We will discourse on the several clinical expressions of depression in a more vivid and colored way than that presented in the "Bible" of North American psychiatry, the traditional and orthodox " Diagnostic and Statistical Manual of Mental Disorders ", best known by the acronym DSM-IV.

The present work translates knowledge on depression, obtained from following up hundreds of patients, in the past 16 years, as well as from our own experience, since we were personally attacked by that illness, from 1986 to 1990.

Let us begin with the most classic and traditional type - the so-called melancholic depression, in which the greatest intensity of the symptoms appears when the patient wakes up. In which the individual, submitted to an inexplicable fatigue, wishes nothing and feels no motivation to leave his bed, after a badly slept night, with a shortened and fragmented sleep. A gloomy and hopeless awakening: "Why to lift for one more day of insipidity and sadness? Why to lift to face the sorrows of existence? If life is such a heavy bale...." Everything is seen under a black or gray optic. Whatever before used to cause joy or satisfaction, is now unpleasant or indifferent. No favorable perspective looks possible. Self-esteem is reduced or gone. He (or she) doesn't care that the sun is shining outside and birds are singing, once a type of shroud seems to be posted between the person and the surrounding world.

Beside indifference, fatigue, asthenia, anhedonia, sadness and despair, the patient is dominated by an overpowering anguish that, mainly when he stands back from his (or her) niche of safety (be it bed or home), it may develop into a panic state. Frequently, patients are also besieged by thoughts of death and suicide. Many do get to plan their exit from the scenery of life. Several move from thought to action. Among those, some accomplish their purpose and...die.

Most of the suicide cases belong to the group of bearers of bipolar depression, previously labeled as manic-depression psychosis.The suicide act frequently occurs soon after drug treatment is started. It is as if the patient in melancholic state and thus, deprived of any will, when he begins to come back, the desire to die appears before the desire to go on living. Or it is an act of despair, seeking to escape from the unbearable anguish that develops in the maniac phase of the process. It must be pointed out that, among the bearers of unipolar depression, the suicide or the attempting to do it are also susceptible to happen, although in smaller number of cases.

Some patients (and now we are just talking about unipolar depression) are so psychologically depressed and physically exhausted that they refuse to leave their bed. At most, they get up to receive a minimum of feeding and to assist to their physiologic needs. The ones that, with great effort, finally rise, pressed by the necessity of going to work, do so in a very slow way, dragging their bodies throughout the day, without any appetite, with fallen shoulders, expression of emptiness, and sadness in their eyes, bitterness in their words and an almost absolute lack of interest for facts and things. Some become easily irritable. Others, totally indifferent. But all of them producing much less than their real capabilities.

The majority of depressed patients, however, do not present such a characteristic and so easily recognizable picture. Actually, depression has several faces.

There exists a paradoxical form, in which the individual, although displaying some degree of sadness, is relatively active, very anxious, with hypersomnia instead of insomnia and with hiperfagia in place of absence of appetite.

In other situations (and they are more common than one imagines), we have the masquerade " modality, in which the patient doesn't accuse significant shortness of humor, the picture being mainly characterized by extreme anxiety (with or without occasional panic attacks). However, a good anamnese verifies that the person suffers moments of discouragement and sadness. The therapeutic proof in those cases is, as a rule, decisive to firm the diagnosis: the intense anxiety does not give in to the action of tranquilizers like benzodiazepines but, almost always, he or she benefits from antidepressant agents .

We also have dysthymia or dysthymic disorder. In the recent past, that alteration of humor was considered as something inherent to the individual's psychological structure, a " personality " characterized by a permanent state of lack of enthusiasm for things, a certain degree of anhedonia, sometimes associated to sadness. The person insists that he or she does not suffer from depression, but admits that, in comparison to relatives and friends in general, his or her state of mind is, almost always, below the normal line, as far as humor is concerned. A kind, let us say, of " mini depression ". In the past (and even today), many doctors restrict themselves, in such cases, to the use of comfort sentences (sic), as ":Do not worry, that is part of your nature. Try to have fun, to go out more frequently. " And, at most, they prescribe some kind of "revitalizing" drug. And nothing else...Nowadays, however, physicians who have a better understanding of the subject, use to prescribe, with success, moderate doses of antidepressants, like serotonin and nor-adrenalin antirecaptators.

Finally, there is a relatively large number of depressed people , whose main complaint is a more or less accentuated fatigue or asthenia, accompanied, in most of the cases, by a feeling of heaviness in the legs, with pains in the musculature of the thighs and a sensation of painful constriction of the muscles of the calves, without the existence of any clinical pathology that justifies such symptoms. Also, a well conducted anamnese reveals that the patient, male or female, usually presents an above normal level of anxiety and, once in a while, transitory moments of inexplicable sadness.

Therefore, we established five main different types of depression, according to the predominance of certain symptoms, and stipulated to denominate them as such: I - melancholic II - paradoxical III - masked IV - dysthymic V - asthenic.

And it is precisely for the patients of this last group that we have been dedicating special attention for the past three years and nine months. Mainly because, in such cases, a certain substance, just presented in the market as an analgesic but, that, actually, possesses other pharmacological actions, can produce effective and almost immediate results on the symptoms of fatigue and muscular pain.The name of that substance is " tramadol ".

In Brazil, tramadol is marketed as Tramal and Sylador. In both, the label specifies that the substance is just a pain-killer. There exists no mention of a possible antidepressant action, although in the " Technical Information" of these products it is written that tramadol slightly inhibits serotonine and nor-adrenaline reuptake. Also, as far as it was possible for us to determine, does not exist, in Brazilian medical literature, any reference to an antidepressant effect of this substance. However, by researching the Internet, we found several theoretical and experimental works attesting that effect and, therefore, proving what, by clinical observation, we have been suspecting for a long time.

Tramadol is a cyclohexanol derivative with mu-agonist activity. Presented as (+/-) tramadol hydrochloride, a synthetic analogue of codeine, it has a central analgesic action with a selective and low affinity for opioid mu receptors. Its two main metabolites, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, show a higher affinity for these opioid receptors than the parent drug. Nevertheless, this affinity for mu receptors of the CNS remains 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity. (+/-)Tramadol is a racemic mixture of two enantiomers, each one displaying differing affinities for various receptors. The (+)tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas the (-) tramadol mainly inhibits noradrenaline reuptake. The action of these two enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-) tramadol.

However, its effects on depression differs from those produced by classical substances that inhibits serotonin and nor-adrenalin uptake. These last substances take weeks to produce the clinical antidepressant response, whereas tramadol acts within about sixty to ninety minutes after the ingestion of the drug. So there must be an alternative mechanism besides that of inhibiting serotonin and nor-adrenalin uptake at the synapses.

Endogenous opioid peptides inhibit the hypothalamic-pituitary-adrenal (HPA) axis by diminishing the release of hypothalamic corticotropin releasing factors and, consequently, that of cortisol, a well known depression enhancer. And tramadol acts like an endogenous opioid peptide, since it is, in fact, a synthetic enkephalin And, as it is well demonstrated in the cascade process of the "Reward Deficiency Syndrome", enkephalin facilitates dopamine penetration into the post synaptic D2 receptors of the hippocampus and nucleus accumbens, thus promoting reward feelings, like pleasure and wellbeing.

By the way, it must be pointed out that the role of dopamine in depression has not been receiving the prominence that it seems to deserve!

Adverse effects are low, nausea and somnolence being the most common. On the other hand, tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. Thus, the number of patients developing tolerance is extremely small. Tramadol should not be administered to patients receiving inhibitors of monoaminooxidase and the concomitant use of antidepressant tricycles should be avoided.

Any way, regardless of the involved mechanisms, the fact is that tramadol significantly reduces the fatigue/asthenia sensation as well as the feeling of heaviness and muscular pain in the lower limbs. This was clearly evidenced in the clinical research that we have carried out.

For the last three years and nine months, we diagnosed and accompanied 94 patient (56 women and 38 men), ages varying between 25 and 65 years, with different depression types, as established by anamnese and clinical examination , as well as by the classic " Clinical Depression Screening Test ", to which we have added a scale of values, for statistical purposes and that we shall now describe.

It consists of ten questions to which the patients were requested to number (from 0 to 6), according to the frequency and intensity of the related symptoms, in agreement with the following criterion: 0 - absent 1 - moderate and little frequent 2 - moderate and very frequent 3 - moderate and permanent 4 - intense and little frequent 5 - intense and very frequent 6 -intense and permanent

07 - fatigue, loss of energy, feeling of heaviness and muscular pains in the lower limbs

Based on the results obtained with the Test, 24 patients were selected (25.5% of the total sampling), in which the predominant symptoms were fatigue/asthenia and heaviness and pain in the lower limbs, characterizing the depression of the asthenic type. We tried to contact all of them, but we just located 20. Of these, one refused to participate in the research and another abandoned the trial before its end, without giving any plausible reason . Therefore, the study was completed with 18 patients (10 women and 8 men).

These 18 patients were considered as belonging to the asthenic group because, in answering to the " Clinical Depression Screening Test ", they marked 5 or 6 points in item 07, which comprised the symptoms fatigue/asthenia and pain, without marking identical punctuation in more than two of the other items. For a better explanation, we will present two cases, that elucidate what we are intending to characterize.

Case 04 - Patient M.J.S., female, 39 years old. Test: feeling of sadness or irritability - 4 pts. loss of interest or satisfaction related to activities which used to be pleasant - 3 pts. alterations of weight and/or appetite - 0 pts alterations of the sleep pattern - 2 pts feeling of guilt - 0 pts. incapacity to concentrate, remind facts or things and to make decisions - 0 pts. fatigue, loss of energy, feeling of heaviness and muscular pains in the lower limbs - 5 pts. restlessness and/or reduction of activity, as noticed by other people - 0 pts feeling of despair or uselessness - 1 pts thoughts of death or suicide - 0 pts.

Case 16 - Patient L.C.G.T., male, 56 years old Test feling of sadness or irritability - 5 pts. loss of interest orsatisfaction related to activities which used to be pleasant - 3 pts. alterations of weight or appetite - 0 pts alterations of the sleep pattern - 3 pts feeling of guilt - 0 pts. incapacity to concentrate, remind facts or things and to make decisions - 0 pts. fatigue, loss of energy, feeling of heaviness and muscular pains in the lower limbs - 6 pts. restlessness and/or reduction of activity, as noticed by other people - 2 pts feeling of despair or uselessness - 0 pts thoughts of death or suicide - 0 pts.

Nine patients, chosen at random, received, each one, a capsule of Tramal 50 mg, to be ingested soon after awakening, for ten consecutive days. The other nine received, in equal conditions, a capsule of identical appearance, containing a pharmacological inactive substance (placebo). In a subsequent phase, in which the same methodology was applied, the samplings were crossed over. In other words, the ones that had received the active drug, started to receive placebo. And vice-versa.

Taking in account tramadol's pharmacokinetics and pharmacodynamics, patients were informed that they should only evaluate the frequency and intensity of their symptoms from ninety minutes to eight hours after the ingestion of the medicine.

Considering the rigidity that one must impose to any methodological process, the subjective character of this research, based only on symptoms, could be taken as a negative factor. However, the consistence of the numbers demonstrates that subjectivity did not influence, at least in a significant way, the results' validity.

All the nine patients who initially received Tramal, accused that the symptoms fatigue, heaviness and pain in the lower limbs were significantly diminished from 40 to 90 minutes after the ingestion of the medication, since the first day of treatment. The ones that also complained of sadness or irritability, alleged relief of those symptoms. Among the patients who received placebo in the first stage, three referred slight improvement of the symptoms and six did not notice any alteration.

1 - Among the ones that now started to receive placebo, seven accused reappearance of the symptoms, since the first day. In three, the symptoms settled with the same intensity seen prior to the use of Tramal. In the other four, the symptoms re-started on the first day and increased progressively, reaching their maximum on the third or fourth days. In the two remaining patients, the symptoms began to re-appear on the second or third day, also progressively increasing in intensity. On the tenth day of placebo, the symptoms, in all nine patients, were identical, in frequency and intensity, to those existent before the beginning of the clinical trial.

2 - In the nine patients that now started to receive Tramal, the therapeutic answer was quite similar to that of the patients who began the trial using the active substance. In regard to the positive effect of tramadol on the symptoms of item 07, it seems important to point out that, in fourteen, such effect extended besides their regular sleeping hour. Four, however, mentioned that, in some days, at the end of the afternoon, the symptoms came back, although with smaller intensity in relation to the pre-treatment period. The ingestion of another capsule of Tramal 50 mg, around 16-17 o'clock, stopped the re-emergence of these symptoms..

No significant collateral reactions were detected during the ten days of use of tramadol. One patient referred discreet nausea, of short of duration, in the first two days of treatment. Three accused, also in the first days, slight sleepiness, which, however, did not impede them from carrying out their habitual activities. On the other hand, during the use of placebo, three cases of slight nausea and one of transitory dizziness were observed

In this group of bearers of "asthenic" depression , the second more frequent symptoms were those constant of item 01 - sadness and/or irritability. Thus, they have been included in the analysis of the present study. And, as we had quantified, in all patients, from the very beginning, the intensity of each symptom, it became possible to determine the statistical evaluation of the difference of results obtained with the active drug and with placebo, by means of the Student's "t" test, whose indexes and equations are the following:

Calculation of "t" and "p" in function of the difference between the means of two samples

Sum of the differences of the individual values between the two samples [between (di) and (dp) and between (di) and (dt)] - Sd

Mean of the differences of the individual values [between (di) and (dp) and between (di) and (dt)] - m where (di) = pr�-treatment or inicial values and (dp) = values after placebo and (dt) = values after tramadol. Sum of the squares of the differences - Sd2

Thus, by taken as reference the data of the tenth day of use of each substance (Tramal or placebo) and analyzing the symptoms of item 07 of the " Clinical Depression Screening Test ", we obtained the following: (Table I):

Pac.	Inicial	Placebo	Tramal
01	6	6	0
02	6	6	1
03	5	3	0
04	5	5	1
05	6	6	2
06	5	5	1
07	6	6	0
08	6	6	1
09	5	5	3
10	5	5	0
11	6	4	2
12	5	5	1
13	6	6	1
14	5	5	1
15	6	6	2
16	6	6	3
17	5	5	0
18	6	4	0
Total	100	94	19

In order to work with only two differences, we took the initial or pr�-treatment individual values (di) and from them we subtracted the values obtained after ten days of placebo (dp) and after ten days of Tramal (dt). Then, we calculated the following indexes, according to Student's " t " test: n = 18 n-1 = 17 m = 4 Sd = 72 Sd2 = 308 (Sd)2 = 5184

Conclusion: in relation to the symptoms of item 07, the difference between the effect of Tramal and that of placebo is, from an statistical point of view, highly significant.

Now, by taking the data of the tenth day of use of each substance (Tramal or placebo) and analyzing the symptoms of item 01 of the " Clinical Depression Screening Test ", we obtained the following (Table II):

Pac.	Inicial	Placebo	Tramal
01	1	1	0
02	0	0	0
03	0	0	0
04	4	2	0
05	0	1	0
06	3	3	1
07	2	2	0
08	1	1	1
09	4	4	1
10	2	2	o
11	2	1	o
12	3	2	0
13	11	1	1
14	0	0	0
15	2	2	0
16	5	4	1
17	0	0	0
18	3	3	1
Total	33	29	06

Using the same statistical method employed for item 07, we had: n = 18 n-1 = 17 m = 1.11 Sd =20 Sd2 = 46 (Sd)2 =400 Applying the equations, we found:

Conclusion: in relation to the symptoms of item 01, the difference between the effect of Tramal and that of placebo, although not reaching the high level of significance observed in item 07, is also statistically significant

Although the present study has been initiate in the third week of January of the year 2000, the eighteen involved people began to receive tramadol or placebo at different dates. Therefore, the experience was only concluded in the last week of March of the same year. Ever since, fourteen of those eighteen patients opted to continue taking tramadol (Tramal 50 mg), daily, before breakfast.

When that decision was taken, all patients were submitted to blood tests, consisting of: red cells, white cells and platelet count, serum creatinine and hepatic functional tests (TGO, TGP, gamma GT and alkaline fosfatase). Those exams were repeated three and six months later. In none were observed any alteration that could be associated to the use of tramadol.

From the clinical point of view, the positive effects of the substance remain constant and consistent. It must be pointed out, however, that, whenever a patient forgets to take the medicine in the usual time, symptoms reappear in elapsing of the day, although with smaller intensity. This could mean that tramadol just acts upon the symptoms and not on the determinant cause of depression or that it gives rise to an abstinence syndrome.

Any way, in the absence of significant clinical collateral effects and also of negative alterations in the blood tests, it is our opinion that, as long as periodic clinical and laboratory evaluations are carried out, the use of tramadol should be maintained. At least until some new factor - if it comes to happen - will demand that such opinion be modified.

Up to the point we were able to investigate, not one single article was found regarding the use of tramadol in the treatment of depression in humans. Therefore, it is quite possible that the current work constitutes the first publication on the subject. Nevertheless, it must be just regarded as a preliminary communication, since, in order to reach a full and definitive conclusion about the exact value of tramadol in the treatment of the asthenic type of depression, it is indispensable to test the drug in a very larger number of patients and for a much longer period of time.

It is also our understanding that tramadol should be tested in other types of depression, like, for instance, dysthymia.

And because tramadol acts more quickly, we feel it is valid to verify the effect of its association with other more potent antidepressants, as sertraline or citalopram (and we have already started doing it), in cases of severe depression, in which the therapeutic answer to these antirecaptators has not been satisfactory.

* - Full Professor in Internal Medicine (UFRJ) . "Livre - Docente" in Cardiology (UFF). Master in Clinical Medicine (UFRJ). Fellow in Cardiovascular Research (St. Vincent Charity Hospital - Cleveland, USA. Specialist in Nutrition. Specialist in Neuroscience. Member of the Editorial Board of the electronic magazine " Brain & Mind " (UNICAMP). Full Member of the Brazilian Military Academy of Medicine.

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Melancholic Depression	Depressive Facies	Dysthymia