Among psychiatric illnesses bipolar disorder (BPD) ranks second only to unipolar depression as a cause of global disability (1). Hospitalized patients spend approximately 20% of their lifetime from the onset of their disorder in episodes (2). Fifteen per cent of sufferers commit suicide. Much of this disability reflects depressive episodes which are more frequent and of longer duration than the manic episodes. The traditional Krapaelinian view of BPD is of an episodic illness with little residual deficit. However, recent studies indicate that 30–60% of patients have significant psychosocial impairment during illness-free intervals (3). This impairment is more strongly predicted by the number of past depressive episodes than past manias (4). This may reflect recurrent depressive episodes contributing to persistent brain changes. If so, it further emphasizes the importance of aggressive prophylactic treatment particularly with regard to depressive episodes.

Despite its clinical importance, the treatment of bipolar depression is under-researched in comparison with mania and unipolar depression. This makes it difficult to formulate evidence-based guidelines and much of what follows reflects the consensus of opinion. Psychosocial interventions, although important, are outside our remit as are non-pharmacological treatments such as electroconvulsive treatment (ECT) and transcranial magnetic stimulation. Alcohol and substance misuse frequently coexist with bipolar depression and require treatment as they can maintain depression. Mania is used to refer to both hypomania and mania.

Antidepressants are effective in bipolar depression although the response rate is less than in unipolar major depression. Antidepressants can cause a switch to mania or the induction or acceleration of rapid cycling, defined as four or more episodes of illness in a 12-month period. These risks are greater with tricyclic antidepressants (TCAs) than with the selective serotonin reuptake inhibitors (SSRIs). In a review of bipolar trials the overall rate of switching to mania was 11.2% with TCAs, 3.7% with SSRIs and 4.2% with placebo (SSRIs vs. TCAs, P < 0.01) (5). Bupropion (6), venlafaxine and mono-amine oxidase inhibitors (MAOIs) also appear safer in this regard. We recommend avoiding TCAs where possible in BPD and certainly in those with rapid cycling.

For most bipolar patients the cornerstone of treatment is long-term prophylaxis with one or more mood stabilizers. If depression arises in a patient who is not prescribed medication one should consider commencing with lithium. Lithium is an effective antidepressant, more so in bipolar than unipolar depression. Furthermore, it remains the gold standard mood stabilizer with proven efficacy in the prevention of mania and depression (7) and as such it can be continued long-term. Lithium also possesses a specific antisuicidal effect (8). In severe depression it will usually be necessary to combine lithium with an antidepressant. Lithium provides protection against antidepressant-induced mania.

If depression arises in a patient prescribed with a mood stabilizer one should optimize the existing treatment, i.e. check compliance and consider increasing the dose of the mood stabilizer. The next step is to add a second mood stabilizer or an antidepressant. In a 6-week double-blind study of patients with bipolar depression treated with a mood stabilizer (lithium carbonate or valproate semisodium) the addition of paroxetine or a second mood stabilizer (lithium carbonate or valproate semisodium) significantly improved depressive symptoms (9). The dropout rate was significantly lower in the paroxetine-group partly reflecting better tolerability. A recent study suggested that adjunctive antidepressants are of most benefit in patients who cannot tolerate high serum lithium levels (10). In patients who require improved long-term prophylaxis, or who have rapid cycling, it is more appropriate to add a second mood stabilizer rather than an antidepressant. If the initial mood stabilizer is an anticonvulsant then lithium is the preferred mood stabilizer to add. Some evidence suggests that mood stabilizers, including lithium, valproate, and carbamazepine, lose efficacy over time and that this tendency is reduced when they are combined (11).

There is increasing interest in using lamotrigine, an established anticonvulsant, as a second line agent in bipolar depression, either as monotherapy or in combination with an existing mood stabilizer. Two randomized controlled trials have found lamotrigine monotherapy to be effective in bipolar depression and to have a low switching rate (12, 13). Gradual titration decreases the risk of skin rashes. If lamotrigine is added to valproate then a lower starting dose and slower titration are necessary as valproate can increase serum lamotrigine levels.

Failure to respond to an antidepressant should lead to an alternative antidepressant being tried, preferably one from a different class. MAOIs are effective in anergic bipolar depression although dietary restrictions and safety issues limit their clinical utility. In partial antidepressant responders augmentation with lithium or tri-iodothyronine should be considered. In rapid cycling patients with frequent depressions thyroid hormones can be used to augment mood stabilizers with or without an antidepressant. `Anecdotal' approaches to treatment refractory bipolar depression include combining a mood stabilizer with an atypical antipsychotic, inositol or a dopamine agonist, with or without an antidepressant.

When depression is accompanied by marked anxiety or insomnia, a short course of a high potency benzodiazepine, such as lorazepam or clonazepam, can be helpful. In psychotic depression one should add an antipsychotic and we favour the atypical agents; their antipsychotic efficacy is equal to conventional agents and preliminary evidence suggests that some atypicals possess antidepressant and mood stabilizing effects. In resistant depression, particularly with retardation and delusions, ECT is highly effective.

The optimal length of antidepressant treatment in BPD is unclear. Guidelines for unipolar depression recommend continuation treatment for 6 months after remission with maintenance treatment being considered for those with recurrent depression (14). Many clinicians favour shorter courses of treatment in bipolar depression (15) but this is not evidence based. The appearance of mania should lead to the antidepressant being stopped or reduced in dose, both strategies can abort mania (17). In other circumstances gradual withdrawal of antidepressants is advisable to minimize the occurrence of discontinuation or withdrawal symptoms (14). Abrupt stoppage of lithium can precipitate early recurrence of mania and depression. The risk is reduced by gradual discontinuation (16). Discontinuation phenomena have not been demonstrated with other mood stabilizers but one cannot assume that they do not occur as there has been little research in this area.

The treatment of bipolar depression must take account of many factors and as such needs to be on an individual patient basis. Educating the patient about their illness, involving them in treatment decisions and maintaining a strong therapeutic alliance are essential. Additional studies are needed to provide a stronger evidence base for the treatment of this common and disabling condition.

  1. This issue of Acta Psychiatrica Scandinavica also includes short biographies of Peter M. Haddad and Serdar M. Dursun.


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