Abstract
Depression, as a matter of fact, is called the disease of our century, is a major problem of the public health. It causes disability and trouble to the patients and their families and concludes with the big social-economic loss. The information tells about 100 thousand people in the world suffer from some types of depression.
According to a study, made in 1991, from the World Organization of Health (WHO), the depression is in the fourth place as the reason of health inability, compare this with all the medical illnesses it is thought that in 2020, it will be ordered the second, after the cardiac diseases.(1-3)
The study tells that many of patients that suffer from depression disorders, can be treated quiet good, but about 30% of them, after the first cycle treatment, and 15% after some cycles, do not reply to the treatment with antidepressants.(4-5) The Resistant Treatment of Depression is commonly in clinical practice and a challenge for the psychiatrist.
Introduction
The purpose of this study is to appreciate the efficacy of the pharmacologic intervention in the treatment of the resistant depression in Psychiatric Hospital and in the Center of the Community in our town, Vlora for the period 2008- 2012.
The present study was performed with the following aims:
- To give an exact definition for the resistant depression.
- To analyze the factors that causes the resistance in the treatment.
- To identify the strategies of the pharmacological intervention.
Methods
The study includes adults from 18-75 years old, females and males, diagnosed with major unipolar depressive disorder, who are refractory to the therapy with antidepressants for 6- 8 weeks.
- The study was realized during 4 years, 2008-2012 on 40 patients in Psychiatric Hospital and treated in Community Center of Mental Health in Vlora.
- The assessment of the diagnosis was done according to diagnostic criteria of DSM-IV-TR based on structured and clinic interviews (information from their families, friends etc.), and the examination of the mental statues.
- Psychometric assessment included Hamilton Rating Scale for Depression (HRSD), Beck Depression Inventor, Global Assessment of Functioning Scale (GAF), for hospitalization patients will be applied in and out of hospital (twice).
The Criteria of Inclusion:
Patients have to be diagnostified with Major Depressve Dissorder and Unipolar, but who did not respond the treatment of 6-7 weeks with an acurate dose , during the period of time.
- The age of patients have to be 18-75 years old.
- Excluded were the patients with bipolar disorders, dysthimic disorders, depressive organic disorders etc.
According to the definition of Refractor or Resistant Depression 3 is called Major Depressive Disorder a medical condition that will not respond to the treatment, at least with 2 antidepressants which are used within therapeutic dosage, the right period and including a good compliance from the patient.
Results
Before determining that a patient doesn't respond to the treatment with antidepressants is needed to:
1- Revalue in order to confirm accuracy of the diagnosis, so we have to do with Major Depressive Disorder excepting enable disorders from the medical problems.
2- Revalue compliance (taking regularly the therapy) and if the depression has been exaggerated from:
- Psychiatric (personality etc.).
- Psycho-social satisfactions.
- The abuse with substances that effect at the beginning negatively, keeping and treating of depression.
Knowing of those factors affects in choosing of medicaments and in prognoses too. Many treatments, not successful, as a result of mal-diagnostic: an incorrect assessment of the symptoms and the final diagnosis.
In Psychiatric Hospital ‘'Ali Mihali'' and Community Center of the Mental Health of Vlora, there is a great number of the patients that are treating for the Resistant Depression. The questions are:
1- Are the resistances really true?
2- Is there the right diagnosis for those patients?
3- What are the options of the treatment?
4- Are they based on clinic assessments and existed researches?
Precisely the reply of those questions will be object to analyze in this study in order to prove and arrive in conclusion, scientifically and accurately with pharmacologic treatment on the patients with Resistant Depression.
The FACTORS that cause resistance are:
The Dosage
During the study it is seemed that the most patients treated with antidepressants (TCA), were treated relatively with low doses or taken it intermittently and only when it was up at the level 150-200 mg, we registered satisfactory clinical improvement (every time monitoring the patients)
The Period under Treatment
The deadline of the time for therapeutic usage of antidepressants needs to be from 4-6 weeks to 4-8 weeks having a gradual increasing of the dosage with the stick monitoring of the patient.
The Tolerance
The patients are monitored carefully for side effects and tolerance, and sometimes this is the reason of pulling out the medicaments. (6-8)
Table 1 summarized data from the treated patients for Major Depressive Disorder in Psychiatric Hospital "Ali Mihali" and Center of Community of the Mental Health in Vlora town.
TABLE 1
No
|
Name
|
Surname
|
Age
|
Gender
|
Community Center
|
Hospital
|
Diagnosis
|
1
|
N
|
D
|
1952
|
M
|
|
X
|
MDD
|
2
|
TH
|
B
|
1960
|
F
|
|
X
|
MDD
|
3
|
SH
|
SH
|
1962
|
F
|
|
X
|
MDD
|
4
|
J
|
S
|
1969
|
F
|
|
X
|
MDD SUICIDAL TENDENCIES
|
5
|
V
|
B
|
1970
|
F
|
|
X
|
MDD
|
6
|
A
|
V
|
1969
|
M
|
X
|
|
MDD
|
7
|
L
|
M
|
1973
|
F
|
|
X
|
MDD
|
8
|
S
|
N
|
1968
|
M
|
X
|
|
MDD
|
9
|
I
|
A
|
1951
|
M
|
X
|
|
MDD HYPERTENSION
|
10
|
T
|
M
|
1963
|
F
|
|
X
|
MDD SUICIDAL TENDENCIES
|
11
|
SH
|
Z
|
1957
|
F
|
X
|
|
MDD
|
12
|
H
|
C
|
1952
|
F
|
X
|
|
MDD
|
13
|
I
|
A
|
1951
|
M
|
X
|
|
MDD
|
14
|
V
|
B
|
1970
|
F
|
X
|
|
MDD
|
15
|
H
|
B
|
1951
|
F
|
X
|
|
MDD CVA
|
16
|
SH
|
XH
|
1957
|
F
|
X
|
|
MDD
|
17
|
Q
|
Q
|
1959
|
F
|
X
|
|
MDD
|
18
|
D
|
I
|
1963
|
F
|
X
|
|
MDD THYROIDECTOMY
|
19
|
G
|
L
|
1960
|
M
|
X
|
|
MDD DIABET MELLITUS
|
20
|
E
|
GJ
|
1945
|
F
|
X
|
|
MDD HYPERTENSION
|
21
|
F
|
M
|
1950
|
F
|
X
|
|
MDD HYPERTYENSION
|
22
|
M
|
F
|
1970
|
F
|
|
X
|
MDD SUICIDAL TENDENCIES
|
23
|
L
|
SH
|
1972
|
F
|
|
X
|
MDD SUICIDAL TENDENCIES
|
24
|
S
|
N
|
1956
|
F
|
X
|
|
MDD DIABET MELLITUS
|
25
|
M
|
M
|
1970
|
F
|
|
X
|
MDD
|
26
|
D
|
R
|
1974
|
F
|
|
X
|
MDD SUICIDAL TENDENCIES
|
27
|
F
|
H
|
1939
|
F
|
|
X
|
MDD HYPERTENSION
|
28
|
V
|
M
|
1939
|
M
|
|
X
|
MDD HYPERTENSION
|
29
|
H
|
K
|
1954
|
M
|
|
X
|
MDD SUICIDAL TENDENCIES
|
30
|
B
|
M
|
1987
|
F
|
X
|
|
MDD
|
31
|
N
|
D
|
1952
|
M
|
X
|
|
MDD HYPERTENSOIN
|
32
|
I
|
A
|
1951
|
M
|
X
|
|
MDD HYPERTENSION
|
33
|
E
|
M
|
1951
|
F
|
X
|
|
MDD
|
34
|
A
|
GJ
|
1961
|
F
|
X
|
|
MDD SUICIDAL TENDENCIES
|
35
|
M
|
K
|
1951
|
F
|
|
X
|
MDD
|
36
|
M
|
R
|
1963
|
F
|
X
|
|
MDD SUICIDAL TENDENCIES
|
37
|
H
|
P
|
1983
|
F
|
X
|
|
MDD
|
38
|
B
|
Q
|
1953
|
M
|
|
X
|
MDD SUICIDAL TENDENCIES
|
39
|
A
|
M
|
1959
|
F
|
|
X
|
MDD
|
40
|
B
|
D
|
1962
|
M
|
|
X
|
MDD
|
The sample included 40 patients with 70% females and 30% males.
< FIGURE 1>
The minimum age of the patients was 27 years old, and a maximum age of goes on to 75 years old.
|
Minimum
|
Maximum
|
Mean
|
Standard deviation
|
Variance
|
Age
|
27
|
75
|
54.28
|
10.442
|
109.025
|
The treatment setting is described in the table below.
|
Frequency
|
Percentage
|
Community center
|
22
|
55.0
|
Hospital
|
18
|
45.0
|
Total
|
40
|
100.0
|
Related to the diagnosis of those patients, the graphic tells that are prevailing the most of the patients with MDD diagnosis (Major Depressive Disorder) 50%, followed by them with MDD ST (Major Depressive Disorder with Suicide Tendencies) 22.5%, then the patients with MDD Hypertension, 17.5% going on with other diagnosis such as MDD Diabetes mellitus, MDD CVA and MDD following Thyroidectomy respectively with 5% and 2.5%.
< FIGURE 2 >
With regard to the used medicaments in order to cure the patients, is observed that the most is used ant depressive Amitriptyline (72.5%), Anafranil (57.5%), Fluoxetine 50% (SSRI), Risperdal (40%) and the mood stabilizers, as Depakin (Valproic acid) (22.5%), and other medicaments (see table below) that were less frequently used and mainly at the patients that are diagnosed with MDD.
Antidepressants
Category
|
Medicaments
|
Usage
|
Total
|
Yes
|
%
|
No
|
%
|
Total
|
%
|
Tricyclic
|
Anafranil
|
23
|
57.5
|
17
|
42.5
|
40
|
100
|
Amitriptyline
|
29
|
72.5
|
11
|
27.5
|
40
|
100
|
Imipramine
|
3
|
7.5
|
37
|
92.5
|
40
|
100
|
Tetracyclic
|
Ludiomil (Maprotiline)
|
3
|
7.5
|
37
|
92.5
|
40
|
100
|
SSRIs
|
Fluoxetine
|
20
|
50
|
20
|
50
|
40
|
100
|
Paroxetine
|
15
|
37.5
|
25
|
62.5
|
40
|
100
|
Fluvoxamine
|
2
|
5
|
38
|
95
|
40
|
100
|
Sertraline
|
12
|
30
|
28
|
70
|
40
|
100
|
Citalopram
|
10
|
25
|
30
|
75
|
40
|
100
|
Atypical
|
Velafaxine
|
10
|
25
|
30
|
75
|
40
|
100
|
Mirtazapine
|
3
|
7.5
|
37
|
92.5
|
40
|
100
|
New
|
Valdoxan
|
1
|
2.5
|
39
|
97.5
|
40
|
100
|
< FIGURE 3 >
Antipsychotics
Medicaments
|
Usage
|
Total
|
Yes
|
%
|
No
|
%
|
Total
|
%
|
Haloperidol
|
7
|
17.5
|
33
|
82.5
|
40
|
100
|
Risperdal
|
16
|
40
|
24
|
60
|
40
|
100
|
Olanzapine
|
11
|
27.5
|
29
|
72.5
|
40
|
100
|
< FIGURE 4 >
Mood stabilizers (anticonvulsivants)
Medicaments
|
Uses
|
Total
|
Yes
|
%
|
No
|
%
|
Total
|
%
|
Depakin (Valproic acid)
|
9
|
22.5
|
31
|
77.5
|
40
|
100
|
Tegretol (carbamazepine)
|
2
|
5
|
38
|
95
|
40
|
100
|
Lithium
|
4
|
10
|
36
|
90
|
40
|
100
|
< FIGURE 5 >
Discussion
1- During the performing of this study we observed that some ‘'Resistance'' was in fact, artifactual or pseudo-resistance. Antidepressants were not used in the right dose and for the necessary time. Very often the unsuccessful treatments are the consequences of a wrong diagnosis. (9-10)
2- SSRIs have an increased efficacy during the treatment of resistant cases, and these drugs are used in a higher percentage rather than other antidepressants.
3- Mostly used antidepressants drugs were Amitriptyline 72, 5% (TCA) and Fluoxetine (SSRI) 50%.
4- IMAOs were not included in the treating options.
5- Among mood stabilizers used were lithium, Depakin (Valproic acid), tegretol (carbamazepine) as add-on therapy. (11, 12)
6- No patient underwent ECT (electroconvulsive therapy) during the period 2008-2012 for the reason of the lack of sources.
Conclusion(s)
This study was realized during 2008-2012 in the Psychiatric Hospital and in CCMH (Community Center of Mental Health) of the city of Vlora. More than 40 patients suffering from Resistant Depressive Disorders and Unipolar were included.
1- The treatment of Resistant Depression is a major problem to the Public Health Services, in spite of the numerous options of the treatment available.
2- There are many factors that cause resistance such as: dosage, period of treating time, side effects, comorbidity, abuse with substances, etc.
3- As comorbid conditions observed we registered mostly cardio-vascular disorders, mellitus diabetes, endocrine disorders, cerebrovascular events and substance abuse.
4- Most of the patients have used tricyclics or SSRIs as the first line of treatment.
5- We observed that in outpatients SSRIs were first line of treatment.
6- Valproic acid (22%), lithium (10%) and carbamazepine (5%) were used to treat resistance, as add-on therapy.
7- Antipsychotics such as Risperdal, Olanzapine and Haloperidol were included in the following percentages (Risperdal 40%, Olanzapine 27.5%, and Haloperidol 17.5%) as further options of the treatment.
The treatment plan to the Resistant Depression
Patients who don't respond to the therapy with antidepressants at the end of 8th week with the actual dose:
1- The Diagnosis is confirmed.
2- The Compliance is confirmed.
3- The Level of medicaments in blood is controlled.
4- The Organic Causes are excluded related to depression.
5- The Comorbidity is assessed;
THAN:
Go to another antidepressant or add to the actual medicament CBT(Cognitive Behavioral Therapy) or bupropion.Take in consideration another psychiatric consultancy.Go to another class of antidepressants (ex. from TCAs to SSRIs) or add to the actual medicament lithium or tri-iodothyronine.Go to venlafaxin or triptofan.Assess ECT.
Recommendations
a- The treatment begins with antidepressants SSRIs (less side effects), if it is impossible, TCAs (tricyclics) with therapeutic and maximum dosage taking into consideration the adverse effects.
b- A psychotic feature will raise the need to add an antipsychotic (possibly atypical).
c- If there is resistance continue with another antidepressant tricyclic or SSRI (or vs.).
d- Add lithium. (Plasmatic level 0, 4 - 0. 6 mmol/l).
e- Add venlaflaxine (200-750 mg ) per day.
f- Add tri-iodothyronine (25-50 micro/g) per dayg- Add triptofan (2-3mg) per day.ETC etc.
References
- Suli A, Udhërrëfyes për përdorimin e psikotropëve në psikiatri (A guide to psychotropic drug usage in psychiatry). Tirana 2004
- Roose P. S, M.D., Glassman H. A, M.D.: Treatment Strategies for Refractory Depression 1990 American Psychiatric Press, Inc.
- Chaimowitz, G. A, Links, P. S., Padgget, R. W., et al (1991) Treatment resistant depression: a survey of practice habits of Canadian psychiatrists. Canadian Journal of Psychiatry, 36, 353-356.
- Nierenberg, A. A. & White, K (1990) what next? A review of pharmacologic strategies for treatment resistant depression. Psychopharmacology Bulletin 26, 429-460.
- Dangëllia A, Trajtimi i depresionit rezistent. (Treatment of resistant depression), Tirana 2005
- Thase, M. E. & Rush, A. J. (1995) Treatment-resistant depression. In Psychopharmacology: The Fourth Generation of Progress (Eds. F. E. Bloom & D.J. Kupfer), pp. 1081-1097. New York: Raven Press.
- Stimpson, N., Agrawal, N. & Lewis. G. (2002) Randomised controlled trials investigating pharmacological and psychological interventions for treatment-refractory depression. Systematic review. The British Journal of Psychiatry, 181: 284- 294.
- Kennedy, N., Paykel, E. (2004) Treatment and response in refractory depression: results from a specialist affective disorders service. Journal of Affective Disorders, 81: 49-53.
- Austin, M. P., Souza, F. G. & Goodwin, G. M. (1991) Lithium augmentation in antidepressant- resistant patients. A quantitative analysis. British Journal of Psychiatry, 159, 510- 514.
- Bauer, M & Dopmfer, S. (1999) Lithium augmentation in treatment resistant depression: Meta–analysis of placebo-controlled studies. Journal of clinical psychopharmacology, 19, 427- 434.
- Guscott, R. & Grof, P., (1991) The clinical meaning of refractory depression: a review for the clinician. American Journal of Psychiatry, 148: 695-704.
- Litte Alison (2009) Treatment resistant depression Am Fam Physician, 2009 Jul 15; 80(2): 167-172.
Source(s) of Funding
No funding received.
Competing Interests
No competing interests to declare.