What is Missing in Treatment Guidelines?

Treatment guidelines for schizophrenia have been released in Germany by Global Public Policy Network and in the United States by the American Psychiatric Association. Careful attention to clinical trials data and other available information and thoughtful consideration in the absence of adequate data provide creditable and meaningful information to guide some aspects of therapeutics for individual cases. Concepts and available data are limits. Three issues may enhance the future development of treatment guidelines.

1. The conceptual framework for schizophrenia is inadequate for addressing therapeutics. Implications of schizophrenia as a disease are quite different from the concept of schizophrenia as a clinical syndrome. Data summarized in 1974 in the Schizophrenia Bulletin supported the syndrome status and rejected Schneiderian symptoms of first rank as marking the presence of schizophrenia as a disease.^1,2 The opposite direction was taken in Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) with first rank symptoms as the premier marker of schizophrenia and the presumption that heterogeneity was addressed. DSM-III and DSM-IV viewed schizophrenia as a disease, and regulatory bodies approved drugs for schizophrenia rather than the specific psychopathologies for which efficacy was compelling (think total Positive and Negative Syndrome Scale score). During the past decade or so, this view has dramatically shifted. DSM-5 states that schizophrenia is a clinical syndrome and provided 8 psychopathology dimensions to help shift from treating schizophrenia to addressing the individual profile of multiple aspects of psychopathology. National Institute of Mental Health, with the Research Domain Criteria Initiative paradigm,³ emphasized separable pathways to psychopathology often cutting across diagnostic boundaries. This is a substantially different paradigm for the discovery of mechanisms of psychopathology, a critical area where schizophrenia vs normal controls methodology has limited success. At the same time, the Hierarchical Taxonomy of Psychopathology program reconceptualizes the nature of psychopathology, viewing dimensions that include normalcy and providing a novel organization of psychopathology.⁴ Computational approaches with large data sets and minimal a priori assumptions will no doubt bring new concepts and new formulations of clinical and functional targets for therapeutics. The bipolar-schizophrenia network on intermediate phenotypes approach with meaningful input data demonstrates how clusters are mixtures of current diagnoses.⁵

2. While the field is now in a rapid change mode, current guidelines are necessarily bound to the science produced in the dominate schizophrenia as a disease framework. Breaking out is just beginning. A remarkable presentation of treatment of “primary psychosis” with over 20 distinct aspects of psychopathology and function addressed.^6,7 Regulator bodies will surely follow with consideration of specific psychopathology targets across diagnostic boundaries. It will be interesting when the clarity around which diagnoses share the same psychopathology mechanisms is worked out (eg, is anhedonia the same pathophysiology in major depressive disorder and schizophrenia?).

3. Addressing therapeutics in a transdiagnostic framework need no longer rely on off-label prescribing. New concepts in nosology and pathophysiology will expand the opportunity for discovery and clinical application. These final remarks address scientific failure to develop evidence for the efficacy and effectiveness of treatments for common clinical issues in schizophrenia. But the doctor has individual patients. There are many common questions without empirically supported answers. Continuous treatment works best for cohorts, but many patients will not accept continuous antipsychotic medication. And how does this universal recommendation fit with early age of onset, or an aging patient, or long-lasting remission, or with health-related adverse effect. And questions regarding optimizing dose for the individual remain unanswered.

Guidance for personalized therapeutics on the use of antipsychotic medications is quite limited, but why? Consider targeted drug therapy (TD), which was developed in the 1980s in part to reduce the risk of tardive dyskinesia by limiting antipsychotic (AP) medication to periods of exacerbation of psychosis. Scientific interest in this approach ended with continuous medication winning randomized clinical trial (RCTs) on relapse prevention and the concern for tardive dyskinesia reduced with second-generation AP medications. But nonadherence to continuous AP treatment is common and a TD approach would be preferred by some or many patients. A number of RCTs were reported and results and implication summarized.⁸ Our first RCT found that TD plus an interpersonal treatment strategy aimed at early detection of an exacerbation was similar to continuous medication regarding relapse, while a second study providing early detection in both groups found fewer relapses in the continuous medication group. But the clinical questions remain. Apart from reducing adverse medication effects, the TD approach may be superior in managing exacerbation compared to relapse occurring when the patient is simply noncompliant. What is missing in the field is good evidence for optimal approach to the subgroup of patients who decline AP medications; or the patient with a long time in remission or the patient who is late in life where reduced psychosis and increased adverse effects may outweigh the benefits of continuous antipsychotic medication.

Another study with patients receiving TD treatment compared 3 treatments at first signs of exacerbation: placebo, fluphenazine, and diazepam. Relapse was the outcome measure. Fluphenazine and diazepam were superior to placebo and similar in relapse prevention.⁹ Is this an option for relapse prevention in persons declining AP drugs? Why are replication studies not conducted?

At a time when dose reduction was seen as important, we did an RCT with patients on long-acting fluphenazine. For 52 weeks, we compared 2 weeks long-acting fluphenazine to a comparison group with placebo substituted for 2 out of every 3 injections. There was no difference in symptomatic course or exacerbation rates.¹⁰ This study also was not evaluated with further RCT, leaving clinicians without scientific evidence to modify dose and frequency.

These examples illustrate that information development for individual application in clinical practice has not attracted enough scientific evaluation and resources. The field seems content with evidence for efficacy for symptom and relapse prevention in controlled circumstances and fails to develop evidence for efficacy in common circumstances. The clinician and patient are left on their own to navigate many issues.