Depression in bipolar affective disorder

A comprehensive update on the diagnosis and management of depression as it occurs in bipolar affective disorder

Bipolar affective disorder affects about 2 per cent of the population and is the sixth-leading cause of disability worldwide (Murray et al, 1997). It typically consists of both manic and depressive episodes separated by periods of normal mood.

Mania and depression were viewed as medical illnesses from the time of Hippocrates and there is a striking description of the condition we would call bipolar disorder from 200AD by Aretaeus of Cappadocia, where both mania and depression are seen as part of the same disease (Marneros, 2009).

Given the disruption caused by manic episodes, it is not surprising that less attention has been paid to the management of the depressive phase, even though most patients experience depressive symptoms three times as often as manic/hypomanic symptoms (Judd et al, 2002) (Baldessarini et al, 2010). The depressive phase contributes to significant functional impairment; for example, 80 per cent of patients with bipolar disorder experience some work-loss, and 30-to-40 per cent experience prolonged unemployment during adult working years, with much of that disability associated with depression (Zimmerman et al, 2010).

Clinical presentations and diagnosis of depression in bipolar affective disorder

According to the ICD-10, bipolar affective disorder is “characterised by repeated (ie, at least two) episodes in which the patient’s mood and activity levels are significantly disturbed, this disturbance consisting on some occasions of an elevation of mood and increased energy and activity (mania or hypomania), and on others of a lowering of mood and decreased energy and activity (depression)” (WHO, 2004). DSM V requires only one episode of mania/hypomania and has a further subdivision into Bipolar 1 and Bipolar 2, depending on whether there is a manic (Bipolar 1) or hypomanic episode (Bipolar 2) (Am Psych Assoc, 2013).

Only 25 per cent of patients with bipolar affective disorder will initially present with a manic episode (Turvey et al, 1999). Sixty per cent of patients will present with an initial depressive or mixed episode. This means that for over half of patients, we can’t know if their illness is part of a bipolar illness or a unipolar depressive illness when they initially present. That is why diagnosis can be delayed for up to 10 years in such patients (Mesman et al, 2013).

Presentation with an initial depressive episode also has implications for the clinical course. When patients present initially with a depressive illness, depressive episodes will dominate the clinical picture (Turvey et al, 1999). Similarly, where patients present with mania/hypomania initially, 75 per cent of their illness episodes will begin with mania/hypomania.

Case report 1

(This is not based on a real case, it is for illustration only)
A 29-year-old woman presented to her GP with severe low mood. She had been crying for days and had not left the house. She had spent a lot of time sleeping. When discussing her symptoms with her GP, she was irritable and restless. She had thoughts of not wanting to be alive and was hopeless. Her husband was worried about her, as he said that this was a big difference from her normal “outgoing and friendly” personality. The patient was not sure about family history but believes that her mother had a “breakdown” in her early 30s. The patient had a milder episode than this four years ago, for which she did not seek treatment. There is no clear history of mania or hypomania. This is the first time she has attended her GP and she has no known medical history. There is no known history of substance misuse or alcohol misuse. Blood tests including TFTs are normal. The patient was started on antidepressant medication but responded poorly. She was referred to psychiatry. She had three more episodes of depression over the next five years, all of which showed a limited response to antidepressants. Six years later, the patient presented with a hypomanic episode.

Discussion

At what point can a patient be diagnosed with bipolar affective disorder?
Using current diagnostic criteria, bipolar affective disorder is diagnosed when a patient presents with a manic/hypomanic episode. This means that the diagnosis can be delayed by seven-to-10 years. (Dagani et al).

What is the ‘bipolar spectrum’?

There is increasing recognition that many patients might not fit neatly into the category of bipolar affective disorder but still show features of mood cycling. This can be important, because such patients can have different clinical responses to antidepressant treatment and can benefit from a second-generation antipsychotic (such as quetiapine) or a mood stabiliser (such as lamotrigine) or lithium. These features are further explored in Table 1.

When there is no past history of mania/hypomania, can we tell if a depressive episode is part of a bipolar disorder or unipolar depression?

When there is no past history of mania/hypomania, there are no features that can allow us to reliably distinguish between depressive episodes occurring as part of a bipolar affective disorder and those occurring as part of a unipolar illness.

There are some features that increase the probability of a bipolar presentation and these are outlined in Table 1 (right). It is important to note that none of these are reliable enough to be predictive.

What percentage of people presenting with a depressive episode will go on to develop bipolar affective disorder?

Over a 10-year period, between 5-to-10 per cent of patients originally presenting with a depressive episode will be diagnosed with bipolar affective disorder (Angst et al, 2005). The percentage depends on clinical setting and is higher for those requiring inpatient admission than patients treated in the primary care setting.

Case report 2

(This is not based on a real case, it is for illustration only)
A father of four had been diagnosed with bipolar disorder at 53 years of age after he presented with mania. Up to that point, he had been noticing mood episodes for several years. These mood episodes were occasional short-lived episodes of depression. When he presented with mania, he was started on lithium and had been doing well for the past three years. A brain MRI performed at that time was normal. He now presents with an eight-week history of profound loss of enjoyment and feelings of being useless and worthless. He is spending most of the day in bed. On mental state examination, his speech and thinking appear slowed-up and he looks dishevelled. He had been working in a job requiring early starts, which he has since given up after he noticed that he could not sleep. Physical examination and medical investigations are unremarkable.

Was the age of presentation unusual for a first episode?

The usual age of onset of bipolar is between 20 and 30 years of age (Yasa et al, 1988). There is a smaller peak later in life, as in this case. It is thought that about 90 per cent have an onset before 50 and of the remaining 10 per cent, half will occur before 60 years (Depp et al, 2004). In later life, the presentation is often preceded by a few years where the mood has been up and down, with periods of low mood interspersed with short periods of milder hypomanic symptoms. An association between increased white matter hyperintensities and cortical atrophy has been reported (Depp et al, 2004).

Is this a mixed episode?

A mixed episode is where features of hypomania/mania and depression coexist. There are no clear mixed features in this case (Case 2), though Case 1 had some. Mixed states account for 15 per cent of episodes in bipolar disorder. They are important to recognise, as the treatment is more challenging and requires treatment of both sets of symptoms. Antidepressants can make mixed presentations worse by increasing agitation and irritability.

Table 1: Risk factors that increase the likelihood of bipolar affective disorder (Mitchell et al 2008, Schaffer et al 2010)

Risk factor	Comments
Family history of bipolar affective disorder	A positive family history of bipolar disorder is present in about 20 per cent of patients who will progress to Bipolar 1 presentation and 20 per cent who progress to Bipolar 2, and about 10 per cent of patients who persist with unipolar depression. A clear family history can sometimes be difficult to obtain and many times vague descriptions of ‘a breakdown’, or a hospitalisation, or of ‘a psychosis’, or of ‘taking to the bed’ are given. Family history of suicide is also important, as it can suggest a family history of bipolar disorder.
Any previous hypomanic episodes?	Collateral history is often helpful if available, as depressed patients often recall events in a depressive way and find it difficult to remember times when they felt better. In Case 1 described in this article, the patient’s husband described the patient as being outgoing. It would be helpful to get more detail on this. Did this behaviour occur in episodes, or was it more of a personality trait? If it did occur in episodes, it would be helpful to find out how long these periods lasted, were they associated with overspending or reckless behaviour, or pressure of speech, or lack of sleep. Did the ‘outgoing behaviour’ cross over into disinhibited behaviour? Sometimes there will be a history suggestive of a hypomanic episode or cyclothymia.
Premorbid personality	There is sometimes a pattern of ‘mood swings’ before presentation. This might be in the form of periods of increased excitability, or disinhibition, or friendliness. The episodes are not severe enough to qualify as hypomania or depression. This may also be part of a cyclothymic picture.
Age of onset	In general, the younger the age of onset of depressive illness, the more likely a bipolar picture will emerge.
Multiple prior episodes	More than five prior depressive episodes increases the risk of a bipolar affective disorder.
Atypical symptoms	Increased sleepiness and increased day-time napping . Increased appetite. ‘Leaden paralysis’ — a marked lack of energy.
Agitated symptoms	Depression with prominent agitation, anger, insomnia, irritability, and talkativeness can be suggestive of bipolar disorder.
Manic/hypomanic symptoms	In depression associated with bipolar affective disorder, the patient can have racing thoughts, increased agitation, pressure of speech and restlessness, but still feel very depressed.
Psychotic symptoms	These are more common in depression associated with bipolar affective disorder but can occur in both conditions.
Mixed affective states	These are presentations where symptoms of hypomania and depression occur in the same episode. These types of presentation are part of a bipolar presentation.

What is the risk of suicide in this presentation?

The risk of suicide is greatly elevated in episodes of bipolar depression. The standardised mortality ratio for suicide in bipolar disorder is estimated to be 15 for men and 22.1 for women (Osby et al, 2001), with most of this occurring in the depressive phase.

What is the rate of comorbid illness in bipolar disorder?

It is thought that bipolar disorder may be concurrent with another significant psychiatric illness in about one-third of patients (McElroy et al, 2001). The most common co-occurring illnesses are thought to be anxiety disorders and substance misuse disorders.

It is thought that bipolar disorder may be concurrent with another significant psychiatric illness in about one-third of patients

Treatment of depression in bipolar affective disorder

Although much of the focus in guidelines is on biological treatments, it is still very important to maintain a bio-psychosocial approach to the management of depression in bipolar affective disorder.

Table 2: Summary of physical treatments used in bipolar affective disorder (abbreviations used: NNT = number needed to treat and NNH = number needed to harm (for side-effects))

Medication

Evidence base

Comment

FDA approved and available in Ireland

Quetiapine IR/XR 300mgs or 600mgs	Largest evidence base of FDA-approved medications. NNT=6. (Calabrese et al, 2005, Thase et al, 2006, McElroyet al, 2010, Young  et al, 2010).	Sedation can be problematic and switching between IR and XR preparations can affect tolerability. Weight gain is also a concern. Also works against manic phase.
Olanzapine and fluoxetine in combination	This combination has been FDA approved — one large trial gave NNT=4 and a response rate of 56 per cent (Tohen et al, 2004, Brown  et al, 2006). Can be useful in clinical practice because olanzapine can reduce agitation or mixed features and then fluoxetine can be added.	Main problems are associated with weight gain and somnolence (NNH for weight gain is 5).

Not licensed for the acute stage but widely studied and widely used

Lamotrigine	Lamotrigine is licensed for longer-term treatment of bipolar disorder but only for the depressive phase. It has no anti-manic properties. NNT as monotherapy of 7. One trial used as an adjunct to lithium showed a response rate of 50 per cent and an NNT of 5 (van der Loos et al, 2009). May be more helpful in longer-term treatment (Bowdenet al, 2003).	Tends to be well tolerated. It takes time to titrate up to clinical dose and caution needed regarding development of a rash.
Lithium	Lithium is licensed for treatment of mania and recurrent depression. There is some conflicting evidence about usefulness in acute depression and it is under-studied in this regard.	Has not shown consistent evidence of usefulness in the acute stage. Nonetheless, is effective prophylactically against depression and can allow the addition of an antidepressant (see below).

Not licensed and less widely used

Pramipexole	Two small studies showed improvement, with an NNT of 2 (Goldberg et al, 2004, Zarate  et al, 2004).	Evidence is limited to these trials. Generally well tolerated but caution on emergence of impulse control disorders and occasionally psychotic symptoms.
Modafinil	Generally inconsistent results. Some small trials showing benefit (NNT of 4) but this was not replicated in larger trials (Calabrese  et al, 2014).	Can cause worsening of agitation. Stimulant medication — possible risk of abuse.
Valproate	Some evidence from a small trial that valproate used at a lower dose than in mania can be helpful (Davis  et al 2005).	Serious risks of teratogenicity and not recommended in women where this can be a concern. Also risks around weight gain.

Somewhat controversial

Antidepressants	See discussion above
ECT	Several trials showing benefit, with about 70 per cent of treatment-resistant presentations showing a response. Also effective against mania (Itagaki  et al 2017, Perugi  et al, 2017, Bahji  et al, 2019).	Generally well tolerated but public image and acceptability are a problem. Thought must be given to maintenance of benefit after treatment.

What biological treatments are available for the treatment of depression in bipolar affective disorder?

Table 2 summarises the pharmacological treatments of bipolar depression available for use in Ireland.

Should antidepressants be used in the treatment of bipolar depression?

There is some controversy on the use of antidepressants in bipolar disorder. Some studies such as the STEP-BD study found no benefit, but this study was limited, in that it was looking only at bupropion and paroxetine. (Sachs et al 2007). A further systematic review found a small benefit, but this study included one study with a very high placebo response rate, which if removed, would have shown a greater benefit (Viktorin et al, 2014). There has also been some evidence for the use of specific antidepressants such as venlafaxine for a short period of time (Amsterdam et al, 2016) in the treatment of bipolar depression.

The main risks with use of antidepressants include worsening of the condition and switch to mania/hypomania (Patel et al, 2015) where an antidepressant is used as monotherapy, but this risk seems much reduced when antidepressants are prescribed with a mood stabiliser (Viktorin et al, 2014).

In general, it is probably best not to use antidepressants on their own for depression in known bipolar disorder and combination with a mood stabiliser or second-generation antipsychotic (ie, quetiapine) can be considered. It is best to be cautious when using them with mixed features (ie, if there are racing thoughts, agitation, increased activity). In general, the use of antidepressants in patients with a rapid cycling picture should be approached very cautiously. When a patient is already on a mood stabiliser such as lithium or an anti-manic agent such as quetiapine, it allows more latitude in prescription of an antidepressant. The optimal medication approach can take time to figure out and given the complexity of the condition and trying to treat both highs and lows, polypharmacy can occur.

What psychosocial treatments can be used to treat bipolar depression?

The main psychosocial approaches to treatment include:

Identifying early warning signs

The relapse signatures associated with a depressive relapse can include signs such as becoming more withdrawn, losing interest in a hobby, or increased sluggishness.

Patients can also notice triggers to specific episodes. For example, in Case 2 (page 27), the person noticed a change to their circadian rhythm — this can predispose to either a depressive or manic episode. Other life events such as job loss or promotion, moving-house or loss of relationship can also precipitate an episode of either type.

Psychological therapy and/or occupational therapy

There is an increasing evidence base for the use of psychological therapies between episodes or when a person has recovered from the most severe depressive stage.

Behaviours can be important in managing illness episodes, such as avoiding over-stimulation leading to a manic episode or encouraging behavioural activation, when appropriate, in a depressive episode.

Cognitive behavioural therapy (CBT) can also be helpful, particularly when somebody has recovered from the most severe of the depressive symptoms. CBT can help deal with problem-solving and coping with some of the challenges posed by the illness.

Patients’ families can understandably be very worried when they see signs of bipolar depression. Patients can be aware of this and in turn try to hide their symptoms or minimise them. Illness episodes can in themselves be very stressful and this can lead to increased expressed emotion at home, which further increases the risk of relapse of depression in bipolar disorder

Psychoeducation and family involvement

Patients’ families can understandably be very worried when they see signs of bipolar depression. Patients can be aware of this and in turn try to hide their symptoms or minimise them. Illness episodes can in themselves be very stressful and this can lead to increased expressed emotion at home, which further increases the risk of relapse of depression in bipolar disorder (Yan et al, 2004). In secondary care settings, social workers are very valuable in addressing these factors.

In summary

Depression as part of bipolar disorder is common and associated with significant distress and functional impairment.

Given the complexity of the illness, it can take time to tailor the treatment for the individual patient and it is not unusual for a combination of different medications and psychological approaches to be used to achieve better outcomes.

Thankfully, as the knowledge base improves, so too does the potential to improve patient outcomes.

References on request