school eats my life

[shinxy]

Abstract
Our goal in this study was to determine the relative efficacy of haloperidol and clozapine in treating the positive and negative symptoms of partially treatment-responsive schizophrenia. We recruited sixty subjects diagnosed with schizophrenia who were currently being treated with fluphenazine without full remission but without being considered treatment-refractory. After a two-week period of decreasing previous medication levels and two weeks without medication, fifty subjects entered a randomized double-blind study of clozapine and haloperidol. The study lasted fourteen weeks, consisting of eight weeks to adjust medication dosages to treatment levels and six weeks of dosage adjustment based on individual needs. Results were assessed based on SAPS and SANS scores taken directly before and after the treatment period. We found that both groups showed significant improvement from pre-treatment levels on both measures. Neither treatment was found to be significantly more effective in the treatment of positive symptoms, whereas clozapine was found to be more effective in the treatment of negative symptoms. These findings contradict previous research, but may have been due to extrapyramidal or secondary negative symptoms, which were not measured directly. We recommend reconducting this study with more diagnostic assessments available.

Relative Efficacy of Clozapine and Haloperidol in Treating Positive and Negative Symptoms of Partially Treatment-Responsive Schizophrenia

Schizophrenia has a long history, possibly as old as humanity itself, but only within the last half-century have we discovered effective treatments for this disease. The accidental discovery of the drug chlorpromazine’s antipsychotic effects in the 1950s was nothing short of a revolution in the treatment of schizophrenia. Although chlorpromazine had a high number of side effects, chiefly an increase in negative symptoms and a high risk of tardive dyskinesia, suddenly there was a truly effective weapon available in the fight against schizophrenia, albeit a somewhat blunt and unrefined one. Over time, drugs with less severe side effect profiles took the place of chlorpromazine, even increasing functioning in some schizophrenic patients to the point where other forms of psychiatric intervention, outpatient care, and even eventual assisted reintegration into society were possible. However, drug therapy is still clearly the treatment of choice for schizophrenia, and other therapies remain ineffective when not used in conjunction with psychiatric medication.
Today, two main drugs are used in treating schizophrenia- haloperidol and clozapine. Haloperidol, which has taken the place of chlorpromazine as one of the most prescribed forms of antipsychotic medication, is a typical and highly potent neuroleptic, with broad antidopaminergic properties. Although it carries fewer side effects than chlorpromazine, it still has a strong risk of early and late extrapyramidal symptoms, often in the form of tardive dyskinesia. Clozapine, on the other hand, is a newer, atypical neuroleptic which more selectively targets limbic dopamine-4 receptors, resulting in far fewer extrapyramidal symptoms, less dyscognitive effects, and a less severe side-effect profile. It is often effective in patients whose symptoms do not respond to haloperidol or other medications in the class of typical antipsychotics. It carries its own side-effects, however, most notably a possibly lethal condition called agranulocytosis, which causes a reduction in white blood cell count, requiring FDA-mandated weekly blood tests to be taken. This side effect was severe enough that trials of the drug were suspended in 1975, before being taken up again a decade later, when clozapine's effectiveness against treatment-resistant schizophrenia was noticed.
However, clozapine's effectiveness relative to haloperidol in treating "normal", treatment-responsive schizophrenia remains in question. It has become relevant within the literature, therefore, to find some absolute means of comparing the two drugs in efficacy studies, in conditions where both drugs could prove effective. Because of a lack of uniform experimental methods between studies, as well as the difficulty in designing objective studies within the context of a disorder as broad and complex as schizophrenia, there is still no solid consensus within the field on the relative benefits of clozapine and haloperidol in non treatment-refractory schizophrenia.
The question my study is addressing is, specifically, what is the relative efficacy of clozapine versus haloperidol in the treatment of positive and negative symptoms of schizophrenia that is not treatment-refractory?
Several studies of this type have already been conducted. In Breier et al. (1994), 41 outpatients who were partially neuroleptic-responsive were put in a ten-week double blind study comparing clozapine and haloperidol, following a six-week fluphenazine trial. Clozapine and haloperidol were found to be equally effective in treating negative symptoms, but clozapine was found to be more effective in treating positive symptoms than haloperidol.
However, the subjects in the study exhibited, by the authors' own admissions, unusually low levels of pre-treatment negative symptoms, and were also on the less severely ill end of the schizophrenic continuum. These findings, therefore, can not necessarily be generalized, and suggest that more robust effect sizes may have been seen, had the subjects shown more pre-treatment negative symptoms.
In seeming response to this and similar lines of inquiry (Rosenheck et al. 1999), researchers conducted a 15-site double-blind random-assignment study comparing the effects of clozapine and haloperidol in 423 schizophrenic inpatients patients with severe negative symptoms and/or deficit schizophrenia. The study lasted for 12 months in all. In this study, it was found that clozapine was significantly more effective than haloperidol in treating positive symptoms of schizophrenia, but not significantly more effective than haloperidol in treating negative symptoms. Neither medication had a significantly larger effect size on either measure of symptoms than the other.
However, in this study, subjects taking haloperidol were administered additional medication for treating extrapyramidal symptoms, and both groups w re provided with a variety of psychotherapeutic and rehabilitative treatments that were not standardized or taken advantage of equally by all the participants. Additionally, the haloperidol group showed an extremely high rate of subject dropout (72%). Certain "crossover subjects" actually switched to the other medication due to complications, but were retained in the study's findings. Thus, there are many sources of potential error that are not accounted for in this study.
More recently, a study (Volavka et al., 2000) comparing the relative efficacy of haloperidol and three different atypical antipsychotic medications (clozapine, olanzapine, and risperidone) was conducted at four different hospitals (two in New York state, two in North Carolina.) 157 treatment-refractory inpatients were randomly assigned to the four treatment types and treated in a blind manner over a 14-week treatment period. All the atypical medications showed significant levels of improvement on the Positive and Negative Symptom Scale over haloperidol. Clozapine in particular was shown to be the most effective out of the three atypical medications for treating negative symptoms, although none of the atypical medications showed clinically significant levels of benefit over one another.
However, these results were to be expected in light of the group being investigated. These patients were historically resistant to typical neuroleptic drugs, including haloperidol. The haloperidol group was being used as a control group rather than as a real treatment group.
The effectiveness of clozapine in treating treatment-refractory schizophrenic patients is already well established, but research has not yet fully validated clozapine as a primary treatment for "normal" partially treatment-responsive schizophrenic patients. Given the significant advantages that clozapine has, anecdotally, in terms of positive and negative symptom response, as well as in overall cognitive functioning, it seems worthwhile to continue this line of inquiry. However, we want to conduct our study in a more controlled setting than many of the ambitious multi-site studies we have cited. We also want to study a population that will show both significant positive and negative symptoms. We will undertake a fourteen-week double-blind trial of haloperidol and clozapine, following a two-week fluphenazine-mediated screening period and a two-week drug free pre-treatment period. We will measure improvement in terms of positive and negative symptoms, using the SAPS and the SANS. We hypothesize that patients treated with clozapine will show significant improvement over patients treated with haloperidol in terms of positive but not negative scores. This is consistent with the data found in the two previous studies the used haloperidol in a similar context to our own study.
Methods
Participants
We recruited subjects for this study by soliciting mental health units across the New England area for patients being treated for schizophrenia. Our inclusion criteria specified for patients who had been shown symptoms of schizophrenia according to the DSM IV over the last 12 months, who were currently being semi-successfully treated with fluphenazine but had not shown complete remission of symptoms. Our exclusion criteria were for patients who had previously been treated with either haloperidol or clozapine, and for patients who showed higher levels of secondary and extrapyramidal negative symptoms than of primary negative symptoms. We also excluded patients whose comorbid symptoms severe enough that their "primary" diagnosis was another disorder besides schizophrenia.
After six months of correspondence with hospital staff, we were able to find 65 patients who were willing to participate in the study. We systematically traveled to each facility and administered the SCID to each of the patients and verified that each patient fit the inclusion and exclusion criteria of the study. Five subjects were eliminated from consideration, while 60 subjects were moved to one facility in Massachusetts, where they could be most closely monitored by experienced masters and doctoral-level clinicians affiliated with the study. Close contact was maintained with each patient's primary clinician so as to keep them abreast of progress, as well as so that they could serve in an advisory capacity in the day-to-day treatment of each subject.
Out of these sixty subjects, thirty were men and thirty were women. 55 of the subjects were white, two were African-American, one was Asian American, and one was Afro-Caribbean. Their ages ranged from 23 to 45 years old.
Measures
During this study, two variables were tracked: positive and negative symptoms. Positive symptoms were measured before and after treatment using the SAPS, and negative symptoms were similarly measured using the SANS. The measures were administered by clinicians affiliated with the study, who had several years of experience treating schizophrenic patients and administering these tests. During the selection process, clinicians used the Structured Clinical Interview for DSM-IV (SCID) to insure a diagnosis of schizophrenia for each participant.
The SAPS and SANS are similar clinician-administered measures designed to assess overall levels of positive and negative symptoms. They were both authored by Dr. Andreasen at the University of Iowa, and were published in 1984 and 1981, respectively. Both have been used as measures of symptom severity in hundreds of other research studies.
Both scales consist of a variety of specific symptoms, which a clinician judges based on their presence or absence. Each symptom is rated along a six point rating scale, from none (0), to questionable (1), mild (2), moderate (3), marked (4), or severe (5). The symptoms are divided into subgroups, and each subgroup is also given a global or overall rating. The SAPS consists of 30 items, divided into four subgroups: hallucinations, delusions, behavior, and thought disorder. The SANS consists of 20 items, divided into five subgroups: expression, speech, hygiene, activity, and inattentiveness.
Procedure
Following selection and transfer to our Massachusetts facility, a two-week screening and acclimation period was begun, using their pre-treatment medications, if any (including fluphenazine.) Medication levels were incrementally decreased each day over a period of two weeks, culminating in a two-week drug-free pre-treatment period. This drug-free period was supervised according to some of the concerns raised in Chen & Moreno's 1997 review of ethical concerns in medication-free research of schizophrenia. These include that there be a compelling scientific rationale for a medication free period, that the medication-free period cause no serious harm or significant discomfort, and that provisions be made to minimize risks of harm. The review also recommended that periods without medication not exceed one month.
We judged there to be a compelling rationale for a medication-free "washout" period because of the need to minimize the confounding influence of previous treatment with a typical neuroleptic. Without this kind of period, the effect size seen in the haloperidol group would have been small, and the haloperidol group would have functioned as a control group rather than as a true alternative treatment.
In order to minimize the risk of harm, clinicians were assigned to the wards in shifts so as to facilitate constant 24-hour supervision, and subjects were closely observed for worsening of symptoms. Subjects were removed from the study and immediately returned to pre-study medication levels if they showed more than one serious positive-symptom related episode, or a severe deterioration of condition in terms of negative symptoms defined as a fluctuation of more than 20 points on the SANS.
Those who completed this four-week pre-treatment screening were administered the SANS and SAPS, then randomly assigned to the two treatment groups in a double-blind manner. Both groups were medicated according to a normative medication schedule, four pills a day. Both sets of pills were identical in appearance. The two medications were administered in a manner clinically consistent with normal treatment of schizophrenia, although no other medications were used in the study. Over the first eight weeks, patients gradually increased their dosage to treatment levels, and as such, several sets of identical pills with varying (increasing) dosages were prepared before the study, to be administered in sequence on different days. Clozapine patients eventually increased their dosages to 150 mg per day, whereas haloperidol patients reached the end-level dosage of 20 mg per day. During the final six weeks, clinicians were able to use their discretion in increasing or decreasing dosage levels according to patients' individual needs during treatment. Both treatment groups also received weekly blood counts for possible agranulocytosis. Throughout treatment, patients were observed for any other complications related to treatment. Following the fourteen-week study, patients were administered the SANS and SAPS in the same manner that they were before beginning the treatment medications.
Results
During the four-week pre-treatment screening, ten patients withdrew from the study (two from behavioral difficulties related to the change in facilities within the first week, four due to positive symptom episodes as defined in the study procedures, and four due to severe increases in negative symptoms also as defined in the study procedures.) The 50 remaining patients remained in the study for its entire duration.
Several t-tests were conducted to assess any pre-treatment differences between the two randomly assigned groups, in terms of age, [t(48) = .310, p = .758] pre-treatment SAPS score [t(48) = .179, p = .858], and pre-treatment SANS score [t(48) = .251, p = .251]. Another set of t tests were conducted to assess any possible differences between genders along the same three axes, age [t(48) = .582, p = .563], pre-treatment SAPS [t(48) = 1.151, p = .255], and pre-treatment SANS [t(48) = -.555, p = .581]. No significant differences were found between the treatment groups on any measure before treatment.
A repeated-measures ANOVA was conducted, comparing pre and post-treatment differences between the two treatment groups. It revealed that, while both treatments offered significant improvement over pre-treatment conditions, haloperidol and clozapine were not significantly more effective than one another in terms of positive symptoms. F(1,48) = .374, p = .543. Clozapine was significantly more effective than haloperidol in treating negative symptoms, F(1,48) = 20.993, p <.001. Refer to Figure 1 for means by condition. In terms of percentages, clozapine offered a 58.3458% mean improvement, while haloperidol offered 30.7788%. Because we speculated that age might have a correlation with effect size, due to increased risk of residual extrapyramidal symptoms, we conducted a correlation between age and percent improvement on the SAPS and SANS. We also conducted similar analyses to compare effects between male and female subjects between the two groups. None of these post-hoc tests revealed a clinically or statistically significant difference.

Figure 1


Mean SAPS/SANS score by treatment group and condition.

Discussion
In this 14-week double blind study comparing clozapine and haloperidol, clozapine and haloperidol were equally as effective in terms of treating positive symptoms, but it was found that clozapine was significantly more effective in the treatment of negative symptoms of schizophrenia. Therefore, our hypothesis proved incorrect, in that clozapine was not more effective in treating positive symptoms in schizophrenia
This contradicts Breier et al. (1994), whose results were roughly the inverse of ours (clozapine and haloperidol equally effective in treating negative symptoms, but clozapine more effective on positive symptoms.) This discrepancy can be accounted for, however, in that Breier’s study was with outpatients who were less severely ill than our treatment group, especially in terms of negative symptoms. The fact that there were more negative symptoms to treat in our group may account for a greater observed effect size.
Rosenheck et al. (1999) also stated that they observed a greater effect on positive symptoms and equal effect on negative symptoms between clozapine and haloperidol. However, due to the somewhat irregular methodology employed by this study, as well as the use of additional medications and therapies within the study which were not standardized, it may be that these findings are subject to significant sources of error not accounted for.
Volavka et al. (2000) found significant benefit of clozapine over haloperidol in both positive and negative symptoms. However, these findings are of limited relevance here because their treatment group of treatment-refractory schizophrenic patients is different from our group of partially treatment-responsive patients- obviously Volavka’s group was not responding to haloperidol before the study, and the haloperidol group was used as a control rather than as a legitimate treatment group.
Our study has many limitations. First of all, we did not document patients' comorbid disorders in detail. We did not document patients' medication histories. Nor did we use any kind of scale to separate primary and secondary negative symptoms, although our exclusion criteria did mention that patients with more secondary than primary negative symptoms were not admitted to our study. Similarly, we did not use any kind of scale to assess extrapyramidal symptoms. Haloperidol often causes extrapyramidal symptoms in both early and late treatment, and fluphenazine can also cause residual extrapyramidal symptoms even after treatment has terminated. It could be that our results in the haloperidol group, which displayed a much higher level of negative symptoms, are due to extrapyramidal or even secondary negative symptoms.
Another limitation was that it was difficult for experienced clinicians to maintain the double-blind in this study, consi0dering the differential side-effect profiles of our two study drugs. Specifically, haloperidol tends to cause dry-mouth and incontinence, while clozapine tends to cause drooling and constipation. Therefore, although our methods attempted to enforce a double-blind, within a few weeks it was clear who was in which medication group in many cases.
Also important to note is that we only used the SANS and the SAPS to measure improvement, while there are other more clinically significant measures of improvement available, which show improvement in terms of overall functioning and wellbeing. Symptom relief is obviously an important concern for schizophrenic patients, but if it is not carried out with an eye towards improvements in overall functioning, we run the risk of doing more harm than good.
In terms of future directions for study, we would recommend conducting a similar study to this one, with more subjects and a greater number of diagnostic measures. This will help researchers draw more reliable conclusions about secondary and extrapyramidal negative symptoms, as well as clinical improvement. It would also be interesting to explore the efficacy of clozapine and haloperidol in a group of patients being treated for their first episode of schizophrenia. Lack of previous medication history would eliminate many sources of error that are an inescapable part of most research on schizophrenia today. We would also recommend a longitudinal study be conducted comparing quality of life and long term prognosis between haloperidol and clozapine, because quality of life over long-term care is probably a better measure of treatment efficacy. Short-term measures of symptom severity can only allude towards clinical improvement, while clinical improvement itself should be a primary focus of schizophrenia research.
Finally, patients being treated with atypical neuroleptics often show greatly increased lucidity and reduced depression from patients being treated with typical neuroleptics. (In 2002, clozapine, in particular, was approved for reducing the risk of suicidality in patients with schizophrenia.) The current paradigm still considers schizophrenia largely an inpatient problem, when it is increasingly being treated with outpatient solutions. As more and more efficacious treatments for schizophrenia are devised, we may be dealing with future generations of 'functional schizophrenics', whose symptoms are reduced to the point that they will be capable of re-entering the workforce in large numbers. However, maintaining a functional schizophrenic population also includes addressing problems related to schizophrenia that have not been understood in depth, such as drug abuse and risky sexual behavior. As schizophrenia becomes more treatable, addressing these secondary problems will be just as important as symptom relief. So far, this area remains an unexplored frontier, but there is huge potential for new research that will be critical to understanding this new and emergent population.

References

Breier, A., Buchanan, R., Kirkpatrick, B., Davis, O., Irish, D., Summerfelt, A., et al. (1994) Effects of Clozapine on Positive and Negative Symptoms in Outpatients With Schizophrenia. American Journal of Psychiatry, 151, 20-26.
Rosenheck, R., Dunn, L., Peszke, M., Cramer, J., Xu, W., Thomas, J., et al. (1999) Impact of Clozapine on Negative Symptoms and on the Deficit Syndrome in Refractory Schizophrenia. American Journal of Psychiatry, 156(1), 88-93
Volavka, J., Czobor, P., Sheitman, B., Lindenmayer, J., Citrome, L., McEvoy, J P., et al. (2000) Clozapine, Olanzapine, Risperidone, and Haloperidol in the Treatment of Patients With Chronic Schizophrenia and Schizoaffective Disorder. American Journal of Psychiatry, 159(2), 255-262
Chen, D. & Moreno, J. (2006) Ethics of Medication-Free Research. Schizophrenia Bulletin 32(2), 307-309.
Wikipedia contributors (2006). Haloperidol. Wikipedia, The Free Encyclopedia. Retrieved 13:44, May 1, 2006 from http://en.wikipedia.org/w/index.php?title=Haloperidol&oldid=50787258.
Wikipedia contributors (2006). Clozapine. Wikipedia, The Free Encyclopedia. Retrieved 13:46, May 1, 2006 from http://en.wikipedia.org/w/index.php?title=Clozapine&oldid=50981602.

(I didn't do "true" APA format here, but formatting on livejournal is a pain.)
(hope you enjoyed.)