Treatment of bipolar depression

3.1 What is the best medication for depression in someone who has a history of mania (bipolar I depression)?

Giving antidepressants on their own to a patient with a history of mania is not to be recommended because antidepressants can precipitate mania (see Q 3.15).

Another reason to avoid monotherapy with antidepressants is that the commonest time to become manic is following an episode of depression and consideration should be given to how to prevent this happening. Although antidepressants are the mainstay of treatment for bipolar depression they should only be used in combination with a medication that will prevent mania (see Q 3.6).

The first line of treatment for bipolar depression is to consider increasing lithium or other longer term treatment, such as valproate or carbamazepine if this is possible.

3.2 Which antidepressants are the most useful?

The choice of antidepressant should be made in the light of previous treatment and response. Choose an antidepressant that has been helpful and safe in the past over one that has not previously been tried. Unfortunately there have been relatively few trials specifically for bipolar depression so a lot of practice is guided by studies of unipolar depression.

3.3 Which types of antidepressant are commonly available?

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used antidepressants in the UK. They are not only the first line treatment for unipolar depression but also the first line treatment for bipolar depression. Tricyclic antidepressants are also effective in the treatment of both unipolar and bipolar depression (Table 3.1).

The benefits of SSRIs over tryclics are that they are simple to take (usually once daily dosage) and the initial dose is usually an effective dose. In addition, SSRIs are less likely to cause manic switch than tricyclics (Table 3.2). In contrast the tricyclics require a gradual increase to an effective dose because of side-effects, usually over at least 2 weeks. The level of side-effects of SSRIs is low and they are relatively safe if taken in overdose.

There have been reports that agitation and suicidal impulses may be increased in the first few weeks on SSRIs (Medicines and Healthcare Products Regulatory Agency 2003). It is difficult to disentangle this effect from a deteriorating depression which is not responding to treatment, as suicidal thoughts are an integral part of depression (see Q 1.8).

Response to antidepressants is idiosyncratic and only a proportion (at best two out of three) of patients will tolerate and recover with treatment with SSRIs. The next line of treatment is usually a tricyclic antidepressant.

3.4 Are there any other types of antidepressant used in the treatment of bipolar depression?

There are other types of antidepressant, two of which are relatively little used in unipolar depression but have been studied in bipolar depression.

MOCLOBEMIDE

Moclobemide (Manerix) has been shown to be effective and to have a low propensity for ‘switch’ into mania compared to the tricyclic antidepressant imipramine (Silverstone 2001) (Fig. 3.1). Moclobemide is a monoamine oxidase inhibitor (MAOI) which often worries prescribers because of concerns about dangerous interactions with foods (the cheese reaction occurs when the amino acid tyramine passes through the gut without being broken down and leads to a rise in blood pressure). However, moclobemide is a specific inhibitor of monoamine oxidase in the brain and does not inhibit the form found in the gut. Tyramine can therefore still be broken down in the gut and so does not get through to cause a hypertensive reaction. Moclobemide is also a reversible inhibitor and is relatively short lived so there is only a short (days) wash-out period before another antidepressant can be started if there is a need to change treatment.

Fig. 3.1 Moclobemide versus imipramine in bipolar depression.

(Based on data from Silverstone 2001.)

BUPROPION

The other unusual treatment is bupropion (amfebutamone) which is not licensed in the UK for the treatment of depression. It is licensed in the UK (as Zyban) as a treatment to increase the success rate in giving up smoking. However, it is commonly used in the United States as an antidepressant at a dose of 300-400 mg daily for unipolar and bipolar depression. It is regarded as an effective treatment for bipolar depression (although trials to date have only been small scale) with a low risk of ‘switching’ the depression into mania. It may be worth considering if other antidepressants have not been successful or have been poorly tolerated but is usually only prescribed by specialists.

VENLAFAXINE AND MIRTAZEPINE

These drugs are similar in their pharmacological action to the tricyclic antidepressants clomipramine and amitriptyline. All of these drugs work on both serotonin and noradrenaline (norepinephrine) systems in the brain and they are considered to be the most effective antidepressants in unipolar illness if they are taken at a high enough dose. They should certainly be considered in bipolar depression if there is a poor response to other antidepressants.

LAMOTRIGINE

Lamotrigine, which is only licensed for the treatment of epilepsy, has been shown to be an effective treatment for bipolar depression. However it is not an easy drug to use. The main problem is that it can cause a rash (in about 10%) which occasionally progresses to Stevens-Johnson syndrome. This can require hospital care and is on rare occasions fatal. To reduce the chance of this allergic reaction occurring lamotrigine needs to be introduced very gradually.

Start at 25 mg daily for 2 weeks and then increase to 50 mg daily for the next 2 weeks. The dose can then be increased by 50 mg every 2 weeks, aiming for 200-300 mg daily according to side-effects and response. Because of the slow titration, it can take 3 months to reach an adequate dose and so this is unlikely to lead to a rapid response. However, it does also help to prevent recurrence of bipolar depression without increasing the risk of mania and so can be a very helpful longer term treatment. The usual reason that lamotrigine is prescribed is in manic depression that is dominated by depression which is difficult to treat. Lamotrigine can be introduced as a long-term measure to reduce the frequency and severity of depression and can lead to a considerable long-term improvement.

3.5 For how long should antidepressants be continued after recovery from depression?

The concern for bipolars who continue antidepressants is that they may be running an increased risk of mania while they are on this treatment. Because of this it would be recommended to discontinue antidepressants at an early stage after recovery from bipolar depression at about 3 months. This is in contrast to the advice for those with unipolar depression which is to continue the antidepressants for at least 6 months after recovery. Unipolar depressives are also often advised to take antidepressants long term as preventive treatment; however this would not usually be appropriate for bipolars.

For bipolars consideration needs to be given to effective long-term preventive treatment such as lithium (see Chapter 4). If they are to continue with antidepressants they must also take an antimanic drug, such as lithium, an antipsychotic or valproate (see Q 3.7).

3.6 Should bipolars continue on their long-term preventive treatment if they become depressed?

Definitely. It is very important that long-term prophylactic treatment (e.g. with lithium) is continued when the patient becomes depressed. This is because the depression is most likely being treated with antidepressants and if the lithium is stopped there is an increased chance of switching into mania (Fig. 3.2). Obviously at some point the patient will need to be reviewed to assess how effective the preventive treatment is, but the usual time to do this is after recovery from the acute episode of depression.

Fig. 3.2 Treatment with lithium in combination with antidepressants reduces antidepressant-induced manic relapse.

(From Prien et al 1984, with permission.)

3.7 Is there a role for long-term antidepressants as a way of preventing depression recurring in bipolars?

Taking an antidepressant on its own as a preventive treatment in bipolar I disorder is definitely not recommended. However, if an antidepressant has proved beneficial in combination with a mood stabiliser and the previous history has been of a preponderance of depression, then continuing antidepressants is likely to be a good strategy. It may also be worth considering other combinations or alternative mood stabilisers in this situation.

Many bipolar II patients are treated successfully in the long term with antidepressants without lithium or other preventive treatments. This usually follows on from a period of treatment with antidepressants that has been successful without a switch into hypomania. As long as an eye is kept on making sure that elated periods are not occurring, then this is a reasonable option. However, there is a need to be wary as many of those who suffer from hypomanias are not good at recognising them or tend to play down the problems that they cause. Ask someone else in the family if the patient is getting on reasonably.

3.8 What is the best medication for depression in someone who has a history of hypomania but has never been manic (bipolar II depression)

The mainstay of treatment for bipolar II depression is antidepressants, one option being the SSRI fluoxetine (Fig. 3.3). However, the initial decision to be made is whether to prescribe a drug that will prevent manic symptoms developing in addition to the antidepressant. This is a matter of judgement–at one end of the scale a patient who has had only short-lived and not disabling hypomania in the past is suitable for antidepressant treatment on its own but with monitoring for the appearance of manic symptoms. At the other end, someone who is currently depressed but with previous prominent, frequent and socially disabling hypomania should certainly be taking treatment to prevent further manic symptoms along with the antidepressant. Judging where a patient is on this spectrum is difficult and prescribing treatment often requires a lot of negotiation as many patients will be keen to relieve the depression but may not be concerned about hypomanic symptoms. It is usually the case that the manic depressive patient is very keen to relieve and prevent depression but the family (and others including doctors) are more concerned about the social disruption of hypomania.

Fig. 3.3 Treatment of depression with fluoxetine in bipolar and unipolar patients.

(From Amsterdam et al 1998, with permission.)

The choice of antidepressant for bipolar II depression is the same as that for bipolar I depression (Case vignette 3.1).

You need to be wary that treatment with an antidepressant on its own in bipolar II patients may be leading to more instability of mood or even rapid cycling.

3.9 What if the depression is not improving with antidepressant treatment?

The following questions should be considered before contemplating a change in medication:

Have you given the treatment long enough?: At least 4 weeks with no response, or 6 weeks with only minor response. It can be difficult to stick with the treatment when there is little improvement; a realistic time scale for improvement should be discussed with the patient from the beginning–it may well take up to 4 weeks to start to see a difference. It is also worth discussing at this point the balance between the time needed to give this treatment a good try against the time it will take to make a changeover to another medicine. Focusing on other ways that the patient can help to make a difference to the level of depression is also useful (see Qs 3.29 and 3.36).

Have you tried a high dose?: If the patient is not improving, doses should be increased to the maximum, provided that the treatment is reasonably tolerated before turning to an alternative antidepressant.

Have you assessed concordance/compliance?: Is the patient really in agreement with this treatment and taking it (see also Q 5.43)? Are they forgetting because they are feeling so tired, lethargic and can’t remember to do anything including taking the tablets? Is there some way of improving this–linking it with some more routine or habitual aspect of their life (e.g. brushing their teeth)?

Are they physically ill? (see Q 3.27): Specifically, are they hypothyroid or anaemic?

Are they drinking alcohol to excess or taking illicit drugs?

Is there another medication that they are taking that might be affecting their depression (e.g. steroids)?

Is there a social or relationship problem that could be addressed?

3.10 What are the next lines of treatment in bipolar depression that has not responded to the first antidepressant treatment?

If the patient is taking lithium in combination with the antidepressant, first increase the dose of lithium up to a level of about 1.0 mmol/l.

If this is not successful, continue the lithium but change the antidepressant to a different class of drug. It would be worth reviewing what treatments the patient has been on previously to see if it is possible to identify another drug that has been helpful in the past. If no clear treatment option is apparent the usual rule of thumb is that if the patient has been on an SSRI, change to a tricyclic and vice versa.

If the patient is not on lithium then this can be added as an augmenting agent as lithium in combination with antidepressants can lead to more improvement than the antidepressant on its own. (If these options are not successful, this is the stage where most experts are starting to scratch their heads too!)

Other options that are available include other groups of antidepressants, thyroid hormone (at above replacement levels), lamotrigine, tryptophan or electroconvulsive therapy (ECT) (see Q 3.22) (Fig. 3.4) and psychotherapeutic talking treatments (see Qs 3.20 and 5.46).

Fig. 3.4 Acute treatment of bipolar depression.

3.11 Is lithium an effective antidepressant?

Lithium can be an effective treatment for bipolar depression either on its own or in combination with an antidepressant. The first step in treating depression in a manic depressive who is currently on lithium is to check compliance, then the serum lithium level. If there is room to increase the dose of lithium, bearing in mind the blood level and the side-effects, then this should be tried initially unless the illness severity is very high and immediate antidepressant treatment is needed. If the patient is not on lithium, then again this can be a sensible first line treatment as it is likely to be required to prevent a manic swing if the patient is going to be taking an antidepressant.

3.12 Is the treatment for depression in the elderly different?

The same lines of medical treatment are useful for the elderly as for other adults. There is a paradox for the elderly that they are more sensitive to medications in terms of side-effects (probably because of reduced metabolism of drugs, and reduced excretion of lithium) but they also seem to be less responsive to medications and may actually require higher doses.

Physical illness is more likely to complicate treatment in older people which may limit the dose of medicines–for example cardiac disease may limit the dose, or even the prescription of tricyclic antidepressants. ECT is more commonly required in the elderly as they are more likely to experience psychotic symptoms, retardation and poor food and fluid intake.

3.13 Is the treatment for depression in adolescents different?

There are very few trials of treatment of bipolar depression but there are virtually no data on the treatment of bipolar depression in adolescents. There have been concerns that unipolar depression in this age group does not show a good response to antidepressant medication. This is difficult to reconcile with the data for adults which show a clear benefit in improving depression–is there some basic change in depression and its response to treatment at 18 (or 17)? There are also concerns that some antidepressants (SSRIs) can cause agitation and an increase in suicidal thoughts and behaviour, and that this effect is more marked in adolescents.

Psychological treatment is often recommended for non-bipolar depression in this age group, but unfortunately it is often not available. In bipolar depression there is little evidence to recommend psychotherapeutic approaches on their own.