SNRIs and TCAs are associated with a higher risk of switching and therefore, if prescribed, should always be prescribed with a mood stabiliser. Other antidepressants would be considered preferable, particularly ones that have sleep cycle restoration benefits, such as Agomelatine.

 

LONG TERM TREATMENT (CONTINUATION AND MAINTAINENCE PHASES)

Aims of long-term treatment: 

• Maintaining mood stability
• Achieving complete functional recovery
• Providing long-term prophylaxis
• Reducing attraction to euphoria and enhanced abilities of past hypomanic states
• Building resilience and improving quality of life (QoL)

Since compliance with medication is linked to efficacy and tolerability, individualising medication choices are important. Below is a slide that shows the efficacy and tolerability of medications used in maintenance therapy in bipolar disorder.

The diagram below shows medications used for maintenance therapy in bipolar disorder lying on an axis of efficacy from mania to depression.  Medications towards the bottom of the axis have greater efficacy in depression while those at the top of axis have greater efficacy in mania.

General principles of long-term treatment in bipolar disorder:

1. Lithium monotherapy is effective against manic, depressive and mixed relapse and has better evidence for the prevention of new episodes than other agents and has more substantial evidence base documenting the risks of prolonged exposure.
2. Lithium is also associated with a reduced risk of suicide in patients with bipolar disorder.  The target serum level range is 0.6-0.8 mmol/L.  Lithium concentrations above 0.8 mmol/L are associated with increased risk of renal impairment, especially in women.
3. Valproate has a weaker evidence base; however naturalistic data indicates its effectiveness as a prophylactic agent.
4. Carbamazepine is less effective as maintenance therapy than Lithium, but it can be used as monotherapy if Lithium is ineffective. There are significant pharmacokinetic interactions with Carbamazepine and Oxcarbazepine may be considered instead due to its lower potential for such interactions.
5. In Bipolar I disorder, Lamotrigine will usually require a combination with an antimanic long-term agent.
6. Lamotrigine and Quetiapine may be considered as long-term monotherapy in Bipolar II disorder.
7. If the patient fails to respond to monotherapy and continues to experience subthreshold hypomanic and depressive symptoms, then two antimanic agents can be combined, for example Lithium, Valproate, Dopamine antagonist or Dopamine partial agonist.
8. When the burden is that of depression, a combination of Lithium, Lamotrigine, Quetiapine, Lurasidone or Olanzapine would be more appropriate.
9. Consider continuation of Clozapine in refractory mania.

Carer’s Guide to Bipolar Disorder (Click on the image below to begin your download)

TREATMENT NONRESPONSE

We covered the management of treatment-resistant mania in the section above on management of acute manic episode.

Below is a diagram that summarises the main steps in managing treatment-resistant bipolar depression.

Other options for treatment resistance:

• Brain stimulation approaches: rTMS
• Adjunctive strategies: thyroid hormones, glutamate antagonists, intravenous ketamine, Modafinil, Armodafinil.
• Complementary therapies – Omega fatty acids, N-acetylcysteine (NAC). You can view the video by Prof Berk on the role of NAC in Bipolar disorder
• Adjunctive nutraceuticals – chelated mineral formula, L-Tryptophan, magnesium, folic acid and branched chain amino acids.

CONCLUSION

The aim of the summary is to assist busy clinicians in navigating the complexity of managing bipolar disorder with the goal of reducing the significant disease burden around the world.

This guideline is best combined with the CPD module on Major Depressive Disorder with mixed features which contain mechanisms of actions (MOAs) and side effects of antidepressants and antipsychotics.

A summary of the commonly used 21 antidepressants can help in individualising the choice of antidepressant therapy.

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