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16. Antipsychotics: Clinical Effectiveness
Keywords
Large pragmatic trialsCATIEEvidence-based psychiatryClinical guidelinesSymptomatic remissionAntipsychotic selectionAntipsychotic switchAntipsychotic discontinuationAntipsychotic withdrawalShared decision-makingQuality of lifeMorbidity and mortalityEssential Concepts
Good clinicians know the clinical trials literature in their area of practice in order to provide evidence-based care wherever possible. Meta-analyses and network meta-analyses are important tools that summarize the evidence base from clinical trials. Guidelines are another source of information that synthesized the literature. You still need clinical judgment to determine how a particular guideline recommendation applies to the patient in front of you.
Large pragmatic trials such as the seminal Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) have ushered in a new appreciation of antipsychotics, both of what they can achieve and also their limitations.
Treatment goals directly related to antipsychotics include reducing the symptoms of schizophrenia, increasing quality of life, and preventing iatrogenic morbidity and mortality.
Antipsychotics are selected based on individualized risk-benefit assessments (balancing psychiatric stability with day-to-day tolerability and long-term medical morbidity, particularly cardiovascular risk). To find the best medication for a patient usually requires sequential trials in a collaborative manner.
Include long-acting antipsychotics in the list of first-line choices to routinely offer your patients, not only to those who refuse medications.
Switching antipsychotics to reduce long-term cardiovascular risk can be an appropriate clinical decision, albeit at the risk of psychiatric instability. Both immediate drug discontinuation and gradual discontinuation over several weeks are possible strategies during a switch.
Knowing how to stop an antipsychotic is as important as knowing how to start one. Antipsychotic discontinuation syndromes are not as well described as SSRI withdrawal.
Shared decision-making empowers your patient to be an active participant in treatment decisions. However, not all decisions are created equal, and physicians need to differentiate between life-or-death decision, best-choice decisions, and preference-sensitive decision and act accordingly. Coercion is only acceptable in life-or-death decision.
Quality of life is an independent treatment target that is determined by clinical variables (depression, medication side effects) and unmet needs (financial insecurity, lack of housing, loneliness unemployment).
Our patients deserve the safest treatment possible. Minimizing iatrogenic morbidity and mortality from our treatments is an important treatment goal.
“Plus ça change, plus c’est la même chose.”
(“The more things change, the more they stay the same.”)
– Alphonse Karr, French critic, journalist, writer, editor of Les Guêpes where the epigram was published in 1849 [1]
The previous three chapters introduced the antipsychotics and reviewed their motor and nonmotor side effects. In this chapter, I summarize clinical lessons learned from the last 20 years of clinical antipsychotic trials, particularly regarding their clinical effectiveness and how these lessons inform important clinical decision such as the choice of antipsychotics or switching antipsychotics. “Clinical effectiveness” contrasts with efficacy. You can view efficacy as working under ideal conditions with homogeneous subjects (in a clinical trial), whereas effectiveness is working under real conditions with real patients (in the clinic). Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) was the first effectiveness trial for antipsychotics that enrolled typical clinic patients with as few exclusions as possible [2]. I will describe CATIE in more detail as it became the model for subsequent trials in schizophrenia that try to answer real-world questions and are not mostly conducted for regulatory approval [3].
Evidence-Based Prescribing
The arrival of second-generation antipsychotics (SGAs) in the early 1990s led to great excitement among both patients and psychiatrists. Although this optimism might seem naïve and unbridled today, it is important to remember that psychiatric drug development had made little (some would say no) progress beyond chlorpromazine at that time, even though the limits of dopamine antagonists, both in terms of efficacy and side effects (i.e., tardive dyskinesia), had become painfully clear. SGAs quickly became the treatment of choice. However, almost all data supporting the superiority of SGAs over FGAs (according to the adage, newer must be better) had come from industry-sponsored drug trials, and some become convinced that the claims of superiority of SGAs were the result of comparing SGAs to what are today considered excessive haloperidol doses [4]. Others found somewhat better efficacy for some (clozapine, olanzapine, and risperidone), but not all SGAs, compared to FGAs, consistent with the heterogeneity of SGAs [5]. Clinicians also started to notice that SGAs (while having a lower risk for tardive dyskinesia) had shifted the side effect burden to metabolic problems.
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)
To remedy the lack of independent and generalizable data, the National Institute of Mental Health (NIMH) decided to sponsor a large, randomized trial, CATIE, comparing the SGAs available at the time (olanzapine, quetiapine, risperidone; ziprasidone was added after the trial was at about the midway point; aripiprazole as the first third-generation partial dopamine agonist was not yet available) with each other and with a fairly low dose of the mid-potency antipsychotic perphenazine (Phase I). In all, 1493 patients were recruited from more than 50 representative sites in the United States and followed double-blind after randomization for 18 months. The main outcome variable was all-cause discontinuation, a summary measure combining efficacy and tolerability. The focus of CATIE on effectiveness (to understand how a drug performs in real-world settings in all-comers) was rather different than the typical pharmacologic efficacy trial (in which drug effects are studied under ideal conditions in highly selected, homogenous populations). CATIE patients who failed their initially assigned treatment because of lack of efficacy could go on to a second phase that included treatment with clozapine. The main results of Phase I were disappointing: only 26% of subjects completed the trial on their initially assigned antipsychotic, pointing toward major effectiveness problems with available antipsychotics [2]. Moreover, contrary to expectations SGAs were not better than perphenazine, including for cognition [6]. Phase II confirmed the superiority of clozapine over available SGAs [7].
Another effectiveness trial conducted in Europe, CUtLASS 1 (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study), similarly found older FGAs (in particular one not available in the United States, sulpiride) as effective and as well tolerated as SGAs [8]. In the end, the SGAs might not have been the major advance for all patients they were once hoped to be. In one treatment satisfaction survey, however, patients were more satisfied with their psychiatric care if they received more recent antipsychotics [9]. In an effectiveness trial named Neuroleptic Strategy Study or NeSSy that allowed some patient choice regarding their treatment, patient-reported quality of life was higher in patients taking SGAs compared to FGAs [10].
Key Point
Large, simple (practical) trials like CATIE attempt to answer one important clinical question by enrolling large numbers of subjects in randomized trials in typical treatment settings. Such trials are often generalizable as opposed to the subjects studied in clinical trials who are often unique and not representative of the world of real medicine (e.g., no substance use allowed).
Clinical Trials Beyond CATIE
Lessons from clinical antipsychotic trials
All antipsychotics have limitations in the real world with regard to efficacy, tolerability, or both; this leaves many patients unwilling to take them in the long run. It has been disappointing that drug development has failed to meet the unmet need with a medication for negative symptoms or cognition |
Type and severity of side effects differ between all antipsychotics, particularly between second- and third-generation antipsychotics; they should therefore not regarded as one class, and patients should have access to all of them to individualize their treatment since no single antipsychotic is optimal for all, or even most, patients [13] |
Olanzapine and clozapine are the most effective antipsychotics but also the antipsychotics with the highest risk for metabolic side effects. Both continue to be needed, particularly clozapine which remains the only antipsychotic with efficacy in treatment-resistant schizophrenia (see Chap. 12) |
Managing long-term metabolic side effects has become a key concern with second-generation antipsychotics. Switching antipsychotics to metabolically lower-risk antipsychotics [12] or adding metformin [11] has become a standard intervention to reduce iatrogenic cardiovascular risk (see Chap. 25) |
Tardive dyskinesia (TD) has not disappeared albeit the risk with newer antipsychotics is lower. New treatments (VMAT-2 inhibitors) offer a better treatment option for patients with TD (see Chap. 14) |
Preventing schizophrenia by intervening early (during the prodromal phase) has become an area of intense interest although no medication has been shown to alter the long-term trajectory of beginning schizophrenia. The optimal pharmacological management in first-episode patients has been characterized, particularly the importance of preventing a second episode of psychosis (see Chap. 11) |
The mode of antipsychotic administration matters since potentially effective antipsychotics have no clinical effectiveness if not taken. Long-acting injectable antipsychotics have emerged as an important treatment tool for all patients (see Chap. 18) |
In addition to an explosion of the sheer number of clinical trials as psychiatry has become a truly international endeavor, major advances in our knowledge in the past 20 years have increasingly used the tool of meta-analyses and, more recently, network meta-analyses (“meta-analyses of meta-analyses”) [14]. Meta-analyses allow for the compilation of similar small trials to increase the power to detect a treatment effect. Network meta-analyses (or multiple treatment meta-analyses) go one step further and allow for the comparison of medications even if they were never directly tested against each other in any of the trials included in the analysis [15]. The resulting evidence is quite indirect, and no statistical maneuver can substitute for a well-conducted clinical trial of enough power that directly answers a specific clinical question. Meta-analyses provide you with a quick summary of the clinical trial literature but provide no guidance how the findings apply to your practice, if at all.
Treatment goals for schizophrenia
Domain | Treatment goal |
|---|---|
Symptomsa | Sustained remission |
Function | Optimal role function |
Quality of lifea | Comfortable life despite illness and treatment burden |
Meaning | Purposeful life in society despite illness |
Mortalitya | Life expectancy of general population |
Tip
Good treatment guidelines summarize the literature based on the strength of the evidence and provide guidance for specific clinical questions. Guidelines differ depending on their purpose, but they represent one attempt to synthesize knowledge [17]. Know guideline recommendations, and follow them for most patients; know why you deviate from them when it becomes necessary for the individual patient in front of you. Several schizophrenia guidelines are listed in the additional resources.
Schizophrenia Treatment Goals
Conceptually, it helps to break down treatment goals into different domains as shown in Table 16.2. Antipsychotics directly influence three of the five treatment goals. First, they are necessary to achieve sustained symptomatic remission as the basis for functional recovery and reintegration into society. Second, antipsychotics contribute to increased quality of life (reduction of distressing symptoms) while at the same time reducing it (side effect burden). Last, antipsychotics reduce mortality from untreated illness while also adding the potential for iatrogenic morbidity and mortality.
Key Point
A psychiatric treatment plan needs to balance symptom control, quality of life, and patient safety. Quality of life may be more important than trying to “eradicate” symptoms. Selecting a safer medication may require a change in treatment.
Practical Considerations
Clinicians have three basic tasks when it comes to antipsychotic medications: they need to select an antipsychotic to start treatment, they need to switch to a different antipsychotic if there is no response or poor tolerability, or they need to discontinue antipsychotics. Augmenting antipsychotics is discussed in Chap. 19, and managing side effects without switching or discontinuing the antipsychotic in the previous two chapters.
Selecting Antipsychotics
Individual patients show marked differences in their clinical response and tolerability to any given antipsychotic. Because you cannot predict which medication is going to show the best benefit-risk ration for individual patients, you will have to do sequential trials to empirically figure this out in collaboration with your patients. As noted in Chap. 20, pharmacogenetic testing is of limited value for antipsychotic selection. The side effect profile can help narrow your initial choices, based on patient preference; for example, for a patient who sleeps poorly, you might consider offering a more sedating antipsychotic first. For some patients, you can take into account personal or family medical history; for example, for an overweight patient with a family history of diabetes, ziprasidone would be one logical first choice. For others, the preference of avoiding a particular side effect (e.g., any degree of possible weight gain) weighs heavily for or against a particular drug. In one population-based study, oral aripiprazole (together with long-acting second-generation antipsychotics) showed the best reduction in mortality compared to no treatment [18] for those patients interested in mortality reduction.
Key Point
For many patients, the best (i.e., most effective) long-term antipsychotic will represent a compromise between efficacy and tolerability. The only way of tailoring your antipsychotic treatment to your patient is by trial and error in the form of sequential trials.
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