The emergence of antipsychotics has made a great breakthrough in the treatment of schizophrenia, but 30% – 60% of patients still lack response to adequate drug treatment or only partially respond [1]. Data show that even in the first episode of schizophrenia, about 14% of patients have difficulty in obtaining the expected efficacy [1]. The results showed that the patients with refractory schizophrenia with severe illness were up to 60% after the standard antipsychotic drugs were treated with sufficient amount of drugs without obvious effect. At present, the treatment of refractory patients has become one of the hot research topics in the field of schizophrenia therapy.

As the name implies, refractory treatment refers to the treatment according to the general method, but can not achieve the ideal effect. In the field of clinical psychopharmacology, refractory treatment is still a rather ambiguous concept, because the treatment of antipsychotics follows the principle of individualization. Is there a general method for all patients? What kind of efficacy can be achieved is ideal? Different people have different understanding.

There are detailed literature introduction of refractory schizophrenia in China [2,3], but unfortunately, there is no widely recognized and well-operated definition. Although this phenomenon can not be simply considered as a bad thing, it has brought many adverse effects from the perspective of clinical research. The main problem is that due to different researchers’ different understanding of refractory, there is no good comparability between the research materials. Therefore, it is very important to define a good operability for the difficult treatment to promote the exchange of research results.

Morrison (1996) thinks that the so-called “difficult treatment” refers to the patients with correct diagnosis, and different ways of administration, different types of antipsychotic drugs full-dose foot therapy therapy has not been satisfied with the effect [2]. The FDA defines the treatment as: schizophrenia patients with severe illness who have received enough treatment without obvious effect. However, how much dose and how long the course of treatment can be considered enough, what kind of efficacy can be satisfied, and no answer can be found in these descriptions.

Recently, there seems to be some relatively better operative definitions of refractory schizophrenia. Refractory patients defined by Juarez Reyes et al. (1997) in a flow-control study included: at least two antipsychotics, at least 600 mg of chlorpromazine daily, who were not effective for at least four weeks; and patients with TD [2]. The refractory cases defined by Kane et al. (198819921995) include: the treatment of three kinds of antipsychotic drugs (at least two of the three drugs with different chemical structures) with appropriate dosage and treatment course in the past five years; the patients can not tolerate the side effects of antipsychotic drugs; and the patients still relapse or deteriorate even if there is sufficient maintenance treatment or preventive treatment. Clearly, to define a cure, at least four of the following issues must be identified:

(1) How long does the drug treatment need to last is enough treatment course?

(2) What is the dosage, that is, the sufficient amount?

(3) How many drugs have you ever used?

(4) What criteria are used to judge the efficacy, that is, what is the satisfaction of the effect?

  1. how long does the drug treatment take to last is enough treatment? From the perspective of clinical treatment, to determine whether a certain antipsychotic drug is effective or not, generally, it can be concluded that the general impression can be obtained after 6 weeks of observation. However, if the highest and final levels of treatment response were to be observed, the time of six weeks was insufficient. The median time required for drug treatment to eliminate mental symptoms was 11 weeks, and the average was 35 weeks. Obviously, the lack of adequate response to the drug during the first six weeks of treatment does not mean that the continued adherence to the treatment will not have the desired effect. Therefore, to judge the patients lack of response to a certain drug, the treatment time should not be less than 12 weeks (Liu tiebang et al., 1994) [6].
  2. how much dose is enough? There is no certain saying. At present, the daily average treatment dose of chlorpromazine, clozapine, haloperidol and other antipsychotics is decreasing gradually. Generally speaking, if some improvement occurs in the past, it is expected that the better response may be obtained by increasing the treatment dose; however, in the past, there is no advantage in high-dose treatment for the drug treatment with adverse or no response. Some research data show that [1] the effect of high dose typical antipsychotics is not better than that of conventional dose; however, some clinical psychiatrists still tend to increase the dose further when the conventional dose is invalid. We tend to believe that judging whether the antipsychotic drugs are adequate can be combined with two indicators: whether the concentration of effective blood drugs, whether the conventional effective treatment dose, and not to overemphasize whether the treatment has been received with the ultra conventional dose.
  3. how many antipsychotics can be called refractory without treatment response? There is no consensus at present. Theoretically, the characteristics of different kinds of typical antipsychotics are different, and the lack of response to a drug does not exclude the treatment reaction after changing other drugs. Most clinicians have similar practical experience. However, the study found that the response of a patient to a typical antipsychotic drug can roughly predict his response to other typical drugs; patients who are not effective in one type of antipsychotic drug often lack treatment response to other typical drugs. Therefore, some scholars doubt the effectiveness of other therapeutic drugs. However, it is difficult to treat a typical drug without treatment reaction. There is no consensus at present. Most scholars do not agree with this view. We believe that from the perspective of clinical practice, it is better to systematically observe two drugs with different chemical structures than one drug for 12 weeks and continuously observe multiple drugs before deciding whether it is difficult to treat. If it is invalid, it should be treated as a case of refractory. Because of this treatment, it appears to be more positive and can obtain possible benefits faster.

Finally, what criteria are used to evaluate the effectiveness of treatment is also an important parameter to determine whether it is difficult to treat. At present, the general method is to use psychopathology indicators, such as before and after treatment, to evaluate the mental symptoms scale, to observe whether the score of the mental symptom scale has improved statistically after a certain period of treatment; or the rate of score reduction is used as the indicator. The method of calculating the score reduction rate is to divide the difference of the scale scores before and after treatment as the divisor, divide by the score of the pre treatment scale, and multiply the quotient number by 100%. Some authors [5,7] adopt the criteria that: the rate of score reduction is less than 20% is invalid, 20% ~ 60% is clinical effective, and more than 60% can be regarded as significant. Kane et al. (1988) [4] the effective provision in a study is that: after treatment, BPRS score is reduced by 20%, clinical overall impression (CGI) scale is less than or equal to mild, or BPRS score is less than 35. Recently, the author (bondolfi et al., 1998) [8] used the effect size as the index of efficacy evaluation. The calculation method was to divide the difference between the scale before and after treatment as the divisor, and divide it by the standard deviation of the difference. Generally speaking, if the efficiency index is less than 0.2, it should be considered invalid, 0.2-0.5 is micro effect, 0.5-0.8 is medium effect, and more than 0.8 is strong effect. In the above-mentioned study, the severity of symptoms at the beginning of treatment has a very important impact on the judgment of symptom improvement. The difference of the effect of BPRS from 70 to 56 (20% of the score reduction rate) and the total score from 40 to 32 (the score reduction rate is 20%) is the same. Different observers have different understanding of this.

The improvement of psychosis or negative symptoms should be paid special attention to when observing the curative effect. If the improvement of mental symptom scale score is very small, but the subjective health status, self-care ability, social and psychological function or the degree of effort to participate in treatment have significant improvement, the therapist cannot ignore its potential clinical importance [5]. Therefore, it is inevitable that the curative effect is biased only according to the improvement degree of psychopathology. We believe that a comprehensive evaluation of efficacy should include psychopathology, social function and quality of life, compliance with drug treatment, subjective experience of patients, risk / benefit ratio and other aspects of information.

In the treatment, clozapine is considered as a positive antipsychotic drug for refractory schizophrenia. The data showed that clozapine can improve 30% – 60% of patients who have not been treated effectively in the past [4,5,9,10]. Clozapine has a prominent advantage that it is not easy to produce extrapyramidal side effects, but it is at risk of granulocyte reduction. The cumulative incidence of granulocytopenia after one year of clozapine treatment is about 0.8 percent, which hinders the widespread use of clozapine [5].

So far, the efficacy of risperidone in refractory schizophrenia has not been clearly confirmed as clozapine. However, before the treatment of clozapine, risperidone with better safety and less side effects may be given to those refractory cases. For example, risperidone is not effective and then clozapine is used. However, some comparative studies have found that the effective rate of risperidone invalid patients is 40% when they switch to clozapine, while only 15% of the patients who are not effective in clozapine use risperidone. It is generally believed that the most suitable time to evaluate the efficacy of risperidone is 6-8 weeks after the treatment. A few of the refractory cases may have curative effect after months of risperidone, so the time for observation should be prolonged.

It can be predicted that in the present and future quite a long time, the treatment of refractory schizophrenia will be a major problem that perplexes psychiatrists and clinical psychiatrists. What is the refractory treatment? Different researchers have different understanding. In order to promote academic exchange, it is necessary to formulate a good diagnostic standard with good operability. To set this standard, at least agreement must be reached on the following issues: how long (what is the course of treatment) at least, how much dose (what is sufficient), how many drugs have been used, and what criteria (which predicate effect is satisfied) used to determine the efficacy.

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