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Treatment of Different Phases of Schizophrenia
In clinical situations, antipsychotic medications can be adminis-tered in oral forms, including oral tablets, oral liquid concentrates and orally dissolving formulations, as short-acting intramuscular preparations, or as long-acting depot preparations (American Psychiatric Association, 2000). In most cases, patients who are cooperative prefer oral administration to parenteral medications. A summary of dosing recommendations for newer agents is pro-vided in Table 77.4. Oral antipsychotic medications tend to be rapidly and well absorbed from the gastrointestinal tract, and reach a peak plasma concentration in 1 to 10 hours (Burns, 2001). The long average half-life (12–24 hours) and active metabolites of most oral antipsychotic drugs allow for once- to twice-daily dos-ing (Marder, 1997; Burns, 2001). Among the second-generation agents, quetiapine and ziprasidone have relatively shorter half-lives (Table 77.4), and should be administered in divided doses (Markowitz et al., 1999). A single or twice-daily dose of an oral preparation will result in steady-state blood levels in 2 to 5 days (Dahl, 1990).
Short-acting intramuscular (IM) medications are particu-larly useful in the management of acute pathologic excitement and agitation (Buckley, 1999). The main indication for the use of a short-acting parenteral form in the acute situation is to treat severely disturbed patients who cannot be verbally redirected, who may be violent, and who may have to be medicated over objection. Short-acting IM preparations can reach a peak con-centration 30 to 60 minutes after the medication is administered (Dahl, 1990).
Selection of an agent in emergency settings for the management of the gross agitation, excitement and violent behavior associated with psychosis might be based on clinical symptoms, differences in efficacy or side effects of candidate drugs, or, more pragmati-cally, the formulation of a drug as it affects route of administra-tion, onset and duration (Hirsch and Barnes, 1995; Allen, 2000). Most agitated patients will assent to oral medication and, in a survey of 51 psychiatric emergency services, the medical doctors estimated that only 10% of emergency patients require injectable medications (Currier, 2000). Practice and legal requirements concerning injectable medications differ substantially across the globe. The US Health Care Finance Administration’s (HCFA) regulations regarding so-called “chemical restraint” call for it to be a last resort, which would suggest that oral medication should be offered whenever it is possible to speak with the patient (Allen, 2000). Intramuscular treatments, however, remain nec-essary for some agitated or aggressive patients who refuse oral medications of any kind (Allen et al., 2001). In these situations, many clinicians avoid high doses on antipsychotic medications in favor of a combination of an antipsychotic and a benzodiazepine (Miyamoto et al., 2002b).
Effective Doses of First-generation Antipsychotics The goal of pharmacotherapy is to maximize efficacy and minimize ad-verse effects with the lowest effective dose. When groups of pa-tients are assigned to higher doses, such as more than 2000 mg chlorpromazine or 40 mg haloperidol equivalent, the rate and amount of improvement are no greater than for those assigned to more moderate doses (Marder, 1996).
Effective Doses of Second-generation Antipsychotics The dosage recommendations for second-generation antipsychotic drugs are summarized in Table 77.4. Although clinical trial data show that second-generation antipsychotics are efficacious and cause fewer EPS than the conventional agents, optimal dosing constitutes a critical issue in their effective use.
Patients with schizophrenia may manifest poor response to treatment because of intolerance to medication, poor compliance, inappropriate dosing, as well as true resistance of their illness to antipsychotic medications. It has been consistently reported
that approximately 10 to 15% of patients with first-episode schizophrenia are resistant to drug treatment (Lieberman et al., 1993), and between 30 to 60% of patients become only partially responsive or completely unresponsive to treatment during the course of the illness (Davis and Casper, 1977; Essock et al., 1996; Lieberman, 1999). Before a patient is considered treatment-resistant, an optimized medication and treatment trial should be employed (Conley and Kelly, 2001). The most accepted criteria for defining treatment resistance in schizophrenia were initially utilized by Kane and collaborators (1988) in the Multicenter Clozapine Trial (MCT), and the modified criteria have been used to define treatment resistance (Table 77.5). Although most definitions of treatment resistance focus on the persistence of positive symptoms, there is growing awareness of the problems of persistent negative symptoms and cognitive impairments, which may have an important impact on level of functioning, psychosocial integration and quality of life (Conley and Kelly, 2001; Peuskens, 1999).
Only clozapine has consistently demonstrated efficacy for psychotic symptoms in well-defined treatment refractory patients. The mechanism responsible for this therapeutic ad-vantage remains uncertain. Thus, clozapine remains the “gold standard” for treatment of this patient population. The evidence is strongest in support of clozapine monotherapy as an interven-tion for treatment-resistant patients; serum levels of 350 µg/mL or greater have been associated with maximal likelihood of re-sponse (Miller, 1996).
Since the approval of clozapine, attention has shifted to a greater focus on the use of other second-generation antipsychot-ics for managing treatment resistance in schizophrenia, but the relative efficacy of other second-generation antipsychotics is less clear.
Given the risk of agranulocytosis, the burden of side ef-fects and the requirement of white blood cell monitoring, the second-generation agents (risperidone, olanzapine, quetiapine and ziprasidone) should be tried before proceeding to clozapine in almost all patients (Conley and Kelly, 2001; Miyamoto et al., 2002a). Many clinicians express the impression that certain pa-tients do respond preferentially to a single agent of this class. Sequential controlled trials of the newer agents in treatment-resistant patients will be necessary fully to examine this issue.
During the resolving phase, the goals of treatment are to minimize stress on the patient, to facilitate the patient’s return to community life, and to establish a long-term maintenance plan (Marder, 1999; American Psychiatric Association, 2000). If a particular antipsy-chotic medication has improved the acute symptoms, it should be continued at the same dose for the next 6 months, before a lower maintenance dose is considered for continued treatment (American Psychiatric Association, 2000). Rapid dose reduction or discontin-uation of the medications during the resolving phase may result in relatively rapid relapse (American Psychiatric Association, 2000). If the psychiatrist has decided to switch the therapy to a long-acting depot antipsychotic agent, this can often be accompanied during this phase. This may also be a reasonable time to educate the patient and family regarding the course and outcome of schizo-phrenia, as well as factors that influence the outcome such as drug compliance (Marder, 1997; American Psychiatric Association, 2000). Patients should be helped to begin formulating a rehabilita-tion plan through realistic goal setting (Marder, 1997).
The goals of treatment during the stable or maintenance phase are to maintain symptom remission, to prevent psychotic relapse, to implement a plan for rehabilitation and to improve the patient’s quality of life (Marder, 1999; American Psychiatric Associations, 2000). Current guidelines recommend that first-episode patients should be treated for 1 to 2 years; however, 75% of patients will have relapses after their treatment is discontinued (Kissling, 1991; Davis et al., 1994; Lehman and Steinwachs, 1998; Ameri-can Psychiatric Association, 2000). Patients who have had mul-tiple episodes should receive at least 5 years of maintenance therapy (Kissling, 1991; Davis et al., 1994; American Psychiatric Association, 2000). Patients with severe or dangerous episodes should probably be treated indefinitely (American Psychiatric Association, 2000).
For conventional antipsychotics, the risk of long-term side effects such as the development of TD inspired a search for strategies to reduce patients’ exposure to these agents, and strate-gies for preventing relapse during the maintenance phase has fo-cused on finding dosages that minimize drug adverse effects and provide adequate protection against psychotic relapse (Marder, 1999). Maintenance studies of the dose–response relationship found that lowering the dose prescribed for acute treatment by about 80% may be relatively safe for maintenance, although re-lapse rates are excessively high when doses are reduced to about 10% of an acute dose (Marder et al., 1987; Hogarty et al., 1988; Kane et al., 1983). The international consensus conference rec-ommended a gradual reduction in antipsychotic dose of approxi-mately 20% every 6 months until a minimal maintenance dose is reached (Kissling, 1991).
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