Defining and characterising treatment-resistant schizophrenia

EurPsychiatry (1995) 10, suppl I, 7s-10s 9 Elsevier, Paris

Defining and characterising treatment-resistant schizophrenia S Marder Psychiatry Service, West Los Angeles VA Medical Center, 11301 Wilshlre Boulevard, Los Angeles, California 90073, USA

Summary - T h i s paper argues for a broader definition o f treatment refractoriness that would include patients with partial drug responses, a relatively recent onset, less dramatic symptonL~ and intolerance to conventional drugs. The drug trials that define their responsiveness should be carefully conducted over a prolonged period of time, but need not include high doses or supplemental medications. If the consensus conference can agree on a definition of responsiveness, it will provide important guidance to cliniciart~ as well a.~ researchers. schizophren|a / treatment / clozaplne

INTRODUCTION Clozapine's unique effectiveness in schizophrenic patients who respond poorly to other antipsychotie medications has emphasised the importance of defining treatment resistance. Reaching a consensus in this area will be useful for clinicians who will have guidance as to when a patient should receive a trial of clozapine or another atypical agent. It will also be helpful to researchers who are designing clinical trials. This report will focus on a number of important questions in characterising treatment resistance including: (i) what constitutes an adequate drug trial in terms of duration, dose and supplemental medications? (ii) is treatment-resistant schizophrenia the same as Kraepelinian schizophrenia? and (iii) would it be preferable to define a continuum of treatment responsiveness rather than a small population of treatment-resistant patients? RESPONSIVENESS V E R S U S REFRACTORINESS The consensus conference should also focus on redefining our mission. I propose that we categorise the relative responsiveness of patients to conventional antipsychotics, rather than merely defining treatment refractoriness. Patients do not fall neatly into the categories of responders and nonresponders. It is my experience that nearly every patient with schizophrenia is improved to some extent by an antipsychotic. For some. this improvement only becomes obvious when medications are discontinued for some reason. At that

time, a patient who appeared to be doing very poorly on medications, becomes worse when they are discontinued. BROAD V E R S U S NARROW DEFINITIONS The interest in treatment-refractory schizophrenia was largely stimulated by the finding in a number of studies - particularly the pivotal study of Kane et al (1988) - that clozapine was more effective than a conventional antipsychotic in severely ill treatment-refractory patients. The rather narrow definition in the Kane study was appropriate for a trial of clozapine, a drug that was associated with some risks. Nevertheless, it is still the best definition available and a good starting point. To be considered treatment-resistant, patients had to meet the following criteria: at least three periods of treatment with an antipsychotic from at least two different classes in doses of at least 1,000 rag/day for a duration of at least 6 weeks; no period of good functioning within the preceding 5 years; and severe psychopathology defined by the BPRS and CGI. In addition, patients had to fail a trial of haloperidol at doses of 60 mg or more. These criteria were useful for defining a relatively homogeneous group of very poor drug responders. However, I believe that it is too restrictive and greatly underestimates the number of patients who are poor treatment responders and who should receive clozapine. First, a broader definition would also include patients who clearly respond to antipsychotics, but who, nevertheless, remain severely symptomatic. A

8S

S Marder

large proportion of outpatients with schizophrenia continue to have persistent positive and negative symptoms. These symptoms interfere with their ability to sustain any substantial rehabilitation efforts. The recent study by Breier et al (1994) indicates that outpatients who are probably partial responders to conventional antipsychotics also did well on clozapine in comparison with a conventional drug. Clozapine is being widely administered to many patients with much milder symptoms than those which were required for entry into the multicentre study. Although European studies indicate that clozapine's advantages in comparison with conventional agents is easiest to demonstrate in the most severely symptomatic patients, this does not mean that it may not have advantages to patients who have milder persistent symptoms. Conceivably, patients who have mild hallucinations or delusions and improve may experience large improvements in their social and vocational adjustment. I would also recommend that criteria permit first-episode patients to be considered refractory. There is a number of reasons to treat first-episode patients aggressively. These individuals have the most to lose if their episodes are sustained. Patients are often involved in jobs or educational programs which can be lost. Moreover, a recent review by Wyatt (1991) indicates that substantial delays in treating psychotic episodes with antipsychotics can have long-lasting negative effects on their need for hospitalisation and their overall social adjustment. The criteria for resistance should also take into account the large nuinber of patients who improve on their antipsychotic medications but who suffer from side effects - particularly EPS - at the doses needed to treat their psychosis. These individuals are functionally nonresponsive since they pay too high a price for treatment of their illness. IIOW LONG A DRUG TRIAL? Patients vary in the length of time it takes them to respond to an antipsychotic. It is not unusual for a patient to require 12 weeks or more to respond to a conventional antipsychotic. Reports by Meltzer (1990) and othe~:s suggest that the response rate to clozapine increases substantially between 6 weeks and 6 months and more gradually between 6 months and a year. However, it is uncommon for a patient who will eventually be a responder to show no improvement during the first three months. This period of time is probably reasonable for identifying nonresponders. The length of time needed to identify the amount of

improvement for responders is more difficult. That is, when can we conclude that a patient's response to a drug is inadequate and that another agent should be tried? The National Institute of Mental Health (NIMH) comparison of different antipsychotics from the 1960's found that patients on antipsychotics improved during the first six months of drug treatment. This parallels the finding by Meltzer and others and suggests that patients should be continued on an antipsychotie at an adequate dose for six months as long as there is evidence that they are improving.

flOW HIGH A DOSE?

When patients fail to respond to conventional doses of an antipsychotic, clinicians usually raise the dose above the usual clinical range. However, studies that compared higher doses in treatment-resistant cases failed to find any advantage of higher doses over conventional doses (Prien and Cole, 1968; Quitkin etal, 1975). These and other studies influenced a recent consensus statement by the Royal College of Psychiatrists which discouraged high dose treatment for refractory patients. (Thompson, 1994). One study that directly addresses the issue of higher dose treatment in refractory patients was recently reported by Kinon et al (1993). Acutely ill patients with schizophrenia were treated with 20 mg of fluphenazine for four weeks. Patients who failed to meet criteria for substantial improvement were randomly assigned to one of the following three groups: (I) an increase to 80 mg of fluphenazine; (2) a change to 20 mg of haloperidol; or (3) continuation on the same 20 mg of fluphenazine. Only 9% of patients went on to become responders and there were no differences among the three groups. These studies suggest that little is to be gained by a high dose trial in patients who have failed a trial on an adequate dose. Recent research (reviewed by Baldessarini et al, 1988) provides guidance as to what constitutes an adequate antipsychotic drug dose. Doses below 300 mg of chlorpromazine (or 5 mg of fluphenazine or haloperidol) are likely to be too low for many psychotic patients. At the same time doses above 1,000 mg of chlorpromazine (or 20 mg of haloperidol or fluphenazine are seldom necessary and may lead to substantial side effects. The only occasion for treating patients with doses outside this range is when there is evidence that a particular patient did better on a higher or lower dose.

Treatment-resistantschizophrenia USE OF PLASMA L E V E L M E A S U R E M E N T Although plasma levels are commonly measured by practising clinicians, there is little consensus as to when and how a plasma concentration can be useful. For patients who have failed to respond to a drug trial, a plasma level can confirm that the patient has a plasma concentration that is within a therapeutic range. Thus, reasons for nonresponse, such as rapid drug metabolism, noncompliance or failure to absorb the drug, can be ruled out. Measuring a plasma concentration may also identify patients who have levels that are too high. Higher concentrations may result in side effects such as akathisia which can be difficult to diagnose. Some of these patients may improve when their levels are reduced (Van Putten et al, 1992). Plasma level ranges have only been identified for a number of drugs, including haloperidol, fluphenazine, trifluoperazine and perhaps clozapine. Nevertheless, if a patient has received one of the drugs for which there is adequate data, a plasma level may convince the clinician that the patient has received an adequate trial. S U P P L E M E N T I N G AN A N T I P S Y C H O T I C There is considerable evidence that supplementing an antipsychotic with lithium can be helpful for patients who have failed to respond to the antipsychotic alone (Small et a/, 1975; Growe e t a / , 1979; Carmen et al, 198 I). The improvements in these Studies were not confined to affective symptoms, but included core psychopathology of schizophrenia. Unfortunately, there are no comparisons of lithium with an antipsychotic versus clozapine. Having used this treatment frequently, my impression is that it results in incremental improvement that is much less substantial than responses to clozapine. Nevertheless, itremains a viable alternative for clinicians who are considering a trial of clozapine. Benzodiazepines have also been used to supplement an antipsychotic in refractory patients. Although a review by Christison (1991) indicates that the results from clinical trials are mixed, there is evidence that patients who are experiencing anxiety and agitation improve with benzodifizepines. Moreover, a number of studies indicate that patients who are neither anxious nor agitated experience improvement in core symptoms of schizophrenia. There is substantially less data supporting the effectiveness of treatments such as carbamazepines or valproate in refractory schizophrenia. None of these supplemental medications have been demonstrated to have the powerful effect on treatment

9s

refractory patients that is seen with clozapine. At this stage, adding a trial of supplementation with an agent to the definition of refractoriness would add months to the drug trial, and would delay the patient receiving a more definitive treatment. NONRESPONSIVE V E R S U S K R A E P E L I N I A N SCHIZOPHRENIA It is also important to consider characterising patients who are poorly responsive to antipsychotics and have had a deteriorating or chronic course. These patients have been considered by some to have Kraepelinian schizophrenia. Recent reports by Keefe et al (1990) indicate that a population of patients can be identified who have an early age of onset, severe deterioration in multiple levels of functioning and poor responses to antipsychotics. These clinical characteristics are also associated with evidence that these patients have structural brain abnormalities, a greater risk of schizophrenia spectrum disorders in first degree relatives and more severe negative symptoms. Although these patients may seem unresponsive to antipsychotics, they may deteriorate when these medications are discontinued. It is also important to evaluate carefully their drug responses over prolonged periods of time, since these patients may only display subtle improvements during the first months of drug treatment, although these small improvements may have a substantial effect on the quality of their lives. I am reminded of several severely ill patients who remained psychotic on clozapine, although their families reported that they seemed much less tormented than they were previously. Criteria for refractoriness or responsiveness should acknowledge these important responses.

REFERENCES Baldessarini RJ, Cohen BM, TeicherMH. Significanceof neuroleptic dose and plasma level in the pharmacologicaltreatment of psychoses.Arch Gen Psychiatry 1988;45:79-90 Breier A, BuchananRW. KirkpatrickBet al. Effectsofclozapineon positive and negativesymptomsin outpatientswith schizophrenia. Am J Psychiatry 1994;151:20-6 Carmen JS, Bigelow LB, Wyatt RJ. Lithiumcombinedwith neuroleptics in chronic schizophrenic and schizoaffectivepatients. J Clin Ps)z'hiatry 1981;42:124-8 ChristisonGW, KirchDG, WyattRJ. Whensymptomspersist:choosing among alternative somatic treatments for schizophrenia. Schizophr Bull 1991;17:217-45 GroweGA, CraytonJA, KlassDB. Lithiumin chronicschizophrenia. Am J Psychiatry 1979;136:454-5 KaneJM, HonigfeldG, SingerJ, Meltzer H, and the Clozaril CollaborativeStudyGroup.Clozapinefor the treatment-resistantschi-

10s

SMarder

zophrcnic: A double-blind comparison versus chlorpromazine/benztropine. Arch Gen Psychiatry 1988;45:789 Keefe RSE. Mohs RC, Silverman .13,|et al. Characteristics of Kraepelininan schizophrenia and their relation to premorbid social functioning, ht: Angrist B, Schulz SC, eds. The nettroleptic nonresponsive patient: characterizathm attd treatment. Washington DC: American Psychiatric Press, 1990; 3-2 I Kinon B,1,Kane,1M, ,1ohns C et al. Treatment of neuroleptic-resistant schizophrenic relapse. P.rychopharlnacol Bull 1993;29:309-14 Meltzer HY, Bemett S, Bastani Bet al. Effects of six months of elozapine treatment on the quality of life ofchronic schizophrenic patients. Hosp Comnlunity Psychiatry 1990;41:892-7 Prien RF, Cole ,10. ttigh dose chlorpromazine therapy in chronic schizophrenia. Arch Gen Psychiatry 1968;18:482-95

Quitkin F, Rifkin A, Klein DF. Very high dosage vs standard dosage fluphenazine in chronic schizophrenia. Arch Gen Psychiatry 1975;32:1276-8 I Small JG, Kellams J,1oMilstein V et al. A placebo-controled study of lithium combined with neuroleptics in chronic schizophrenic patients. Am J Psychhttry 1975; 132:1315-7 Thompson C. The use of high-dose antipsychotie medication. Br J Psyc41iatO, 1994;164:448-58 Van Putten T, Marder SR, Mintz ,1, Poland RE. tlaloporidol plasma levels and clinical response: A therapeutic window relationship. Am J Psychiatry 1992;149:500-5 Wyatt RJ. Neuroleptics and the natural course o fsehizophrenia. Schi. zophr Bull 1991;I 7:325-51