Antipsychotic Medications: Enhancing Use to Improve Outcomes

The search for more effective and better-tolerated antipsychotics continues, a strategy that is important but also challenging.1,2 In the meantime, we still have much to learn regarding the drugs currently available and it would be unfortunate if we do not continue to address these gaps in knowledge. Almost 70 years of experience with antipsychotics suggests that there is little left to know regarding optimal clinical use. Regretfully, this is not the case—there remain numerous questions regarding clinical use as basic as dose, dosing, and switching. We highlight this point with recent evidence that advances our knowledge in these areas, at the same time calling into question current strategies that arguably have achieved the status of clinical dogma. The relationship between antipsychotic dose and efficacy, that is the “dose-response curve,” generally represents a hyperbolic curve, with the lowest dose significantly superior to placebo in terms of efficacy representing the “minimum effective dose (MED).” 3 Increases thereafter, during which efficacy may proportionally increase, capture “target dose,” and the dose where efficacy plateaus represents “maximum dose.” The majority of clinical guidelines related to pharmacological treatment of schizophrenia recommend use of target dose, which corresponds to 1- to 3-fold MED in acute treatment.4–6 In actual clinical practice, though, use of higher doses continues to be common, even in the absence of evidence.7 Two recent meta-analyses speak to this issue, one demonstrating that both efficacy and number of adverse events proportionally increase within 1- to 3-fold MED in a dose-dependent fashion.8 The second revealed that while dose-response curves differ between antipsychotics, increased efficacy dramatically diminishes above risperidone equivalent 3.7 mg/day, corresponding to 2-fold MED.9 Accordingly, evidence supports prescribing 2-fold MED in the acute treatment of schizophrenia if response is insufficient at MED. Numerous questions also surround maintenance dosing. This has, perhaps, best been captured more recently by the ongoing debate regarding antipsychotic discontinuation in individuals with schizophrenia.10 Unfortunately, this strategy is also associated with higher risks of relapse11,12 and symptom exacerbation.13 Although some patients with schizophrenia can maintain clinical stabilization without antipsychotic treatment,14 there are presently no established factors that accurately predict successful antipsychotic discontinuation.15,16 Intermittent or targeted antipsychotic treatment has been investigated but it too is associated with a greater risk of relapse versus maintenance treatment12,17 despite a lower relapse risk compared to placebo.17 “Extended” antipsychotic dosing may represent a promising option,18 but awaits larger controlled trials to confirm this. Given that relapse, even one, contributes to attenuated response,19 maintenance antipsychotic treatment represents the safest strategy in terms of clinical outcome. However, adherence to oral antipsychotics, measured by electronic adherence monitoring, is as low as approximately 70% in patients with schizophrenia,20 mainly due to lack of insight into illness21; if this is the case, use of long-acting injectable formulations is a reasonable option. At the same time, antipsychotics can induce various undesirable side effects, most of which increase in a dose-dependent fashion22; thus, clinicians should consider whether the dose that proved effective in acute treatment represents the dose necessary for maintenance. A recent meta-analysis demonstrated that antipsychotic reduction to chlorpromazine equivalent 200 mg/day, which corresponds to MED, is not associated with a higher risk of relapse but is linked to improvement in negative, extrapyramidal, and neurocognitive symptoms in stable patients with schizophrenia.23 If evidence of clinical worsening occurs, an increase back to the previous dose can alleviate the exacerbation.23 Antipsychotics are routinely prescribed once daily or in divided dosing if their plasma half-lives are ≥24 hours or <24 hours, respectively; however, neuroimaging work examining the relationship between dopamine D2 occupancy and response has challenged this notion.24 More recently, a systematic review summarized studies evaluating the time course of dopamine D2 receptor occupancy and antipsychotic blood concentrations, concluding that peripheral antipsychotic pharmacokinetics do not mirror what is observed centrally.25 More specifically, there was a slower reduction in central dopamine D2 occupancy compared to that observed in antipsychotic blood concentrations, regardless of antipsychotic type. In line with this observation, there are a number of randomized controlled trials (RCTs) comparing efficacy and tolerability between the 2 dosing regimens specific to risperidone (half-life: 23 h),26–28 olanzapine (half-life: 30–60 h),26 quetiapine (half-life: 7 h),29 asenapine (half-life: 24 h),30 and perphenazine (half-life: 8–12 h),31 although there has been only a single small study for quetiapine and asenapine. A recent meta-analysis combining these studies concluded that once daily antipsychotic administration is not inferior to divided dosing in terms of efficacy, while clinical superiority is observed for at least some side effects, eg, sleepiness.32 In terms of clozapine (half-life: 12–16 hours), a cross-sectional study involving 2 large academic settings indicated once daily administration in approximately 75% of patients, with no significant difference in positive symptom remission or risk of seizures versus divided dosing.33 It warrants comment, though, that peak and trough plasma clozapine concentration is higher and lower, respectively, in once daily dosing compared to divided dosing,34 and plasma clozapine concentration is associated with abnormal electroencephalograms.35 Taken together, evidence indicates that all currently approved antipsychotics, regardless of plasma half-life, can be prescribed once daily, preferably at bedtime given sedative effects, a strategy that may be advantageous in terms of side effects as well as medication adherence, which, in turn, can translate to improved outcomes. Switching antipsychotics is routine as clinicians seek to achieve adequate response while minimizing associated side effects. Whether switching to another antipsychotic is superior to increasing antipsychotic dose in patients with schizophrenia not responding remains unknown as only 1 small RCT36 was identified by a systematic review.37 Surprisingly, work specific to this topic has been limited to date and various strategies are observed clinically.38 In terms of existing antipsychotics, strategies can be classified as (1) abrupt or immediate discontinuation; (2) gradual discontinuation (ie, tapering over >1 d); and (3) wait-and-gradual discontinuation (ie, waiting >1 d after introduction of the new antipsychotic before tapering the existing antipsychotic over >1 d). Both gradual and wait-and-gradual discontinuation have been recommended when switching antipsychotics,39 given concerns regarding, in particular, dopamine-related withdrawal phenomena.40 At the same time, there is the evidence already noted indicating that reduction in central dopamine D2 receptor occupancy as a function of time is slower than what is observed with peripheral plasma levels,25 calling into question the risk of adverse events such as dopamine supersensitivity psychosis in the face of immediate antipsychotic discontinaution.25 In line with this, recent meta-analyses have demonstrated no significant differences in efficacy or effectiveness between immediate, gradual, and wait-and-gradual discontinuation in switching antipsychotics, except for all-cause study discontinuation, which favors wait-and-gradual versus immediate discontinuation.38,41,42 In addition, there were no significant differences in any adverse events, not just dopamine-related withdrawal phenomena. In terms of the new antipsychotic (ie, the agent being started), a recent meta-analysis found that immediate introduction was inferior to gradual introduction in terms of all-cause study discontinuation when switching antipsychotics.43 Summarizing, in switching antipsychotics the current antipsychotic can be immediately discontinued, particularly when it is necessary to undertake an urgent switch, while the next antipsychotic is gradually introduced. It should also be noted that there have been no RCTs to date comparing immediate versus gradual discontinuation of clozapine in switching antipsychotics. We conclude with 2 final points. First, while evidence is critical in guiding treatment decision making, this is not an endorsement of “cookbook” medicine. The goal is personalized medicine, and good clinical practice calls for evidence to be integrated with a careful consideration of differences in pharmacological properties of antipsychotics as well as patients’ clinical characteristics. For instance, clinicians should take into consideration individual factors that can affect plasma concentrations of antipsychotics such as pharmacogenetics and smoking. Second, we too embrace the notion that progress will bring significant advances in our understanding of schizophrenia, its complexity, and the varied approaches required to optimize both clinical and functional outcomes, including new drugs. Unfortunately, the nature of schizophrenia also translates to rates of progress that are slower than what we would wish. As we await these advances, it is no less important to ensure optimization of all treatments we currently have in hand. In the case of pharmacotherapy, decades of use may have lulled us into thinking that we know how to use these drugs, and this is not the case. H.T. has received speaker’s fees from EA Pharma, Kyowa, Janssen, Meiji Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomiyakuhin. S.L. has received honoraria as a consultant/advisor and/or for lectures from Angelini, Boehringer Ingelheim, Geodon Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, SanofiAventis, Sandoz, Sunovion, TEVA. J.M.K. has been a consultant or received honoraria from Acadia, Alkermes, Intracellular Therapies, Janssen, LB Pharma, Lundbeck, Merck, Minerva, Neurocrine, Otsuka, Roche, Saladex, Sumitomo Dainippon, Sunovion, Takeda and Teva. He has received grant support from Janssen, Lundbeck and Otsuka. He is a shareholder of LB Pharma and Vanguard Research Group. O.A. has received advisory board or consultant fees from Janssen-Ortho (Johnson & Johnson), Otsuka, Lundbeck, Sumitomo Dainippon Pharma, and Minerva Neurosciences; speaking engagement fees from Janssen-Ortho (Johnson & Johnson), Lundbeck, Otsuka, Mylan Pharmaceuticals, HLS Therapeutics, and Medscape; research contracts from Janssen-Ortho (Johnson & Johnson), Otsuka, Boehringer Ingelheim, Neurocrine Bioscience, Acadia, Syneurx, and DiaMentis. G.R. has received research support from HLS Therapeutics. He has received advisory board support from HLS Therapeutics and consultant fees from Mitsubishi Tanabe Pharma. None declared.

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