The management of new-onset schizophrenia continues to be an enormous challenge. Patients at this phase of illness have a complex and variable array of personality characteristics, premorbid adaptation, cognitive dysfunction, comorbid conditions, attribution style, and family and social dynamics as well as their specific signs and symptoms of schizophrenia. The range of emotional reactions on the part of the patients and family to the illness and its symptoms, the fears and anxieties regarding the future, and the stigma that continues to surround schizophrenia add further challenges.
The treatment team has to be sensitive to and aware of these different elements and at the same time develop an appropriate short- and long-term treatment plan. In this context we have to consider pharmacological treatment strategies, which will be the focus of this article.
The choice of medication in treating a patient with new-onset schizophrenia has different contributing factors compared with a similar decision in a multiepisode patient. First, there is no prior history of response to treatment (either therapeutic or adverse) to inform treatment decisions. Second, there might be more reluctance than there would be subsequently to accept the diagnosis and the need for treatment. Third, first-episode patients can be more sensitive to side effects, both in terms of their incidence, but also in terms of their salience and effect on subsequent adherence. For example, Robinson et al. (1) in a study of predictors of nonadherence in first-episode patients who had already experienced one relapse found that the occurrence of extrapyramidal side effects during the treatment of the first episode was the strongest predictor of subsequent nonadherence. These investigators also found that symptoms of depression during the index episode were predictive of nonadherence as well. These data highlight the importance of avoiding adverse effects and being sensitive to comorbid conditions. Elbogen et al. (2) also reported depressive symptoms to be a strong predictor of nonadherence in a sample of 528 adults with schizophrenia and related disorders. Although there are many factors that can contribute to subsequent nonadherence such as poor insight, substance abuse, shorter illness duration, inadequate discharge planning or aftercare environment, poor therapeutic alliance (3), negative attitude, and/or subjective response to medication can also be associated with nonadherence. Lambert et al. (4) reported that all antipsychotic side effects, present or past, can have a durable negative impact on patient's attitude toward antipsychotic treatment and adherence. Stigma and lack of appropriate social support or living stability, cost of medication, and more frequent dosing requirements can also play important roles.
Vauth et al. (5) found that patients with greater cognitive dysfunction (verbal memory and cognitive flexibility) attributed their engagement in neuroleptic treatment to their relationship with others, whereas patients with higher levels of attention and memory relied more on perceived benefits of treatment as motivation for treatment compliance. Robinson et al. (1) also reported that better executive cognitive functioning was associated with decreased risk for nonadherence. Lower parental social class and less education on the patient's part were associated with medication nonadherence.
Thus, the better that we do in assessing and managing these risk factors early in the course of treatment, the greater will be the likelihood of enhanced adherence.
There are far fewer data to inform a decision as to antipsychotic medication choice in first-episode compared with multiepisode patients. In general, first-episode patients tend to respond to lower doses (often 50% lower) than patients with more chronic disease (6—8); however, this might not be the case with quetiapine (9), and there are as yet insufficient data with ziprasidone or aripiprazole in first-episode patients.
In comparison of medications for the treatment of first-episode patients, it is also important to recognize that overall, first-episode patients have higher "response" rates than individuals who have had multiple episodes; therefore, it is more difficult to detect potential differences among medications. There is also debate as to how response should be measured. Most clinical trials use rating scales and will assess change scores or the proportion of patients who improve a certain percentage over baseline scores. When clinicians read these reports and attempt to apply the findings to their own clinical practice, the implications are not always clear as criteria used to define "response" in some studies (particularly involving patients with chronic disease) might actually represent minimal improvement (10, 11) In first-episode patients achieving "remission" would be a more appropriate (and attainable goal). Criteria for remission have been suggested (12) but depend upon the application of quantitative assessment using eight items taken from rating scales. Clinicians are not accustomed to using quantitative measures in their assessment of treatment response, but measurement-based decision making would be an important advance in clinical practice. Given the powerful impact of subjective response to medication and adverse effects in influencing subsequent attitudes toward pharmacotherapy and risk of nonadherence, it is important to recognize that first-episode patients can be particularly sensitive to extrapyramidal side effects, weight gain, and metabolic side effects (6—8).
There is renewed debate as to the relative merits of first- and second-generation medications based on the results of recent large effectiveness trials (13, 14). These studies have not demonstrated consistent superiority of second-generation medications in comparison with selected first-generation drugs. However, these studies primarily involved multiepisode patients with average illness durations of well over 10 years. The extent to which these results are generalizable to first-episode patients remains unclear.
In addition, although second-generation medications are often referred to as a "class" of medication, there is considerable variability in the preclinical and clinical characteristics among these drugs, particularly in their side effect profiles. Those second-generation drugs with lower propensity to produce metabolic side effects are only now being studied in first-episode or drug-naive young patients. In general, the dichotomy of first- and second-generation medication has served some limited purposes, but it has also tended to maximize the differences between classes and minimize the differences within classes.
A number of industry-sponsored trials have been conducted in first-episode patients to compare clozapine to chlorpromazine (15), olanzapine and haloperidol (6), or risperidone and haloperidol (7, 16). None of these trials revealed statistically significant differences between first- and second-generation medications in overall response rates. One industry-sponsored trial, (9) and one National Institute of Mental Health-funded trial (8) compared second-generation medications in first-episode patients and found no major differences in short-term efficacy but did report significant differences in adverse effects, particularly metabolic sequelae.
It may be that maintenance treatment and the prevention of relapse is a domain in which second-generation medications demonstrate a meaningful advantage. Leucht et al. (17) examined relapse rates in double-blind controlled trials lasting at least 1 year and comparing first- and second-generation antipsychotic medications. The average relapse rate at 1 year with first-generation medications was 23% compared with 15% for second-generation drugs (p<0.0001), a 35% reduction in relapse risk. It did not appear that this effect was attributable merely to increased adherence.
Two industry-sponsored studies (7, 18) reported advantages for risperidone and olanzapine compared with haloperidol for relapse prevention in first-episode patients. Schooler et al. (7) reported a significantly longer time to relapse in first-episode patients treated with risperidone, and Green et al. (18) reported a significantly longer time to treatment discontinuation with olanzapine compared with haloperidol.
One of the major advantages of the second-generation antipsychotics has been a reduction in the risk of acute extrapyramidal side effects (EPS) (19). In the first-episode studies discussed, EPS were more frequent in patients treated with first-generation, low-potency medications (even when given in very low doses). At the same time it is important to recognize that EPS can also occur with some frequency in first-episode subjects treated with second-generation drugs. Although reference has been made to the performance of perphenazine (a mid-potency conventional antipsychotic) in Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (13), it is important to recognize that significantly more patients discontinued perphenazine due to EPS than the other medications, even though the rating scale scores did not reveal significant differences. In addition, more than 200 patients with preexisting tardive dyskinesia (TD) were excluded from the randomization to perphenazine, and these patients are probably among the most sensitive to EPS.
With regard to TD, there are relatively few prospective studies in first-episode patients (20), but those that have been published find incidences similar to those in patients with more chronic disease, even after the first year of treatment. At the same time, many such patients were assessed after exposure to high-potency conventional antipsychotics, and there is the possibility that some lower-potency medications might be associated with a lower incidence.
Oosthuizen et al. (21) reported a high incidence of TD in first-episode patients even when a very low dose of haloperidol (mean 1.7 mg) was used. Schooler et al. (7) did not detect a difference in TD incidence between risperidone and low-dose haloperidol, Green et al. (18) reported significantly higher Abnormal Involuntary Movement Scale scores with low-dose haloperidol than with olanzapine.
Therefore, in choosing medication for the treatment of first-episode patients it is important to be aware of the relative merits of a variety of medications and to be very sensitive to identifying potential adverse effects, even subtle ones, that might impact patient attitudes and experience. Most experts continue to favor the use of second-generation medications, because of the reduced potential to produce EPS and TD (22); however, first-episode patients are also very vulnerable to metabolic side effects (6), and patients need to be monitored carefully for all side effects. Even medications with an apparent low propensity for such side effects can still produce them in a substantial proportion of drug-naive, first-episode patients.
If a first-episode patient does not respond to an initial course of medication, the question is what strategy to pursue next. First, a reevaluation of the diagnosis is called for as well as a careful assessment of adherence in medication-taking. If available, drug blood levels might be informative. Most clinicians will consider raising the dose or switching to a different medication, and some might entertain the use of polypharmacy. Unfortunately, there are no systematic data testing any of these strategies in a controlled fashion in first-episode patients. At some point if poor response persists, a trial of clozapine might be warranted. Although clozapine has been used as a first-line treatment in two studies (15, 23), neither showed sufficient advantage to warrant its use as an initial treatment. However, a limited amount of data suggest that clozapine might be helpful when other medications fail to produce adequate response in first-episode patients (24).
After the treatment of an acute episode and the achievement of symptom remission or at least partial remission, decisions have to be made regarding long-term pharmacotherapy. There is no clear-cut point at which maintenance treatment starts, but I would consider the first 6 months to include acute and continuation treatment aimed to control acute symptoms and making sure that the response is optimum and stable. Clearly, in schizophrenia some illness domains (positive symptoms) are more responsive to treatment than others (negative symptoms and cognitive dysfunction).
In addition, many first-episode patients have difficulty accepting the need for long-term treatment. The better their response to treatment has been, the more difficult it can be for them to continue to take medication on a long-term basis. The unfortunate reality, however, is that the better the functional gains that have been achieved, the more risky a relapse becomes in terms of potential consequences.
A relatively small number of placebo-controlled trials have been conducted in first-episode schizophrenia. The first such study to be reported (25) showed a 41% relapse rate with placebo versus 0% with medication after 1 year. Other studies showed relapse rates of 62% versus 46%, 57% versus 0%, and 64% versus 43% with medication compared with placebo (26—28). Although there is clear and consistent superiority of medication over placebo, there are differences in relapse rates across the studies, which may be explained by differences in stability of response before random assignment, definitions of relapse, frequency of assessments, and duration of the trial. It is also clear that not all patients experience relapses, even with placebo. Unfortunately, there are no reliable and valid predictors to help us to identify those individuals who might not require maintenance treatment. In addition, none of the placebo-controlled trials lasted for more than 2 years.
In long-term, naturalistic, prospective or follow-up studies the overwhelming majority of patients experienced at least one relapse within 5 years of the first episode. Robinson et al. (29) reported that at 5 years of follow-up, 82% of subjects had experienced at least one relapse. In addition, the single most powerful predictor of relapse risk was medication discontinuation. Those individuals who discontinued medication were five times more likely to experience a relapse than those who continued to take medication.
Again the existence of the subgroup of 18% of patients who did not experience a relapse within 5 years raises the question as to whether or not maintenance treatment is indicated for all first-episode patients. However, our inability to distinguish this subgroup from the larger population forces us to make benefit-risk recommendations for first-episode patients in general. It is also clear that some patients will experience a relapse even with continued treatment. Further research to understand this heterogeneity will be very important.
CONTINUOUS VERSUS INTERMITTENT MAINTENANCE TREATMENT
The ultimate goal in managing first-episode patients is to bring about functional recovery. Although most clinical trials in the past have focused on symptomatic improvement, there is greater focus now on functional outcomes, which will include areas in which patients might continue to be impaired despite improvements in symptomatology. Liberman et al. (30) have proposed criteria for recovery that require sustained improvement in symptoms, role functioning, and social adjustment.
There are relatively few prospective studies of recovery in first-episode patients. Robinson et al. (31) reported on data from a sample of 118 first-episode patients studied at The Zucker Hillside Hospital. Subjects were followed for up to 5 years. The recovery criteria were derived from Liberman et al. (30). Basically, requirements for recovery were ratings of mild or less in positive symptoms and moderate or less in negative symptoms, appropriate role function (paid employment or attending school at least half-time, or performing adequately or better as a homemaker), and ability to perform day-to-day living tasks and social interactions with a peer outside the family at least once per week. To be considered recovered, all four of these criteria must be met concurrently for a continuous period of at least 2 years. Only 13.7% of subjects met the full recovery criteria after 5 years. These data underscore the need to develop and deliver more effective treatments (both biological and psychosocial) to patients experiencing the recent onset of schizophrenia.
Other major questions include the following. To what extent are second-generation antipsychotic medications superior in first-episode patients in terms of overall effectiveness for acute and or maintenance treatment? When, why, and by what criterion should treatment be changed? Are there patients for whom long-term maintenance treatment might not be necessary (or in whom there is a meaningful difference in risk-benefit ratio)? What strategies can be used to enhance disappointingly low rates of apparent recovery? When is a trial of clozapine appropriate? What can be done to facilitate adherence? For which patients would long-acting injectable medication be appropriate?
The management of patients with new-onset schizophrenia is an enormous challenge. At the same time the success of our efforts at this phase of illness can have a major effect on course and long-term outcome. We have emphasized the potential increased vulnerability to adverse effects and the consequence of these effects on attitudes toward medication as well as long-term adherence. Therefore, it is critical that early and thorough assessment of subjective response and adverse effects is a routine part of the treatment plan. Patients should be warned regarding the more common and more severe, although less frequent, side effects of whichever medication has been prescribed.
Decision-making regarding switching medication or adding medication should be evidence-based and measurement-based. Whenever possible patients should share in the decision-making process.
Patients should have full access to an array of psychosocial and vocational therapies and families should also receive counseling and psychoeducation.
The duration of maintenance treatment remains a critical issue, but the consequences of relapse can be devastating. In my opinion, because the overwhelming majority of patients are at risk for relapse and at present we cannot identify those who can safely discontinue medication, it is hard to recommend medication discontinuation, certainly within the first 2 years after the first episode. It is hoped that future research will help to identity subgroups of patients with different treatment requirements.