The evolution of polypharmacological treatment initiated in an acute phase of illness will depend upon the context of the presentation. Use of more than one medication in a first manic presentation may arise from the need to control a combination of agitation, possible psychotic symptoms and elevated mood. Acute control of disturbed behavior is an initial high priority with fine tuning of mood-stabilizing medication following thereafter. There is an acknowledged contrast between European and North American practice in this regard with antipsychotic medications being used in the former case initially, mood-stabilizing treatment being added in thereafter. North American practice is focused more on the rapid introduction and upward titration of mood-stabilizing medication in this situation. The situation where a patient already on maintenance treatment has suffered a manic relapse is clearly somewhat different as, provided medication compliance has continued, the initial mood-stabilizing regime is already established at the point of relapse, additional medications being added to this to control the acute illness dependent upon the nature of its presentation. Similarly, the order of instituting different treatment modalities for a depressive episode will be dependent upon the stage in illness course in which the patient presents. The most common and readily recognized circumstance would be that of a depressive phase of illness in an individual who has already experienced a manic episode and is thus defined as bipolar. Less easy to prepare for and define is the initial presentation of a bipolar patient with a depressive phase that will, by definition, be initially treated as a unipolar depression. The likely use of combination treatment in this scenario is when depressed mood alters to the opposite (i.e., elevated) pole. While discontinuation of the antidepressant will be the normal first step in such situations, recurrence of low mood may indicate the need for further treatment. Should a mood stabilizer alone be unsuccessful in achieving this, there is a clear logic to re-introducing an antidepressant in combination with it.
Bipolar I disorder, with comparable duration and intensity of manic and depressive swings, may warrant the addition of specific treatments for either pole of the illness on top of an established mood-stabilizing regime dependent upon the responsiveness and severity of those individual episodes of abnormal mood. Should the illness prove resistant to effective prophylactic monotherapy, there is clearly a need for prophylactic treatments to be combined.
Bipolar II disorder, by contrast, is often characterized by more lengthy and persistent depressive episodes and relatively time limited and/or mild elevations in mood. It can thus be conceived that combination treatment in bipolar 2 disorder is more likely to require longer-term use of an antidepressant should mood stabilizer use (single or multiple) be insufficient to effectively control both poles of the illness.
Rapid cycling bipolar disorder is denned by the occurrence of four or more affective episodes in a 12-month period and there is evidence to support better response of this subtype of illness to anticonvulsants, specifically valproate, than to lithium. Rapid cycling illness is often difficult to treat and thus might be considered a form of bipolar illness more likely to result in the institution of combination treatment aimed at gaining greater control of fluctuations in mood. The relationship here between combination treatments that include antidepressants is complex, as antidepressants may be required for effective recovery from depressive swings but, in their own right, may precipitate or worsen rapid cycling.
Phases of Illness
Acute manic or mixed affective presentations include, in varying combinations, elevated mood, agitation and overactivity, reduced need for sleep, and psychotic symptoms. Initial treatment would normally be with (following the European and North American tradition, respectively) an antipsychotic medication with a mood stabilizer then introduced or rapidly titrated sodium valproate or lithium with supplementation with an antipsychotic if necessary. Concurrent with this initial antima-nic treatment, there may be necessity for use of an hypnotic, benzodiazepines being generally preferred for this purpose. Benzodiazepines might also be necessary to further reduce the waking agitated state. Administration of all medications should normally be oral, but all the earlier-mentioned categories have specific drugs available for parenteral administration also in patients unwilling to accept oral treatment. The usual aim on gaining control of symptoms would be to gradually reduce combined treatment to arrive at maintenance medication with a single mood stabilizer. Both typical and atypical antipsychotics have antimanic properties in the acute phase. Continued symptoms in the face of adequate treatment with a first-line mood stabilizer or antipsychotic is an indication for the addition of further medication such as a second mood stabilizer or an antipsychotic in addition to the initial mood stabilizer. The combination of treatments for which most evidence exists is perhaps that of lithium and an anticonvulsant such as valproate or carbamazepine. Other investigated combinations with efficacy beyond that of monotherapy include those of a typical or an atypical antipsychotic with valproate or lithium.
Presentation of an individual already on established long-term treatment for bipolar disorder in a manic or hypomanic state will usually have treatment with any pre-existing mood stabilizer optimized and compliance ensured. Should such treatment prove inadequate, addition of an atypical antipsychotic or second mood stabilizer, as noted earlier, is appropriate.
Ongoing treatment resistance may warrant the addition of a third or subsequent antimanic agent with caution due to potential interactions.
Treatment of depression may be required in the following contexts. A patient may present with a depressive episode while not on mood-stabilizing medication but with a previous history of mania; alternatively, depression may occur within the context of pre-existing prophylactic treatment for bipolar disorder.
In the case of depression in an individual without prophylactic mood-stabilizing treatment, there is a significant risk of precipitating switch to mania if antidepressants are used unopposed by a mood stabilizer. Treatment should thus initially be with the establishment of mood-stabilizing/antimanic medication (lithium, an appropriate anticonvulsant or antipsychotic) along with institution of an antidepressant, most appropriately an SSRI, there being evidence to suggest that this group of antidepressants have lesser propensity to result in a switch to mania . Use of an antipsychotic in the depressive phase of illness is appropriate, particularly where psychotic symptoms themselves are present. Monotherapy with a mood stabilizer may be sufficient to treat bipolar depression, although the evidence for this is limited. There is some evidence for lamotrigine having a particular role in bipolar depression, with the aim of improving depressed mood without tendency to induce mania.
The occurrence of a depressive episode in a patient taking prophylactic mood-stabilizing treatment warrants an initial assessment to ensure adequate serum levels of mood stabilizer where appropriate. It may be possible to address precipitating stressors in a practical or psychological sense without the need for antidepressants, but should depressive symptoms be severe, or the earlier-mentioned maneuvers not be effective, addition of an antidepressant is appropriate. Revision of any preexisting antidepressant treatment should be considered as would be the case with unipolar depression, provided the protective presence of an antimanic agent is established. Detail of the relative merits of individual antidepressants in bipolar disorder has been reviewed in site. There is little evidence specific to the management of treatment-resistant depression in bipolar disorder, the recommendation for management of this thus being that it should be treated in the same way as unipolar treatment-resistant depression in the context of mood-stabilizing/antimanic medication.
The final broad area of treatment in which combination medication may be indicated is that of prophylaxis. Monotherapies have been dealt with in other chapters and it is the addition of subsequent treatments to these strategies that will be considered here.
An individual on a simple monotherapy regime for prophylactic treatment will inevitably encounter stressful situations or changes in day-to-day life that may increase the risk of an acute episode due to stress or, for example, disruption of sleep-wake cycles. In these circumstances, short-term addition of a benzodiazepine to aid coping with anxiety or, alternatively, as an hypnotic may be an effective strategy to increase prophylactic defenses against an acute episode of illness. Such strategies might also be useful to tackle very early signs of recurrence. For individuals where such medication is insufficient, particularly with regard to manic relapse, short-term adjunctive treatment with an additional antimanic agent (e.g., an antipsychotic) may be appropriate.
Where strategies of short-term adjunctive treatment are insufficient to prevent relapse, longer-term combination treatment is appropriate, the choice of medications being logically dictated by the predominant illness pattern experienced by the patient. Where mania dominates the character of illness episodes, the most appropriate combinations with initial mood stabilizers would be the addition of one or, if necessary, progressively more medications with defined antimanic properties. Lithium, valproate, and antipsychotics, particularly atypical antipsychotics, would be appropriate in this case. When recurrent illness is more frequently characterized by depression, a second mood stabilizer such as lamotrigine (more effect in the depressive than the manic phase of illness) is appropriate. Further propensity to depression might be treated by the addition of an antidepressant in the longer term, provided there was no evidence of an increased risk of the individual switching to mania when compared with the usual course of their illness.
As mentioned previously, rapid cycling bipolar illness is noted to be difficult to treat. Combination therapy in this situation may have both positive and negative aspects and requires close examination. Should antidepressants be thought to contribute to rapid cycling presentations they should be reduced and discontinued, further treatment focusing on combination mood stabilizer use. Choice of these medications should be guided by the character of relapses experienced by a patient. It is necessary to assess the benefit or otherwise of treatment regimes over a period (e.g., 6 months) that allows assessment of frequency of cycling.
Thyroid hormones: There is limited evidence only for the efficacy of supraphy-siological thyroid hormone use in bipolar depression specifically. The use of this as strategy for augmentation in unipolar depression, however, is well recognized and thus its role in treatment-resistant bipolar depression may be justifiable where other measures have been ineffective.
Use of depot typical neuroleptics has a limited place in maintenance treatment, particularly where concordance issues arise, and thus the combination of these agents with other drugs used in a more short-term role for either pole of the illness warrants note. There are yet no specific data relating to the recently launched depot atypical antipsychotic risperidone.