Restricting study to medication-naive individuals with bipolar disorder is one strategy to avoid any potential confound of medication upon neuroimaging measures. This strategy would likely limit recruitment to small numbers of participants who may not be representative of the chronically ill bipolar populations managed in most clinical settings. The inclusion of only unmedicated individuals in neuroimaging studies in bipolar disorder necessarily involves withdrawing individuals from psychotropic medication, since maintenance treatment is usually required to decrease the probability of a relapse because of the recurrent nature of the disorder. For the individuals who are able to tolerate medication withdrawal and washout, there are clear benefits. These include not only the potential of identifying biomarkers of bipolar illness but also the opportunity provided by medication washout to identify biomarkers that may predict individual response to subsequent treatments without confounds of current psychotropic medication. There are other justifications for implementing medication withdrawal and washout. The process may decrease copharmacy, whose rational use is hampered by a lack of systematic research on its safety and efficacy (5
). Furthermore, there are instances in which psychiatric symptoms or physical side effects improve upon discontinuation of ongoing medications.
There are two difficulties inherent in medication withdrawal. First, withdrawing individuals from medication may increase the probability of relapse for individuals in remission and a worsening of clinical status for individuals experiencing an acute episode (6
). This may therefore make medication withdrawal clinically unfeasible for some individuals with bipolar disorder. A related problem is that the medication withdrawal period may need to be long to include both withdrawal itself and a subsequent medication-free washout period to ensure the absence of potential withdrawal phenomena that may confound neuroimaging measures. This may further increase the risk of relapse or a worsening of symptoms in individuals with bipolar disorder. It takes five half-lives to eliminate 97% and six half-lives to eliminate 98% of residual drug (7
). For medications with a long half-life, this translates into a washout period of several months. The clinical setting in which the washout and withdrawal are performed clearly plays an important role in the evaluation of the risk-benefit ratio of the procedure, and careful examination of the history of each individual is necessary to determine the level of risk and potential complications that the procedure would entail.
A second potential difficulty with medication withdrawal and washout is that it may carry the risk of selection of a subpopulation that is not representative of the bipolar population as a whole. Individuals with a history of severe manic or psychotic episodes, individuals with co-morbid anxiety disorders, and those with a high suicide risk or a high risk of dangerous behaviors may be underrepresented in subpopulations that are able to tolerate the washout procedure and remain medication free. Conversely, individuals with less severe symptoms are likely to be overrepresented in these subpopulations. For the development of new treatments for bipolar disorder, the most at-need group includes individuals with correctly diagnosed bipolar disorder yet who are poorly responsive or nonresponsive to existing treatments. These individuals with bipolar disorder are likely to be medicated and, as discussed above, may be unable to tolerate medication withdrawal. Biomarkers of bipolar illness and treatment response identified from neuroimaging studies of unmedicated individuals only may not, therefore, be generalizable to medicated groups. This limitation may reduce the usefulness of any putative investigations.
Some neuroimaging studies have been able to recruit unmedicated individuals with bipolar disorder type II (8
), small numbers of unmedicated individuals with bipolar disorder type 1 (9
), or unmedicated individuals in a first episode (10
) or with pediatric bipolar disorder (11
). Recruitment of large numbers of unmedicated individuals with bipolar disorder type 1 remains difficult, however. Indeed, the actual proportion of individuals with bipolar disorder type 1 excluded from neuroimaging studies because of an inability to tolerate medication withdrawal and washout has not been previously reported, probably because individuals with the disorder at higher risk of experiencing problems with withdrawal are usually not referred for study.