Daniel C. Javitt, MD, PhD
When treating patients with schizophrenia, the overarching goals are to alleviate acute symptoms, maximize quality of life and functioning, and maintain recovery from acute illness.1
Optimal treatment should involve an integrative approach that combines psychosocial, educational, and pharmacologic management. This article discusses the overall management of schizophrenia, including recommendations from practice guidelines, results of important clinical trials, factors involved in choosing an appropriate antipsychotic agent, and issues involved in managing drug side effects.Pharmacologic Treatment
Antipsychotic medications are the mainstay of schizophrenia drug treatment. All of the antipsychotics are thought to work, at least in part, through actions on the dopamine type 2 (D2) receptors, and these agents have traditionally been categorized into first-generation or second-generation groupings.2 The first-generation antipsychotics (FGAs), previously referred to as “typical” antipsychotics, are thought to work almost exclusively through D2 antagonism. It has been demonstrated that 65% to 70% occupancy at D2 receptors is associated with an antipsychotic response, whereas 80% occupancy and higher is associated with extrapyramidal symptoms (EPSs), such as dystonia, psuedoparkinsonism, akathisia, and tardive dyskinesia.2 Due to their strong affinity for the D2 receptor, FGAs have a significant risk of side effects even at the lowest possible therapeutic dose. Haloperidol and fluphenazine are the FGAs with the most potent affinity for the D2 receptor. The FGAs that are associated with somewhat lower rates of EPSs are those with less potency at the D2 receptor and more anticholinergic receptor affinity, such as chlorpromazine and thioridazine (Table 13,4
). Although these differences in receptor affinities lower the risk of EPSs, they also increase the risk of sedation and secondary cognitive impairment.
The second-generation antipsychotics (SGAs), also termed “atypical” antipsychotics, have more potent antagonism at serotonin type-2A (5-HT2A) receptors, and reduced binding affinity for D2 receptors, which is thought to reduce (but not eliminate) the risk of EPSs and prolactin elevation.2 However, many SGAs have turned out to have a high potential for metabolic adverse effects, such as weight gain, lipid abnormalities, glucose abnormalities, and even diabetes; although the exact metabolic risk profile varies from agent to agent (Table 23,5-7
).Place of Antipsychotics in Schizophrenia Therapy
One of the major focuses of schizophrenia research over the past decade has been to examine the relative treatment benefits of each generation of antipsychotics. Results from several landmark clinical trials have been published during this time, the largest of which was funded by the National Institute of Mental Health. This trial, one of a series referred to as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), compared rates of all-cause discontinuation in 1432 patients treated with either an SGA (ie, olanzapine, quetiapine, risperidone, or ziprasidone) or the FGA perphenazine.
Olanzapine showed a longer time to discontinuation for any reason compared with the other antipsychotics (9.2 months for olanzapine vs 3.5-5.6 months for the others); however, this difference was not significant when compared with perphenazine alone. Perphenazine showed effectiveness comparable to that of the other SGAs used in the study. Patients with schizophrenia treated with olanzapine experienced higher rates of clinically significant weight gain (≥7% of body weight) compared with the other antipsychotics (30% with olanzapine vs 7% with ziprasidone, 12% with perphenazine, 14% with risperidone, and 16% with quetiapine; P
<.001) and had greater increases in glycated hemoglobin (A1C), total cholesterol, and triglycerides. Other adverse effects seen were generally consistent with those observed in clinical practice. Risperidone was associated with the greatest increase in prolactin (P
<.001) and perphenazine had the highest rate of discontinuation due to EPSs (P
= .002), although there were no significant differences in the rates of EPSs between the different treatment groups.8 Another trial with a similar goal to CATIE was the European Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). This trial examined improvement in quality of life as measured by the Quality of Life Scale (QLS) in 185 patients who were treated over a period of 1 year with either an FGA or an SGA. No significant difference was observed in the primary outcome (QLS) in either treatment arm, nor in any of the secondary outcomes, including symptom improvement, treatment adherence, attitudes toward medication, or extrapyramidal side effects.9
Similar studies were completed in patients with schizophrenia who were experiencing their first episode of psychosis (FEP). The European First Episode Schizophrenia Trial (EUFEST) examined 498 such patients over 1 year of randomized treatment with haloperidol, amisulpride (an SGA not approved in the United States), olanzapine, quetiapine, or ziprasidone. More patients discontinued haloperidol for any reason than the other antipsychotics (72% vs 40% for amisulpride, 33% for olanzapine, 53% for quetiapine, and 45% for ziprasidone; P
<.001). There were no differences in symptom improvement or rates of hospital admission between the treatment groups. Patients treated with haloperidol experienced the most EPSs, and patients treated with olanzapine experienced the most weight gain.10
In the Comparison of Atypicals for First Episode Schizophrenia (CAFE) trial, patients treated with either olanzapine, quetiapine, or risperidone had similar all-cause discontinuation rates at 1 year, no differences in overall symptom severity measures, and side effects similar to those seen in other trials.11
Prior to these clinical trials, most practice guidelines unequivocally recommended the use of an SGA as a first-line agent for most patients with schizophrenia due to the lower risk of EPSs and the perceived enhanced efficacy.12,13
Given the comparable effectiveness of FGAs seen in recent trials, and the concern about metabolic adverse effects with SGAs, current guidelines favor SGAs less enthusiastically, and encourage a careful risk/benefit analysis for each individual patient (Table 3
Ideally, factors such as patient preference, prior treatment response, side effect profile, medical history and risk factors, and adherence history would be taken into consideration when selecting an appropriate antipsychotic.1,4,17
In patients with schizophrenia experiencing their FEP, the SGAs are generally preferred for initial treatment.1,14-16
These patients are also particularly vulnerable to the adverse effects of antipsychotic medications, such as weight gain and EPSs, and are generally more responsive to lower doses than patients who have experienced multiple episodes. Therefore, the lowest possible dose, typically about half the dose used in patients with chronic schizophrenia, should generally be used in these patients, although dosing recommendations vary depending on the particular antipsychotic being used.4,15Treatment-Resistant Schizophrenia and the Role of Clozapine
For patients who have failed treatment with adequately dosed trials (generally 4-6 weeks) of more than 1 antipsychotic medication, the most evidencebased treatment strategy is to initiate clozapine.1,4,14-16
Clozapine may be instituted earlier in the treatment of patients with schizophrenia who have persistent suicidality, aggression, or hostility, as these patient populations in particular seem to benefit from clozapine (as in 1 meta-analysis which demonstrated a 3-fold reduction in suicidal behaviors compared with other antipsychotics).1,4,19
The high risk of weight gain and other metabolic effects, and the risk for agranulocytosis, myocarditis, orthostatic hypotension, seizures, and other adverse effects limit the use of clozapine, but many experts agree that the agent is likely underutilized.15,20
For patients who do not respond to at least 8 weeks of clozapine treatment with plasma levels greater than 350 mcg/L, there are limited data to support the use of clozapine augmentation with other antipsychotics.21
Data collected from a meta-analysis of 5 randomized placebo-controlled trials also suggest that, in comparison with placebo, augmentation with lamotrigine improved outcomes in patients with schizophrenia treated with clozapine.22Long-Acting Injectable Antipsychotics
A considerable challenge in the treatment of schizophrenia is medication nonadherence. Approximately 40% to 60% of patients with schizophrenia are nonadherent or only partially adherent to their antipsychotic medication.23
One strategy for dealing with adherence issues is the use of long-acting injectable (LAI) antipsychotics. First-generation LAIs have been available since the 1960s, but the repertoire of options has expanded recently to include the SGAs, such as risperidone, paliperidone, olanzapine, and aripiprazole.
Traditionally, LAIs were used predominantly in patients with a history of nonadherence to medication and/or relapse of illness related to nonadherence. More recently, some authors have recommended considering an LAI in any patient for whom long-term treatment is needed.24
The potential benefits of using an LAI over an oral antipsychotic medication include the potentially earlier detection of relapse (because the patient is coming in for regularly scheduled injections), a reduced risk of accidental overdose or missing doses of medication, and the ability to differentiate between symptom relapse due to lack of efficacy versus poor treatment adherence.23
Pharmacoepidemiologic and naturalistic studies have demonstrated that the use of LAIs may aid in relapse prevention, although randomized controlled trials have failed to show a difference in relapse rates when comparing an LAI, such as risperidone or olanzapine, with oral antipsychotic medications, such as olanzapine, fluphenazine, or risperidone.25Managing Metabolic Adverse Effects
A key issue in the successful treatment of patients with schizophrenia is the management of adverse drug reactions such as EPS, hyperprolactinemia, and, in particular, metabolic syndrome, which is a focus of this article. Metabolic adverse effects are not a new phenomenon in antipsychotic drug treatment. De Hert et al recently compared a historic cohort of patients with schizophrenia experiencing their FEP treated with FGAs with an age- and sex-matched cohort of those treated with SGAs. They found no differences in the incidence of metabolic syndrome at baseline in the 2 treatment cohorts, and both had an increase in the rate of metabolic syndrome over time. However, after an average of 3 years of drug treatment, the patients treated with SGAs had a 3 times higher rate of metabolic syndrome (odds ratio, 3.6; 95% CI, 1.7-7.5) and, on average, twice the amount of weight gain and body mass index (BMI) increase, as those treated with FGAs.26 Another study estimated that antipsychotics account for 3.1% of diabetes cases over and above the 10% base rate of diabetes seen in patients with schizophrenia.27
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