The aim of the study was a comparative analysisof the results of treatment of endogenous depression using three selected drugs: sulpiride, clomipramine (Hydiphen) and mianserin.

Sulpiride, an atypical1-4 neuroleptic from the group of benzamides exerts antiautistic, stimulating effects. It exerts also a positive influence on productive symptoms of psychosis. It shows antidepressant activity. The analysis of many papers on sulpiride action encouraged the author to use this drug in the treatment of endogenous depression. Sulpiride has been unpopular among psychiatrists in the treatment of endogenous depressive syndromes. In spite of that, numerous reports are available demonstrating the purposefulness of the use of this drug in endogenous depression.

Pharmacologically, sulpiride is a selective dopaminergic receptor, namely D₂ and D₃ receptor antagonist.

Sulpiride selectively blocks the above mentioned types of dopaminergic receptors. It is an exceptionally hydrophilic drug and not lipophilic like most drugs of this type. It causes no strong extrapyramidal symptoms which could result from D2 receptor blockade in the corpus striatum and which are the equivalent of catalepsia in animals.5

The receptor studies demonstrated particular affinity of sulpiride to D₂ receptor in limbic structures.2

This affinity was determined according to the following scale:

- sulpiride affinity to D₁ receptors (+)
- sulpiride affinity to D₂ receptors ++++
- sulpiride affinity to a1 receptors (+)
- sulpiride affinity to 5-HT₂ receptors +/0

Another favourable feature of sulpiride is the fact that it fails to form, in human body, many biologically active metabolites which could change its pharmacological profile and enter into various pharmacological interactions. Sulpiride, selectively blocking D₂ and D₃ receptors, causes slight activation of D₁ dopaminergic receptors which are blocked by other neuroleptics. Slight activation of D₁ receptors which, contrary to D₂ and D₃ receptors, are positively correlated with adenyl cyclase, can exert a favourable effect in neurosis or depression.⁵

Clomipramine^4,6-8 - one of the most frequently used drugs of tricyclic structure, a dibenzoazepine derivative, has been introduced to treatment by Kuhn (1963) and registered as antidepressant in most countries, and in the USA it is intended for treatment of obsessive-compulsive disorders.

Clomipramine is a drug strongly inhibiting intraneuronal serotonin uptake, contrary to all the group of tricyclic antidepressants (5-HT/NA index = 500). It demonstrates central and peripheral cholinolytic effects (slightly weaker than those of amitriptyline, affinity to muscarinic receptor only 20 times lower than that of atropine). It is metabolised in the body to demethylclopramine. The biological half life of the drug is 17-28 hours.

Psychotropic profile, indications : clomipramine is indicated mainly in depressions with psychomotor inhibition, including anxiety symptoms (but without psychomotor agitation states). Therapeutic effects in depressions with high restlessness, motor agitation, hypochondriac features are less good. Suicidal ideation and tendencies are not contraindications to drug use (of course with observation of adequate precautions).

Clomipramine is regarded as relatively safe drug. Many cases were reported of survival after taking of 5000 mg of the drug, however, death was described after consumption of 750 mg.

Preparations: Anafranil, Hydiphen.

Mianserin^4,6-8 - a tetracyclic antidepressant - dibenzopyrazinazepine derivative. In laboratory studies it demonstrates no pharmacological effects typical of TADs: it is not potentiating catecholamine effects, and not counteracting the effects of neuroleptics, particularly catalepsia. Only the influence on EEG record, characteristic of TADs (analysed by computer-assisted method) called attention to mianserin as a potential antidepressant drug. The biological half life is about 32 hours.

Psychotropic profile, indications: the effect of mianserin in depression resembles that of amitriptyline (antidepressant and sedating actions), in some treated patients it shows an inhibition-abolishing (stimulating) effect. The drug is used mainly in the treatment of depressive states of endogenous type and medium intensity, and depressions of other origin. Although controlled studies showed drug effectiveness that is comparable with that of the basic antidepressants (imipramine, clomipramine, amitriptyline), many years of clinical experience have demonstrated that it is a slightly weaker drug which should not be used in severe depressive conditions (with delusions, anxiety and motor agitation).

Mianserin is particularly useful in patients in whom contraindications are present to TADs administration (circulatory system diseases, glaucoma, prostatic hypertrophy), it sometimes causes a therapeutic effect in patients in whom TADs failed. Recently, attempts have been undertaken at combining TADs with low doses of mianserin in such patients (drug-refractory). A series of papers was published which point to the usefulness of the discussed drug in the treatment of chronic idiopathic pain.

Cases were described of leucopenia with agranulocytosis (data are insufficient to estimate the incidence of this complication), liver enzyme activity increase with jaundice, epileptic seizures. During drug use changes of depressive phase into manic phase were observed. In comparison to TADs, mianserin overdosage (intoxication) is rarely life-threatening.

Daily dose: doses usually administered in depression treatment are 60-90 mg, the maximum dose is 120 mg; the doses in chronic pain treatment are 100-150 mg.

The data for the studies were collected from the case records of patients treated with the studied drugs. Each patient was examined in detail, at the beginning and the end of the 6-week monitoring period using the 24-point Hamilton Depression Assessment Scale and Beck Depression Self-Assessment Inventory and Montgomery-Asberg Scale.

These tests have no normal value range and are not standardized. Therefore, they cannot be used for depression intensity assessment. They can be, however, definitely useful for the assessment of therapeutic effectiveness of drugs used in endogenous depression treatment. These tests served for the evaluation of clinical improvement in individual patients.

The author evaluated the therapeutic effect on the basis of clinical examination of the patients and also by CGI, Hamilton scale, Beck Depression Self-Assessment Inventory and Montgomery-Asberg scale.

The basic method of statistical analysis was the comparison of several groups of patients. The significance of differences between the groups with respect to one feature was tested by analysis of variance. The significance of p value was calculated on the basis of F statistics with several degrees of freedom, designated as: df Effect and df Error.⁹

This was done, e.g. when individual questions in Hamilton and Beck tests were compared in order to check whether the results obtained after treatment were significantly lower than those before treatment. For this purpose, Student’s t-test was used for dependent variables.¹⁰

The significance of the relationship between these questions and therapeutic results were studied using Kendall tau correlation coefficient.¹¹

The reliability of Hamilton and Beck tests was also studied. It was important in the first place for the characteristics of our study material. Therefore, Pearson coefficients were calculated of correlation between individual questions and the total result of the test. Besides that, Cronbach alpha coefficients were calculated, characterising the degree of agreement of test questions.¹²

Two groups were compared, where Student’s t-test was applied. The statistical analysis of per cent values was done by chi-square statistical method.¹³

Hamilton Test

In the Tables 1-4 the per cent values are presented of patients before and after depression treatment with sulpiride, Hydiphen and mianserin.

1. Depressive mood

As presented in Table 1 in all groups before the treatment all patients (except one case in group M, treated with mianserin) had depressive mood; half of them demonstrated depression spontaneously. 40% of the patients in group H treated with Hydiphen) and 53% of the subjects in group S (treated with sulpiride) demonstrated no depression after the treatment.

In group M this was true of 20% of the patients.

In the remaining cases a significant improvement was obtained, least pronounced in group M. This demonstrated that sulpiride improved mood in a higher degree than the remaining drugs.

2. Discouragement to life, suicidal ideation and tendencies

As presented in Table 2 suicidal ideation or intentions were found in group S in 17% of the patients, in group H in 36% of the patients, and in group M in 16% of the subjects (options H3, H4).

These symptoms were absent in 53% of patients in group S, only in 4% in group H, and in 24% in group M.and intentions persisted only in 1% of the subjects (option H3, H4).

In group H, 48% of the patients had no symptoms while suicidal ideation and tendencies persisted in 20% of the subjects (option H3, H4).
In group M the absence of the symptoms after treatment was found in 28% of the patients while suicidal ideation or intentions persisted in all, i.e. 16% of patients (option H3, H4). The above demonstrates that sulpiride almost completely eliminated real risk for suicide (option H3, H4) which could not be said about the two other drugs.

3. Somatic manifestations - general

As presented in Table 3 in all groups, these manifestations were found in about 90% of the patients but their significant intensity was found in group S in 29%, in group H in 20% and in group M in 16% of the patients (option H2).

After the treatment, complete remission of the manifestations was found finally in 58% of the patients in group S, in 44% in group H, and in 28% in group M. In group S and H almost complete elimination was also found of high-intensity complaints. In group M the number of patients with significant intensity of the complaints decreased only from four to three.

Sulpiride and Hydiphen demonstrated excellent therapeutic effects in patients with significant intensity of general somatic manifestations (option H2). The effects of both drugs were satisfactory in patients with moderately intense general somatic manifestations (option H1).

4. Depersonalization, derealization

As presented in Table 4 this symptom was found in about 40% of the patients in the three groups, and in 9% of the patients in group S, 24% in group H and 4% in group M the intensity of the symptom was significant (option H3).

After the treatment, in group S the per cent of cases with significant symptom intensity was reduced to 2%; generally speaking, improvement occurred in about half the patients; a similar situation was observed in the case of Hydiphen: in groups H and M, the per cent of cases with high intensity of the symptom dropped to 0.

Drug M: It is difficult to draw firm conclusions here: only two cases were present of moderate or significant intensity (option H2, H3) of the symptom (in one case improvement occurred), while mild intensity (option H1) responded to treatment only in a slight degree. Sulpiride and Hydiphen were particularly effective in depersonalization and derealization of high intensity (option H3) but their effects were barely satisfactory in cases of moderate intensity of these symptoms (option H2).

5. Obsessions, phobias

As presented in Table 5 the symptom was present in 70% of the patients in group S, 84% in group H and 56% in group M, and significant intensity of obsessions and phobias was observed in 36% of patients in group S, in 48% in group H and 28% in group M (option H2).

The drugs S and H exerted similar effects. In these cases, the per cent of patients with significant symptom intensity decreased to 5% (S) and 8% (H). The per cent of patients with complete regression of the symptom increased significantly (by 33% in group S and by 40% in group H).

In the case of the M drug, the per cent of patients with significant symptom intensity decreased only by 4% (one patient).

Sulpiride and Hydiphen proved particularly useful in the treatment of anancastic symptoms of high intensity. These drugs exerted almost no therapeutic effect on the above symptoms of medium intensity.

Tables 6-10 the per cent values of patients before and after depression treatment with sulpiride, Hydiphen and mianserin are presented.

In Tables 6-10 the per cent values are presented and not the absolute numbers of patients.

6. Sadness, depression

As presented in Table 6 all patients in groups S, H and M were feeling sadness and depression of various intensity. The most intense variant A3: “unbrearable sadness and depression” was present in 19% of the patients in group S, in 32% in group H and 40% in group M) “constantly experienced sadness, depression and could not get rid of these feelings” (option A2).

in 53% of the patients in group S all symptoms of sadness and depression regressed; in cases of the most severe variant (option A2 and A3), improvement developed in 81% of the patients. Of interest was the fact that also in A2 option an improvement was reported in 85% of the patients complaining of this symptom. In group H, in patients with A3 option, improvement was observed in 75% of cases and in those with A2 option - in 58%. In 40% of the patients all symptoms regressed.

In group M - the symptoms regressed completely in 16% of the patients, and in the case of A3 and A2 options - in 40% of the patients.

In the patients with the greatest mood lowering, most effective was Hydiphen and sulpiride exerted slightly less good effect. On the other hand, sulpiride proved most effective in patients with moderate mood lowering.

7. Looking into the future

As presented in Table 7 in all groups almost all patients had concerns, of various intensity, about future. In group S, 69% of the patients had “black” outlook at the future or feeling of hopelessness; in group H this was true of 92% of the patients, and in group M - of 76% (option B2, B3).

After the treatment the per cent of patients in whom this symptom regressed was 50% in group S (increase from 8% to 58%), 36% in group H, and 12% in group M.
Intensive concerns about future decreased to 15% in group S, 32% in group H, and 56% in group M (option B2, B3).

Hydiphen and sulpiride were more effective here than mianserin. Sulpiride proved most effective in patients with the most pessimistic view on the future and also in patients with medium intensity of this symptom. On the other hand, this drug exerted even unfavourable effects in patients with slight intensity of the symptom.

8. Weeping

As presented in Table 8 from 16 to 26% of the patients in all groups were not weeping more frequently than usual. Constant tearfulness or impossibility to weep (J2 and J3) were reported by 67% of the patients in group S, 64% in group H, and 52% in group M.

As the result of the treatment in groups S and H the per cent of patients not weeping more often than usually increased from 26 to 64% in group S and from 16 to 40% in group H. In group M the per cent of such patients increased only by 4% (from 24 to 28%).

The most severe options (J2 and J3) decreased to 10% in group S, to 16% in group H, and to 36% in group M.

Sulpiride and Hydiphen failed to exert here very favourable effects (option J3). As the result of the treatment, patients who earlier were relieving their emotions by weeping, could not weep anymore.

9. Ability to work

As presented in Table 9 only 12-20% of the patients in all groups could work as previously. In group S, 64% of the patients with great effort forced themselves to do anything or were unable to do anything; the per cent of such patients was 68% in group H and 52% in group M (option O2, O3)

After the treatment, the per cent of patients without problems with work increased to 52% in group S, 44% in group H, and 28% in group M.

The per cent decreased simultaneously of patients with greatest problems - to 20% in group S, to 20% in group H, and to 24% in group M (option O2, O3).
In patients with highest intensity of the symptom of lacking energy to work, most effective was Hydiphen, while sulpiride was most effective in patients with medium symptom intensity. Mianserin fairly well enhanced drive to act in the patients who could not perform any activity at all or who forcedthemselves with great difficulty to any activity.

10. Concern about own health

As presented in Table 10 the concern about own health was not greater than usual in 42% of the patients in group S, 36% in group H, and 32% in group M. On the other hand, 12% of the patients in group S, 36% in group H, and 36% in group M worried so much about their health that they could not think about anything else (option T3).

After the treatment, the per cent of patients not worrying about their health more than usually, increased to 59% in group S, to 56% in group H, and to 40% in group M. The per cent of patients constantly thinking about health decreased to 1% in group S, 12% in group H, and 28% in group M (option T3).

In extremely hypochondriac patients, the best therapeutic effects were produced by sulpiride, slightly less good by Hydiphen, while mianserin exerted weakest effects. In hypochondria of medium intensity, sulpiride was found to be the most effective drug. Mianserin as slightly less effective. Hydiphen failed to exert here any therapeutic effect.

It was observed that Hydiphen was slightly more effective than sulpiride in the elimination of the most severe symptoms. The symptoms considered below, included in the questions of Hamilton and Beck tests, correlated with depression intensity. Only their most severe, least favourable options are taken into account. Table 11 presents the per cent values of symptom alleviation or regression.

Then the symptoms are considered, included in Hamilton and Beck test questions, correlated with treatment effects, and, as above, only their most pronounced options are taken into account. Table 12 presents the per cent values of alleviation or regression of the symptoms.

Using chi-square test, the significance was studied of the differences of symptom regression in Hamilton test (in the case of Beck test the results were analogous). In symptoms correlated with depression intensity, the difference was insignificant, although close to significance (c2 = 3.15, p - 0.09). In symptoms correlated with therapeutic effects the difference was significant (c2 = 8.32, p = 0.04).

This could advocate Hydiphen administration in most severe cases of depression. Attention should be paid to the fact that, besides these most severe cases, the results of sulpiride treatment were at least as good, and in most cases, better than the results of Hydiphen treatment.

Sulpiride was at least as effective and very frequently, more effective than Hydiphen in all other forms of depression, with the exception of the most severe cases.

1. Sulpiride is a good, effective drug in the treatment of endogenous depression. Its onset of action after administration is very rapid and the drug is relatively safe - it produces few mild complications, frequently including galactorrhoea and amenorrhoea in women.
2. The general results in Hamilton and Beck tests very strongly correlate with depression intensity and therapeutic effects. Only a part of detailed assessments of patient’s status included in the questions in Hamilton and Beck scales correlates with depression intensity and therapeutic effects; the others occur with equal incidence in various levels of depression intensity and with various therapeutic effects.
3. The treatment of endogenous depression can be regarded as effective if the general result of Hamilton or/and Beck tests improved by at least 60%. Treatment is effective usually in the case when the summarized score in Hamilton and Beck scales before treatment is 25 point or lower.
4. The therapeutic effects of sulpiride and Hydiphen are correlated with the initial depression intensity. Treatment with these drugs produces almost the same effects, but:

• in mild and medium depressions, slightly better effects were obtained after sulpiride,
• in most severe depressions slightly better effects were obtained after Hydiphen.

As compared with sulpiride and Hydiphen, mianserin proved less effective.