1. THE RATIONAL USE OF ANTIDEPRESSANTS COMBINED WITH BENZODIAZEPINES Izabela Fulone Silvio Barberato Filho Luciane Cruz Lopes THIRD INTERNACIONAL CONFERENCE FOR IMPROVING USE OF MEDICINES Antalya, Turkey Master in Pharmaceutical Sciences UNIVERSITY OF SOROCABA, SOROCABA, SP, BRASIL Rational use of drugs Research group

2. BACKGROUND Combining antidepressants and anxiolytics, mainly benzodiazepines (BDZ), is common practice in the treatment of major depression; Meta-analysis shows that combined therapy presents a higher rate of response to depressive symptoms and lower dropout rate ONLY up to the fourth week. From then on, the benefits recede.

3. OBJECTIVES Evaluating the rational use of the antidepressants/benzodiazepines combination in major depression patients who were attended in the public health care system of Porto Feliz city, state São Paulo, Brazil.

4. METHODS Design: observacional, transversal, retrospective, analytical; Setting: public health care system in the city of Porto Feliz, São Paulo State, Brazil; Inclusion criteria: all patients under treatment with antidepressants, whether combined with benzodiazepines or not, who were attended by the public health care system; Follow- up: january 2008 to december 2009; Outcomes: Primary: rational use of antidepressants combined with benzodiazepines or not (appropriate indication, adequate posology and recommended time of use); Secundary: risk factors for Adverse Drug Reactions, severe drug interactions;

5. METHODS Terms definition Monotherapy: therapy with only one antidepressant; Combined therapy: therapy with antidepressant plus benzodiazepine; Mixed therapy: alternation between monotherapy, combined therapy and therapy with more than one antidepressant; Continuous use: continuos using 1 month; Rational use: appropriate drug, adequate posology and recommended duration;

6. METHODS Adequacy of the use of antidepressants Appropriate drug: indication according to clinical evidences; absence of contraindications for use (absolut impediment); Adequate dosage: dose by day considering age level; Duration of the treatment: at least three months for monotherapy ( The Canadian Psychiatric Association, 2001; NICE, 2009; The Brazilian Medical Association, 2009); up to 4 weeks for combined therapy ( Cochrane Meta-analysis FURUKAWA et al., 2009);

7. Methods CITY PUBLIC DRUGSTORE Forms for withdrawing medicines PRIMARY CARE HEALTH, MENTAL HEALTH AMBULATORY Medical records DOCTORS, NURSES Intervewies with the health care system Source of data collection Statistical analysis of the data : the frequencies were analyzed by means of proportions, Chi-square and Fisher exact; 1° step2° step3° step

8. RESULTS

9. 3,9 2,0 53,8 44,7 42,3 53,3 0 10 20 30 40 50 60 Major depression (n=1601 ) Other CID (n= 3212 ) Propor ç ão (%) Treatment Therapy with more than one antidepressant Combined therapy Monotherapy *p<0,05 Figure 2: Types of therapies used for the treatment of major depression and other CID at SUS in Porto Feliz-SP, from January 2008 to December 2009. 1601 ANTIDEPRESSANTS PRESCRIPTIONS 23,7% (n=204) fluoxetina plus diazepam 65,4% (p0,oo1) fluoxetine

10. 1355 users of antidepressants 485 EXCLUDED users 1,4% (n=7) dead patients 21,1% (n=102) incomplete forms 77,5% (n= 376) patients whose medical records were not found 64,3% (n=870) users of antidepressants with medical records duly completed 30,5% (n= 265) major depression PATIENTS 69,5% (n=605) patients with others CID (International Classification of Diseases) 41,5% (n=110) in combined therapy 44,5% (n=118) in monotherapy 13,9% (n=37) in mixed therapy 62,7% (n=69) in continuous use 60,1% (n=71) in continuous use 64,8% (n=46) in recommended duration 1,4% (n=1) in recommended duration Figure. 1: Characterization of the use of antidepressants 94,3% (n=67) with appropriate drug 94,3% (n= 67) adequate posology RATIONAL USE 94,3% (n=67)adequate posology 1601 antidepressants PRESCRIPTIONS

11. 265 PATIENTS with major depression 1601 antidepressants PRESCRIPTIONS 13,6% (n=36) with SEVERE DRUG INTERATIONS 9% (n=169) SEVERE DRUG INTERACTIONS 40,2% (n=68) fluoxetine plus amytriptilyne Cardiotoxicity Toxicity with tricyclic antidepressants Figure 2: Characterization of the severe drug interations SEVERE DRUG INTERATIONS

12. COMORBITIES 57,7% (n=153) -Arterial hypertension 35,3% -Diabetes mellitus 10,8% COMORBITIES 57,7% (n=153) -Arterial hypertension 35,3% -Diabetes mellitus 10,8% POLIPHARMACY 84,5% (n=224) - Agents action on the Renin- angiotensin system (14,8%) - Psycholeptics (14,5%) Diuretics (9,7%) POLIPHARMACY 84,5% (n=224) - Agents action on the Renin- angiotensin system (14,8%) - Psycholeptics (14,5%) Diuretics (9,7%) ADVANCED AGE 27% (n=72) elderly RISK FACTORS FOR ADVERSE DRUG REACTIONS

13. CONCLUSIONS/ IMPLICATIONS KEY LESSONS High consumption of fluoxetine and diazepam; More use of combined therapy, especially the combinations of serotonin reuptake inhibitor plus BDZ; Prolonged use of combined therapy: over 50% of patients have used it for more than one year; Overuse of BDZ exposes patients to dependence, tolerance and fractures; Monotherapy favors the rational use of the medicine better than combined therapy;

14. CONCLUSIONS/ IMPLICATIONS KEY LESSONS The most common severe drug interaction was selective serotonin reuptake inhibitors more tricyclics antidepressants (possible risk of cardiotoxicity or toxicity with tricyclic); Polimedicated patients with no pharmacotherapeutic follow-up, which indicates that the patient is not well assisted;

15. CONCLUSIONS/ IMPLICATIONS Policy implications Elaboration of pattern policies for the treatment of major depression in Brazil; Education of patients on the risk of dependence to BDZ; Continued education of prescribers, mainly on adverse effects of prolonged use of BDZ, mainly by elderly people; Future research Assessment of the effectiveness of the antidepressant therapy applied; Analysis of suspected Adverse Drug Reactions; Cost analysis;

16. REFERENCES BARBUI, C. et al. Depression in adults (drug and other physical treatments). BMJ Clinical Evidence, v. 06, n. 1003, 2007. DEPRESSION: the treatment and management of depression in adults. Nice Clinical Guideline 90, Inglaterra, oct. 2009. FLECK, M. P. A. et al. Review of the guidelines of the Brazilian Medical Association for the treatment of depression. Rev Bras Psiquiatr, v. 31, p. S7-17, 2009. FURUKAWA T. A. et al. Antidepressants plus benzodiazepines for major depression. In: THE COCHRANE LIBRARY, Issue 10. Art. No. CD001026. DOI: 10.1002/14651858.CD001026.pub1. 2011. KENNEDY, S. et al. Clinical Guidelines for the Treatment of Depressive Disorders. Medications and Other Biological Treatments. The Canadian Journal of Psychiatry, v. 46, supl. 1, june 2001.

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