Models of treatment with antipsychotics of the schizophrenic patients.

The aim of this study were to determine which antipsychotic are currently in use, to establish which doses are administrated to patients, to find out is there a practice of proscribing simultaneously more then one antipsychotic drug, to determine whether antipsychotic are proscribed in divided doses, to establish whether there is, besides antipsychotics, treatment with other medicaments (co-administration), especially with antiparkinsonics. The research (study) is epidemiological-clinical prospective, descriptive and analytical and it was conducted at University hospitals in Sarajevo, Tuzla and Mostar. Criteria for inclusion, non-inclusion and exclusion from the study were precisely defined as a mean for formation of sample. Based on this hypothesis were established, zero and alterative. According to zero hypothesis in the treatment of schizophrenia at University hospitals in FBiH new antipsychotic drugs are in use, small doses are proscribed (up to 20 mg), not more then one antipsychotic drug is used simultaneously, antipsychotics are administrated once a day and alongside with antipsychotics other medicaments are not co-administrated, especially antiparkinsons. The results of our study are showing that majority of patients are treated with classical antipsychotics. Minority of patients is treated with atypical neuroleptics like olanzapine, which is proscribed only in Sarajevo. Use of risperidone and ziprasidone is registered also only in Sarajevo, but only small number of patients is treated with these drugs. Most frequent antipsychotics were promazine and haloperidol. The range between minimal and maximal daily dose of promazine was from 50 to 450 mg/daily, and for haloperidol from 1 to 75 mg/daily. Above-mentioned drugs were administrated in an average from two to three times a day. Alongside with antipsychotics, other drugs were used. Most frequent was the use of biperidine in oral and parenteral formulation, as well as nitrazepam and diazepam. The importance of this study is following: data are useful for the current mental health care reform in FBiH, results will point out place and position of FBiH in contemporary world trends in the treatment of schizophrenia, they will contribute to rational use of antipsychotic therapy, they will point out possible ways in reduction of side effects, often dangerous adverse effects of antipsychotics, and they will give contribution to faster rehabilitation of schizophrenics with the reduction of financial means for the treatment of patients with schizophrenia.


Introduction
Classic (typical) antipsychotics have two important lacks: poor effect in the treatment of negative schizophrenia symptoms and tendency to cause extrapyramidal side effects. It is considered that - of schizophrenic patients did not react (nonrespondents) on the treatment with typical antipsychotic medications. A need to discover new medications that will be more efficient than the existing ones, as well as growing demands of the health services for application of the psychoactive medications, implied ongoing interest for faster development of pharmaceutical industry. Nevertheless, beside the great enthusiasm and proven benefit to the patients by new medications, provision of more comfortable and more bearable work to the staff at the psychiatric institutions, and contribution to the better economic situation in the society, the interest for identification of direct side effects and potential risk of their application is rising, beside the fact that the side effects of the psychopharmacological treatment are much smaller compared to other biological methods of therapy in psychiatry (electroconvulsive, insulin therapy and others). Atypical antipsychotics are mostly medications which have similar structure as already known antipsychotics (close to haloperidol and sulpiride), but others which have different chemical structure and mechanism of action are discovered (serotonin and dopamine antagonists) (). Application of atypical antipsychotics is more common in the world than in our country (except clozapine), due to their high cost and because the current health insurance system cannot provide to the patients in our country affordable everyday use. However, we have to hope that soon these new antipsychotics will be available also to the professionals in our country.

Results
Sample is consisted of  patients. From this number eighty five () patients are from Sarajevo, forty-four () from Mostar and eighty seven () from Tuzla. According to age structure, distribution of the patient is generally equal. The least number of patients is in the age group younger than twenty years ,, and older than sixty , as in the whole sample, as well as in each center. Majority of patients is in the age group from forty to forty nine years of age , in Sarajevo and Mostar, and in Tuzla the most dominant age group from fifty up to fifty nine years , ( In Mostar the leading antipsychotic is haloperidol, orally administered, and with which  patients were treated. This represent , of total number of patients in Mostar (Table ). Fewer patients were treated with atypical narcoleptics such as olanzapine, which was applied in treatment only in Sarajevo for  patients or ,. Clozapine was applied in all three centers but in very small percentage of cases (Table  and Chart ). Among other medications in Sarajevo most frequently administered is nitrazepam in  cases (,), as well as in Tuzla in  cases (,). In Mostar most fre-quent medication is biperidine in oral and parenteral form in  cases which is more than half of treated patients, or ten cases (,) ( Table  and Chart ). In Sarajevo  patients (,) was treated with only one antipsychotic,  (,) with two, while the combination of three or more antipsychotics received only five patients (,). In Tuzla  patients (,) received only one antipsychotic medication,  (,) with two, while combination of three or more antipsychotics wasn't use in the treatment. In Mostar seven patients (,) was treated with only one antipsychotic, the majority of patients was treated with two  (,), and the combination of three or more antipsychotic was used for  patients (,). We can notice within the total sample that the majority of patients was treated with only one antipsychotic  (,), and  (,) patients was treated with two antipsychotics. Few patients were treated with three or more antipsychotics,  of them or , (  (Table ). There is a significant statistical difference between the centers by application by haloperidol daily doses applied at the , level (Table ).
FREQUENCY OF HALOPERIDOL ADMINISTRATION Frequency of haloperidol application is similar as well among the centers as well in the total sample (Table ).
Analyses of variance showed that there is not a statistically significant difference between the groups (cities) regarding the frequency of haloperidol administration in the oral form (Table ).  (Table ). A significant statistical difference was not noticed between the tested centers regarding the applied individual clozapine doses (Table ).

DAILY DOSES OF CLOZAPINE APPLICATION
Average daily dose of clozapine was , mg, while the lowest daily dose is applied in Mostar , mg, and highest in Sarajevo , mg. Within the total sample, minimal daily dose of clozapine is  mg, and maximal daily dose is  mg (Table ). A significant statistical difference was not noticed between the tested centers regarding the applied daily clozapine doses (Table ).

FREQUENCY OF CLOZAPINE USE
In all centers clozapine was administered three times per day, so there is not a statistically significant difference between the centers regarding the frequency of clozapine administration (Tables  and ).

Biperidine applied in individual doses
In Sarajevo a total of  patients were treated with biperidine, in Tuzla , and in Mostar  patients. Total number of treated with biperidine is  (,) within baseline (Table ). Significant differences were not found between the centers in the relation to administered individual doses of biperidine (Table ).

Biperidine administered in daily doses
Average daily dose of biperidine was , mg, while the lowest daily dose is applied in Mostar , mg, mg, and highest in Sarajevo , mg (Table ). Significant differences between the centers were not notices regarding the administered daily doses of biperidine (Table ).

FREQUENCY OF BIPERIDINE APPLICATION
Average frequency of biperidine administration varies in the total sample as well as between the centers (Table  ). There are statistically significant differences regarding the frequency of biperidine use between the centers (p=,) (Table ).

Discussion
Conducted a comparative research regarding the applied antipsychotics in the period from . until . Dur-ing the  antipsychotics were prescribed to  patients () from a total of  hospitalized patients. The treatment begins usually within the first  hours, while the hospitalization lasted around eighteen days. Highly potent antipsychotics were used , times more frequently than the low potent;  of patients were treated with clozapine. Average daily doses of the applied antipsychotics equivalent to daily doses of chlorpromazine was  mg; and the maximal doses was  higher. Doses of highly potent antipsychotics (fluphenazine and haloperidol) are only - above the mean values (). Very rarely two or more antipsychotics were used, but it is noticed that there was a co administration of anticonvulsants (in  of cases, among which  was treated with valproate), benzodiazepines (), lithium (), one antidepressant () or more (). The doses were in average higher by  among males,  lower for the patients older than  years com-SVJETLANA LOGA-ZEC ET AL.: MODELS OF TREATMENT WITH ANTIPSYCHOTICS OF THE SCHIZOPHRENIC PATIENTS pared to the patients aged -, and  higher for the patients with schizophrenia or schizoaffective disorders compared to other diagnoses. A comparison with . indicates that the average duration of hospitalization (N=) seventy-three days which can indicate some differences in application of neuroleptics and benzodiazepines, while there was present lower frequency of anticonvulsants and lithium use. Authors concluded that the highly potent antipsychotics and clozapine are the mostly used during the , also that the doses of the highly potent are just slightly lower than the doses of low potent antipsychotics, and that the combination with the mood stabilizers also more frequent during , wile the duration of hospitalization is  longer during the . However, our research showed that in the minority of cases atypical antipsychotics, such as clozapine, were used. In Sarajevo three patients were treated with clo-zapine, in Tuzla eleven, and in Mostar four patients. Total number of treated with clozapine within the total sample was eighteen (,). Average individual dose that was administered to these patients within the total sample was , mg, while the lowest individual dose was administered in Mostar , mg, and highest in Sarajevo , mg, with standard deviation of , and standard error of mean of ,, or , and , regarding city. The confidence interval varied from , to , or from , to , for the patients from Mostar and Sarajevo. Two long-term controlled comparison studies of clozapine use with the conventional antipsychotic medications discovered the advantages of clozapine, reflected in better psychological, social and functional results. Although this effect was not extreme, it was a long lasting and confirmed the profitability of its use (). The doses in the United States are approximately double as the doses in the Europe (- mg/day). Some of the side effects of clozapine use, such as: convulsions, confusion and sexual dysfunction, are related to dose and blood levels. However, increase of body mass was not dependant on dose. Latest reports about the optimal blood levels shows that the levels should be between  and  μg/ml, although many patients had a good response even on lower concentrations (). Contemporary researches provided a strong evidences about the efficiency of second generation antipsychotics in the treatment of schizophrenia, and clearly indicated that cause much less extrapyramidal side effects (EPS) than the traditional medications (). In addition, there are evidences that these medications have less potency to cause tardive dyskinesia (TD) than the first generation antipsychotics, and can be useful in the treatment of preexisting TD. In general, patients tolerate much better these medications than older antipsychotics, with few important exceptions, including the risk of agranulocytosis in clozapine use and potential to increase body mass by many medications from this group. Due to their superior safety in terms of neurological side effects, it is consider that the second-generation antipsychotics should be available as the first choice of treatment in schizophrenia, and preferred in first episode patients (). Conducted a study in the public hospitals in Hong Kong with obtained data about the treatment with antipsychotic medications in relation to the dose of antipsychotics, combined use of multiple antipsychotics, administration in divided daily doses and co administration of antipsychotics with the medication for Parkinson's disease. Sample was consisted of  schizophrenic patients randomly selected. A census was made, and the questionnaire was consisted of items about demographic and clinical data, as well as description of all medications that patients received on the day of census.
Results of study indicates that the average dose of antipsychotics was  +/- (mean ; rang -) mg CPZeq. More than two thirds of patients received multiple medications simultaneously, while less than  take their medication in divided daily doses. Antiparkinsonics was used in , of patients. Authors opinion is that the treatment with antipsychotics in mainly in accordance with international standards. Problem area is simultaneous use of multiple antipsychotics both in acute and chronic cases, than use of higher doses than recommended, as well as frequent use of antiparkinsonics in chronic cases. Because of disseminated results, authors consider that the continuous medical education will lead to improvement of treatment quality for the patients with schizophrenia (). Compared use of antipsychotics among hospitalized patients during the three months of  (n=), . (n=) and . (n=). Results showed that during the . Atypical antipsychotic was mostly used e.g. olanzapine was used more than risperidone and quetiapine while all three medications were prescribed more frequently than any other antipsychotic. Two or more antipsychotics were simultaneously applied during the hospitalization for  patients () during . Total dose (dose equivalent to chlorpromazine) administered during  was  mg/ day,  higher than doses for the patients during , and  higher than doses used in . Higher doses of antipsychotics were applied for the patient s with psychotic disorders compared to the patients with the affective disorders. Higher doses also lead to significant improvement of clinical state, multiple pharmacological therapy, and was applied among younger patients. Authors concluded that there is a trend of higher total antipsychotics doses and use of multiple medications, which requires a critical assessment of cost-benefit ratio (). In Sarajevo  patients (,) received treatment with only one antipsychotic medication,  (,) with two antipsychotics, while the combination of three or more antipsychotics received only five patients (,). In Tuzla  patients (,) was treated with only one antipsychotic medication, and  (,) with two, the combination with three or more medications was not applied in treatment. In Mostar  patients (,) was treated with only one antipsychotic medication, and the majority of patients was treated with two antipsychotics, in total  (,), while the combination of three or more antipsychotics received  patients (,).
This research achieved goals that were set: . It is determined which antipsychotics are currently used. . Ranges of the individual and daily doses were determined. . Simultaneous administration of multiple antipsychotics is determined. . It is determined that the antipsychotics are administered in divided daily doses. . The existence of treatment with other medications beside antipsychotics is determined, especially antiparkinsonics.