“Extended” Dosing in Schizophrenia: Must Medication Be Taken Every Day?

As a clinician treating schizophrenia, the 2 most difficult challenges I face are (1) the limited efficacy of the medications I currently have at my disposal and (2) getting people to acknowledge the illness and take their medications. Yes, I feel somewhat hypocritical at times harping on the need to take these medications when I recognize their limitations, but I also know that these same drugs are the crux of moving beyond acute psychosis. I am also fully aware of the dangers of relapse in not continuing treatment—so why muck around with the party line that effective maintenance therapy demands taking medication daily? After all, it is not so long ago that we threw out a similar challenge vis-à-vis the need to take antipsychotics indefinitely, only to be clearly reminded that this does seem to be the case for most patients.1

There are at least 5 lines of thinking that should have us challenge the requirement for daily antipsychotic administration.

1. We don’t know that you have to take the medication daily to maintain response. What we do know is that you have to take the medication regularly, that is without prolonged gaps,2–4 but what defines this is not entirely clear.
2. Recent evidence suggests that sustained exposure to antipsychotics may incur tolerance.5,6
3. These medications harbor significant side effects that impose medical (eg, weight gain, diabetes, tardive dyskinesia) and functional (eg, sedation, cognitive impairment) costs. While low-dose strategies may provide benefits across at least some of these dimensions, there is a low threshold beyond which relapse increases, so can we invoke further gains by attenuating overall exposure? Whether we can or we can’t, and for what side effects, represent unanswered questions.
4. It is common now to view schizophrenia as “heterogeneous,” best understood as diverse in terms of pathophysiology, presentation, course, and outcome,7 yet we insist on a “one treatment fits all” strategy from the standpoint of antipsychotic use.
5. In the current climate of health care, where fiscal demands routinely shape practice patterns, can nondaily dosing be an opportunity to diminish medication costs?

As has been noted, a strategy like “extended” antipsychotic dosing has its own potential pitfalls, not the least of which is the added complexity (ie, it’s simply easier to take medication every day versus every other day). Returning to the “heterogeneity” issue, it is also quite likely that there are those who will not do as well without daily dosing. Cynically, one could even argue that, given the estimated high rates of nonadherence associated with schizophrenia and antipsychotic use,8 it is better to advocate for daily dosing to buffer against a certain level of nonadherence that is likely to occur.

I’m not sure where “extended” antipsychotic dosing will take us, and, if accumulated evidence indicates it is misguided, let’s abandon it (as we did with “intermittent” dosing). But let’s not say we already know the answer or that we can be sure that the practical risks outweigh possible benefits to our understanding of schizophrenia and its clinical care.

Financial disclosure:Dr Remington is a consultant for Roche; has received grant/research support from Novartis, Neurocrine Biosciences, and Medicure; and is a member of the speakers/advisory board for Novartis.

References

1. Wunderink L, Sytema S, Nienhuis FJ, et al. Clinical recovery in first-episode psychosis. Schizophr Bull. 2009;35(2):362–369. PubMed

2. Herz MI, Glazer WM, Mostert MA, et al. Intermittent vs maintenance medication in schizophrenia: two-year results. Arch Gen Psychiatry. 1991;48(4):333–339. PubMed

3. Jolley AG, Hirsch SR. Continuous versus intermittent neuroleptic therapy in schizophrenia. Drug Saf. 1993;8(5):331–339. PubMed

4. Pietzcker A, Gaebel W, Köpcke W, et al. Intermittent versus maintenance neuroleptic long-term treatment in schizophrenia: 2-year results of a German multicenter study. J Psychiat Res. 1993;27(4):321–339. http://www.sciencedirect.com/science/article/pii/002239569390059B. http://www.gulfportpharmacy.com/xanax.html Accessed August 16, 2011.

5. Samaha AN, Reckless GE, Seeman P, et al. Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery. Biol Psychiatry. 2008;64(2):145–152. PubMed

6. Samaha AN, Seeman P, Stewart J, et al. “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci. 2007;27(11):2979–2986. PubMed

7. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 4: Clinical features and conceptualization. Schizophr Res. 2009;110(1–3):1–23. PubMed

8. Remington G, Kwon J, Collins A, et al. The use of electronic monitoring (MEMS) to evaluate antipsychotic compliance in outpatients with schizophrenia. Schizophr Res. 2007;90(1–3):229–237. PubMed​