Master in Pharmaceutical Sciences
UNIVERSITY OF SOROCABA, SOROCABA, SP, BRASIL
Rational use of drugs
Research group
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
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.
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.
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;
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;
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
FURUKAWA et al., 2009);
Meta-analysis
Methods
Source of data collection
1° step
CITY PUBLIC
DRUGSTORE
• Forms for
withdrawing
medicines
2° step
PRIMARY CARE
HEALTH, MENTAL
HEALTH
AMBULATORY
• Medical records
3° step
DOCTORS, NURSES
• Intervewies
with the health
care system
Statistical analysis of the data: the frequencies were analyzed by means of proportions,
Chi-square and Fisher exact;
RESULTS
23,7% (n=204)
fluoxetina plus
diazepam
*p<0,05
Therapy with more than one antidepressant
Combined therapy
Monotherapy
1601
ANTIDEPRESSANTS
PRESCRIPTIONS
60
53,8
50
53,3
65,4% (p≤0,oo1)
fluoxetine
44,7
42,3
40
30
Proporção (% )
20
10
3,9
2,0
0
Other CID (n= 3212)
Major depression (n=1601)
Treatment
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.
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
41,5% (n=110) in
combined therapy
44,5% (n=118) in
monotherapy
62,7% (n=69) in continuous use
94,3% (n=67)with appropriate drug
94,3% (n= 67) adequate posology
13,9% (n=37) in
mixed therapy
60,1% (n=71) in continuous use
94,3% (n=67) with appropriate drug
69,5% (n=605)
patients with others
CID (International
Classification of Diseases)
1601
antidepressants
PRESCRIPTIONS
94,3% (n=67)adequate posology
1,4% (n=1) in recommended duration 64,8% (n=46) in recommended duration
RATIONAL USE
Figure. 1: Characterization of the use of antidepressants
SEVERE
DRUG
INTERATIONS
265 PATIENTS with
major depression
1601 antidepressants
PRESCRIPTIONS
9% (n=169)
13,6% (n=36) with
SEVERE DRUG INTERATIONS
SEVERE DRUG INTERACTIONS
40,2% (n=68) fluoxetine plus amytriptilyne
Cardiotoxicity
Toxicity with tricyclic antidepressants
Figure 2: Characterization of the severe drug interations
RISK FACTORS
FOR
ADVERSE
DRUG
REACTIONS
POLIPHARMACY 84,5% (n=224)
- Agents action on the Reninangiotensin system (14,8%)
- Psycholeptics (14,5%)
Diuretics (9,7%)
COMORBITIES 57,7% (n=153)
-Arterial hypertension 35,3%
-Diabetes mellitus 10,8%
ADVANCED AGE 27%
(n=72) elderly
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;
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;
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;
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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