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Efficacy of Somatic Treatments in Treatment Resistant Schizophrenia

Nilamadhab Kar, Jagadisha, Murali N,

Department of Psychiatry

Kasturba Medical College, Manipal, 576119, India


« Psychiatry


The treatment resistance of patients with schizophrenia is a frequent and important clinical problem. It has been described since the days of insulin coma therapy (Vanelle, 1995). The proportion of patients with treatment resistant schizophrenia has been consistent over time since the introduction of conventional antipsychotics (Conley and Buchanan, 1997). The demonstration of efficacy of clozapine in treatment resistant schizophrenia has led to studies looking into the efficacy of various treatments in this patient group. This article reviews some studies looking into treatment efficacy in treatment resistant schizophrenia. For the purpose of review, a medline search was conducted looking for articles about efficacy of treatments in treatment resistant schizophrenia since 1990.  The key words used for the search were: treatment, schizophrenia and resistant. 

Definitions of Treatment Resistant Schizophrenia

Definitions of resistance have kept changing with advent of newer kinds of therapeutic interventions. The introduction of clozapine necessitated a clear definition of treatment resistance.  A narrow definition of treatment resistant schizophrenia was introduced by Kane et al (1988).  The criteria included the aspects of patients' clinical history, cross-sectional measures and prospective assessments (Table-1). Many trials exploring new therapeutic strategies have used these criteria.  However, medication dosages and treatment duration that define adequate drug trials have undergone revisions.  A 4-6 week trial of 400-600mg of chlorpromazine is now accepted as a standard for an adequate trial (Dixon et al 1995; Barnes and McEvedy, 1996).  Though various authors have used varied definitions of treatment resistant schizophrenia, the most common definition of treatment resistant schizophrenia denotes patients who despite at least two adequate trials of classical neuroleptic drugs have persistent moderate to severe, positive, or disorganization, or negative symptoms together with poor social and work function over a prolonged period of time (Meltzer 1997). Approximately 30% of schizophrenic patients (10-45%) meet these criteria. This definition may be inadequate for a few whose positive symptoms respond adequately to neuroleptics, but have clinically significant negative symptoms, poor social and work functions, cognitive dysfunctions, poor quality of life and who constitute a significant burden to the family and society.  In addition, this definition does not consider suicidality of the patient (Meltzer 1997).



Table-1 Definition of treatment resistant schizophrenic patients:

Clinical history (previous treatment) No good level of functioning over past 5 years Received 3 periods of treatment in preceding 5 years with antipsychotics of at least 2 different chemical classes for at least 6 weeks, with an equivalent of at least 1000 mg chlorpromazine daily without significant relief.
Cross-sectional BPRS total score > 45 Rating > on at least 2 of the following BPRS items: conceptual disorganization, unusual thoughts, hallucinatory behavior, suspiciousness CGI score > 4
Prospective Failure to reduce score by > 20%; plus either a post-treatment BPRS score ? 35 or CGI score > 3 with 60mg haloperidol daily for 6 weeks

Efficacy of Treatments in Treatment Resistant Schizophrenia:

Studies with clozapine

Since the landmark study of clozapine by Kane et al (1988), various authors have studied different aspects of clozapine in treatment resistant schizophrenia.  Rodriguez et al (1998) compared clozapine responders, partial responders and non-responders from a group of resistant schizophrenic patients.  They looked into four factors (positive symptoms, negative symptoms, cognitive disorganization and behavioral disorganization) which they got using factor analysis of the initial symptom profile for comparison.  They reported that cognitive disorganization was higher among non-responders and behavioral disorganization was higher among partial responders. Fujii et al (1997) reported that patients with treatment resistant schizophrenia show significant global cognitive improvement, as measured by Wechsler Adult Intelligence Scale-Revised (WAIS-R) Full Scale, after a minimum of one year of treatment with clozapine. Meltzer and Okayli (1995) have reported decrease in suicidality of treatment resistant schizophrenic patients with clozapine treatment of 6 months to 7 years duration. Some authors have studied the relationship between the duration and efficacy of clozapine treatment. Jalenques et al (1992), in an open prospective trial of clozapine in treatment resistant schizophrenic patients reported significant improvement in positive symptoms by 1 month and negative symptoms by 3 months with improvement in social functions and reduction in use of concomitant medications. Lieberman et al (1994) reported 50% of the patients with treatment resistant schizophrenia and 76% of the treatment intolerant patients responded to 1-year trial of clozapine, and opined that an optimal period of trial of clozapine was around 12 -24 weeks. In a 2.5-year follow-up study of 169 chronic treatment resistant schizophrenic patients from a public psychiatric hospital, Avnon and Rabinowitz (1995) reported that 37.8% of patients discontinued clozapine treatment because of non- compliance, non-response, or side effects.  Recipients had significantly more decline in BPRS than dropouts; longer treatment was associated with more improvement. More number of patients on clozapine were either discharged or prepared for discharge than those stopped clozapine. Potkin et al (1994) using plasma clozapine concentration in patients receiving fixed dose of clozapine reported that a plasma concentration 420 ng/ml of clozapine distinguished responders from non responders, as significantly more number of patients with levels above 420ng/ml responded than those with lower levels. Connelly and Fullick (1998) in a retrospective design reported moderate to marked improvement in 63% of patients with treatment resistant schizophrenia based on Clinical Global Improvement scale (CGI). They also reported marked reduction in the number of days of hospitalization. Two reports have looked into the cost-effectiveness of clozapine treatment in treatment resistant schizophrenia.  Meltzer et al (1993), reported that after a 2 year treatment with clozapine there is significant reduction in treatment cost and it was almost exclusively from the decrease in the frequency and the cost of rehospitalization. Davies and Drummund (1993) based on the consensus about management of treatment resistant schizophrenia in UK have reported that clozapine would lead to a net gain of 5.87 years of life with no disability or only mild disability.  The direct costs of using clozapine were 91 pounds less per annum than standard neuroleptic therapy.  In addition, they opined that clozapine treatment could be cost saving or cost neutral.  From the above reports clozapine treatment for treatment resistant schizophrenia patients seems to be cost effective.

Studies of Clozapine with ECT:

There are two reports of combination of clozapine with ECT in treatment resistant schizophrenia.  Kales et al (1999) studied 5 patients and found that supplementing clozapine with a course of bilateral ECTs to be effective in treatment resistant schizophrenia.  However, its beneficial effects were short-lived.  Bhatia et al (1998) reported that a patient, who had not shown response to conventional neuroleptics alone, to a combination of conventional neuroleptics and ECT and with clozapine alone, showed improvement when clozapine was combined with ECT.  Both the reports opined that such a combination is safe. 

Studies Comparing Clozapine with Risperidone:

One double blind comparative study found both clozapine and risperidone to be equieffective.  There was no difference in the severity of EPS in the study (Bondolfi et al 1996).  Similarly, a trial comparing risperidone with clozapine found that both drugs were comparably effective in a group of 11 supersensitive psychosis patients, who were considered to be drug resistant schizophrenics (Chouinard et al 1994).  However, Flynn et al (1998) differed in their findings.  In an open trial comparing clozapine and risperidone, they found clozapine to be more effective than risperidone on various parameters like symptom profile, global functioning and clinical global improvement.  Still et al (1996) found that none of the 10 patients who remained treatment resistant on clozapine showed improvement when switched over to risperidone.  On the other hand, there was worsening of symptoms and side effects with the change, which caused high dropout rates. More controlled trials comparing the two drugs are required before concluding the superiority of one over the other. 

Studies comparing risperidone with other drugs:

Mercer et al (1997) reported marked improvement in general psychopathology in patients treated with risperidone compared to those receiving standard treatment.  This was explained on the basis of non-sedating side effect profile of risperidone. There are two studies, reporting the effect of risperidone on cognitive functioning in patients with treatment resistant schizophrenia.  Green et al (1997) in a randomized double blind comparison of risperidone and haloperidol studied verbal working memory.  Risperidone had greater beneficial effect than haloperidol.  Kern et al (1998) in a randomized double blind comparison of risperidone and haloperidol found that patients receiving risperidone showed greater improvement in reaction time and manual dexterity than patients receiving haloperidol. In the latter two studies the difference in performance was explained on the basis of specific beneficial effect of risperidonerather than a general reduction in extra-pyramidal symptom (EPS) liability.

Olanzapine in treatment resistant schizophrenia:

Martin et al (1997) conducted an open trial with olanzapine wherein they included patients who met Kane criteria for resistant schizophrenia.  However, their response criterion was more strict (BPRS < 18; 35% improvement vis-à-vis 20% in Kane et al study).  They used 15-25mg/day of olanzapine.  Only 36% showed improvement.  In a study including clozapine intolerant patients, olanzapine in doses above 20mg/day caused only 11% improvement. None of the patients reached the 20% criteria for response (Ratakonda et al 1997).  In contrast, another study showed that in doses of 40-60mg/day, olanzapine was useful in clozapine resistant patients (Launer et al 1997).  According to the case series published by Sheitman et al (1998), a comparable dose (30-40mg/day) did not only caused EPS in 5 out of 8 patients, but also all the patients remained psychotic.  However, 4 (50%) patients improved socially.  In a double blind 8-week trial, Conely et al (1998) compared olanzapine with chlorpromazine in 84 treatment resistant schizophrenia patients. Olanzapine and chlorpromazine showed similar efficacy, and the total amount of improvement with either drug was modest.  Olanzapine treated patients had fewer side effects than chlorpromazine treated patients.   In an open 16-week trial of 16 cases of treatment resistant schizophrenia, Dursun et al (1999) found olanzapine at moderate to high doses offered an effective treatment for a significant proportion of patients. In conclusion, one can say that the evidence for efficacy of olanzapine in resistant cases remains variable and inconclusive. It can be inferred from above reports that patients may improve with higher than recommended doses olanzapine, but they run a risk of developing EPS. 

Studies with other drugs:

Lal and Nair (1992), found that use of levomepromazine in a series of 23 chronic hospitalized treatment resistant schizophrenic patients resulted in improvement in 16 patients. Improvement led to discharge in 7, placement on a waiting list for a foster home in 4 and improved behaviour and autonomy in 5 patients.  Wolf et al (1992) put 9 patients with treatment resistant schizophrenia successively on four-week placebo, 1.25mg/day of bromocriptine, placebo and 2.5mg/day of bromocriptine, and found significant improvement in global symptomatology during the two bromocriptine treatments.  Chennapattana et al (1999) reported that 58 of 114 patients with treatment resistant schizophrenia met remitter criteria when treated with a combination of flupenthixol and ECT. Fifty-one of these were randomized into 3 treatment groups for maintenance therapy.  At the end of 7 months, the group which continued on combination treatment had significantly less relapse rates (40%) than those of who received flupenthixol alone (93%) or ECT alone (93%). 

Studies with adjuvant medications added to antipsychotic drugs:

Before the advent of clozapine for treatment resistant schizophrenia, many psychotropic drugs were used as adjuvants to antipsychotics.  They included beta-blockers, lithium, antidepressants and many others.  Wahlbeck et al (2000) reviewed 5 randomized controlled trials involving 117 patients comparing addition of adrenergic beta-blocking drugs and addition of placebo to the standard antipsychotic medication.  They noted that addition of beta-blockers did not have any effect, and concluded that beta-blockers can not be recommended as adjuvant in management of treatment resistant schizophrenia.  Christinson et al (1991) reviewed literature about augmentation strategies for treatment resistant schizophrenia.  The definition and documentation of treatment resistance was poor in most of these studies.  There were three studies of double blind placebo controlled multiple crossover design of adding lithium as an augmenting agent to the neuroleptic drugs. Improvements in multiple spheres (positive symptoms to social competence) were reported in about half to one third of patients.  The improvement did not depend on the presence of affective features. In a 4-week single blind, randomized, clinical trial patients failed to show improvement after the addition of lithium to the antipsychotic medication (Collins et al 1991).  Of the four studies of double blind placebo controlled crossover design with benzodiazepine augmentation reviewed by Christinson et al (1991), two showed significant benefits for benzodiazepines as compared to placebo. After reviewing two studies of patients with "treatment refractory schizophrenia plus symptoms of mania, excitement and overactivity" the reviewers concluded that the main effects of carbamazepine in patients with treatment resistant schizophrenia may be reduced aggression and improved control in interpersonal situations. Since glycine potentiates NMDA receptor-medicated neurotransmission, it may theoretically serve as an effective agent for schizophrenia.  There are, however, conflicting reports on addition of glycine. Heresco et al (1996) conducted a double blind, placebo- controlled, 6 week, randomized crossover trail of addition of glycine (0.8gms/Kg) to the on going antipsychotic therapy.  They found significant improvement in negative, depressive and cognitive symptoms with addition of glycine.  On the other hand, Potkin et al (1999), after a double blind placebo controlled study of addition of glycine (30gm/day) to optimal doses of clozapine, found that glycine actually interfered with the efficacy of clozapine.   In an open trial of addition of famotidine to antipsychotics, Oyewumi et al (1994) reported that 7 out of 12 subjects with treatment resistant schizophrenia improved, implicating the possible role of H2 receptors in the pathogenesis of deficit syndrome in schizophrenia. In the light of this, it can be said that there seems to be a proportion of patients with treatment resistant schizophrenia who respond to addition of lithium, benzodiazepines, and carbamazepine. Studies using more rigorous definition of treatment resistant schizophrenia areneeded to draw firmer conclusions. The Schizophrenia Patient Outcomes Research Team (PORT) has recommend a trial of adjunctive pharmacotherapy with benzodiazepines, carbamazepine, propranolol or lithium in persons who experience persistent and clinically significant positive symptoms despite adequate antipsychotic therapy, including trials with the newer antipsychotics (clozapine or risperidone) (Lehman et al 1998).


To date, clozapine is the only medication with demonstrated efficacy in treatment resistant schizophrenia. It has been shown to improve outcome in various domains like psychopathology, cognitive functioning, social and occupational functioning, and cost effectiveness in these patients.  However, the latter observations need replications.  The efficacy of other atypical antipsychotics also needs to be evaluated on the same lines. Patients failing to improve with clozapine may benefit from a combination of clozapine/neuroleptics and ECT, which seems to be safe and effective in the short run. However, improvement by such combination can be sustained only by maintenance treatment with the combination. The research data with the use of adjuvants and other drugs in treatment oftreatment resistant schizophrenia is too inadequate and conflicting to make firm conclusions about their efficacy. Further studies on treatment resistant schizophrenia need to look at other issues, like negative symptoms, suicidality, social functioning, disability and quality of life, in addition to positive symptoms. 


This study was supported in part by Quality of Life Research and Development Foundation, Bhubaneswar




Nilamadhab Kar* DPM, MD, DNB; Jagadisha, MD; Murali N, DPM, DNB
Assistant Professors, Department of Psychiatry, Kasturba Medical College, Manipal, 576119, India


* Corresponding Author. 

« Psychiatry


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