Combination Therapy in Bipolar Disorder

By | February 8, 2015

Monotherapy for bipolar disorder is well established as both acute and prophylactic treatment, the most familiar drugs used in these roles being lithium, sodium valproate, and carbamazepine. The choice of agent can be guided at least in part by the subtype of bipolar disorder, for instance, valproate possibly being more efficacious in rapid cycling illness than lithium. More recently, a literature is beginning to accumulate regarding the efficacy of other anticonvulsant drugs — although gabapentin does not have evidence to support this action — and also antipsychotic medication, particularly atypical antipsychotic drugs. Indeed, formal recognition of the value of such alternative agents in the treatment of bipolar disorder is now reaching the level at which, at least in the case of atypical antipsy-chotics, licenses are beginning to be granted to them specifically for this purpose.

The availability of an increasing number of medications with recognized mood-stabilizing capabilities opens an ever wider potential for their use in combination when a single agent has proved ineffective in either controlling acute illness or preventing illness relapse. A literature regarding combination treatment is gradually developing and informing practice, and an important trial of lithium and valproate as monotherapies and in combination is in progress, but, at present, empirical data remain scant.

A further aspect of bipolar illness often necessitating the use of more than one drug is a persistent depressive phase that is unresponsive to treatment with a mood stabilizer alone. Most clinicians will thus be familiar with the use of an antidepressant medication in combination with a mood stabilizer in the treatment of bipolar depression. Despite its frequent use, this is not a combination treatment without risk, with evidence suggesting the induction of both mania and increased frequency of cycling with antidepressants.

In an attempt to guide clinicians in the use of the ever more complex array of potential treatments for bipolar disorder, there have been published both expert consensus guidelines and, more recently, evidence-based guidelines that recognize both the type and strength of evidence for specific treatments and the international differences in the approach to drug use in this illness. There is relatively little work that attempts to systematically assess actual clinical practice in the treatment of bipolar disorder, and such evidence as does exist may be locality specific and/ or reflect evolving practice over time. That which does exist, however, gives some indication of increasing complexity of medication regimes in bipolar disorder but variability in the closeness of this to recommended practice and guidelines. This chapter will consider, in turn, reasons that combination therapy might be required, the relationship of such combination treatment to illness phase, potential risks of combination treatment, and finally a summary of advantages and difficulties relating to various potential combinations of medications.

Why Combine Treatment For Bipolar Disorder?

There are a number of situations in which combination treatment of bipolar disorder might be indicated. Such circumstances may be more or less common dependent upon the phase of illness considered and this is examined with specific regard to illness phase in the next section. In addition to treatment of the mood swings that characterize the illness, it may be necessary to add specific treatments for particular groups of symptoms such as agitation or psychotic phenomena. A particularly significant feature of manic illness that often warrants treatment in its own right is sleep reduction. The need for specific use of antidepressants in bipolar depression has been alluded to previously. Anxiety symptoms may accompany both the depressive and manic phases of illness and may warrant symptomatic treatment when prominent. A further need for progressively more complex medical treatment may be difficulty in establishing euthymia following an acute illness episode or difficulty in maintaining euthymia without frequent relapses.

Combination Treatments In Relation To Illness Subtype And Illness Phase

Hazards Of Combination Treatment

As with all complex pharmacological management, there is an increasing risk of the combined impact of side effects and of potential interactions between drugs as the number of medications taken by any individual progressively increases. Crosschecking of such possibilities and close follow-up of patients are thus essential, particularly when instituting new combination treatments. A number of possible problems warrant particular attention and should be considered alongside the potential advantages of the suggested combination therapies in the section on Drug Combinations.

Lithium combined with an SSRI may give increased risk of serotonergic side effects. Lamotrigine combined with valproate has a particular risk of increased likelihood of skin rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis. A number of anticonvulsants and antipsychotic medications have the propensity to cause bone-marrow suppression, and thus hematological monitoring is warranted in such cases. Carbamazepine, in combination with other drugs, presents the clinician with the problem of liver enzyme induction, and thus the potential for plasma levels of these concurrently prescribed agents to be lowered. Although use of antidepressants in the context of antimanic treatment reduces the risk of switch to mania, it does not remove this and thus careful monitoring is required when antidepressants are introduced. It would seem reasonable to select an antidepressant with a shorter half-life such that, should there be a need for discontinuation, clearance from the patient’s system will be reasonably rapid. Weight gain is a problem with many of the individual medications used in bipolar disorder, and combination treatment may thus compound this to an extent that patients may not tolerate. Prospective discussion of this issue is recommended, as is ongoing monitoring of weight and related concerns and ways in which they may be addressed. In embarking upon combination therapy there is a risk of progressive addition of medications — i.e., increasing poly-pharmacy — owing to some of those treatments employed being ineffective rather than incompletely effective. There can be no clear guidance on removal of apparently ineffective treatments when they have not yet been tried in combination with other drugs in a particular patient. Regular review of efficacy and tolerability with appropriate adjustments to medication regime is perhaps the only rational advice that can be given under such circumstances in a situation where specific evidence is lacking.

Drug Combinations

With an increasing number of drugs with available evidence to suggest efficacy in bipolar disorder, there is an ever-increasing number of potential treatment combinations that could be considered. Table: Recognized Benefits and Problems of 2-Drug Combinations in Bipolar summarizes potential benefits and recognized problems of a number of two-drug antimanic and/or mood-stabilizing combinations with specific reference to their use in bipolar illness. With any attempted combination therapy, it is essential that up-to-date information on known potential interactions be consulted. The risk of adverse effects and interactions clearly increases with the number of drugs combined, thus additional caution is needed when moving beyond the combination of two drugs, but it is hoped that the information given here will aid the choice of the components of combination therapies. This section does not attempt to give treatment algorithms — as this is a field that is developing rapidly a textbook is perhaps not the best place for such time-sensitive material. For additional guidance, the reader is referred to treatment guidelines currently in existence and to their subsequent revisions . The detailed nature of the individual mood stabilizers has already been considered in site.

Combinations of these drugs with others for antidepressant, anxiolytic, or sedative actions have been considered in principle in preceding sections of this post. For details of the drugs themselves and their indications, see site.

Other combination therapies are generally considered as add-ons to other regimes: thyroid hormone administration to supraphysiological (150% normal) levels (regardless of previous thyroid status) has some limited evidence for specific efficacy in rapid cycling bipolar disorder as an augmentation strategy. This is also recognized in expert opinion as having a role in non-rapid cycling illness also. Bone-density monitoring should be considered in post-menopausal women in whom such strategy is employed. Additional treatments that are occasionally employed as augmentation strategies in bipolar disorder but for which specific evidence is relatively weak or lacking include the use of calcium antagonists, omega-3 fatty acids, adrenergic antagonists, and tiagabine for mania and the use of dopamine agonists, omega-3 fatty acids, inositol, buspirone, and calcium antagonists in depression.


As in many illnesses, there is evidence to suggest that progressively more complex combination therapies are effective in gaining additional control of symptoms in patients who have been previously unresponsive or only partially responsive to treatment. Some strategies for such treatments are suggested here and are expanded upon in other treatment guidelines. Difficulty arises in that the more complex the treatment regime considered the fewer data specific to that combination that are available. There is an ongoing need for research into this area in order to inform practice in the future and it is an area in which evidence is likely to develop. A controlled trail of lithium and valproate as monotherapies and in combination is currently underway and may address more robustly the role of this particular combination in maintenance treatment. There is an obvious need for detailed discussion of combination therapies, their advantages, and disadvantages with the patients for whom they are being recommended, and while this section has dealt only with combination of pharmacological treatments, the role of psychological and psychotherapeutic interventions in bipolar disorder should be emphasized in its importance running alongside the drug regimes. Of particular relevance to combination drug treatment is evidence that work in a cognitive framework can increase concordance with medication regimes, thus optimizing the benefit derived from them at any particular level of complexity of treatment. A further treatment strategy that might also run alongside or as an alternative to combination medication therapies is ECT.

In conclusion, it should be acknowledged that, provided adverse effects and possible difficulties for a patient with any specific drug or combination of drugs allows, incremental complexity of combination treatment in bipolar disorder is warranted when adequate response to more simple treatment regimes has not been achieved.


Selections from the book: “Handbook of Bipolar Disorder: Diagnosis and Therapeutic Approaches”, 2005.