Since the DSM-III, the category of dysthymia includes patients that were previously considered as neurotic, reactive, characterological, temperamental, minor or atypical depressives as opposed to a category of endogenous, autonomous, morbid, major or typical depressives. Despite certain confusion, the need for a nosological category is very important for patients suffering from years of depressive mood, with a significant impact on their life-styles and adaptation, as they can benefit enormously from modern antidepressant treatments. DSM-IV and ICD-10 describe dysthymia in a very similar way although there are significant differences. The differences are the consequence of the lack of sufficient scientific data in some points and the need to take a decision, but also to indicate areas for future research. Other differences are the consequence of major discrepancies in basic perspectives of the classifications (ie, the importance given to disablement for the diagnosis). The similarities between both classifications allow the use of either of them for most purposes. Research on the different classifications should help in better defining the concept of dysthymia and mood disorders in general (ie, the cut-off points between them) and of psychiatric nosology.

Dysthymia is estimated to afflict at least 3% of the population worldwide. Because it is a chronic disorder, its prevalence is high in psychiatric and general medical settings. The mystery of this incapacitating depressive subtype — long recognized but only recently sanctioned in the DSM-IV and ICD-10 — is that, in their habitual condition, those suffering from dysthymia lack the classical ‘objective’ or ‘major’ signs of acute clinical depression, such as profound changes in psychomotor and vegetative functions. Instead, patients consult their doctors for more fluctuating complaints consisting of gloominess, lethargy, self-doubt, malaise, and lack of joie de vivre. They typically work hard, but do not enjoy their work. If married, they are deadlocked in bitter and unhappy marriages which lead neither to reconciliation nor separation. For them, their entire existence is a burden: they are satisfied with nothing, complain of everything, and brood about the uselessness of existence. As a result, in the past they were labeled ‘existential depressives’ or ‘depressive characters’ and condemned to the couch, often on a chronic basis. Several lines of research over the past fifteen years have shed new light on the biological origins of this disorder. Sleep neurophysiologic findings have shown that many parameters of paradoxical sleep in dysthymia (such as REM percentage, REM latency, and circadian distribution of REM) are similar to those observed in major affective illness. Furthermore, family studies of dysthymia have demonstrated a significant excess of mood disorders. Indeed, dysthymia has been identified in childhood, and prospective follow-up has demonstrated major affective breakdowns including bipolar switches in up to 20%. Coupled with sleep findings, these family and follow-up data suggest that dysthymia is best considered as ‘trait depression’, a constitutional variant of major affective illness. As expected from the early onset chronic nature of the disturbance, in both clinical and epidemiological studies, the social and health burden of dysthymia has been found to be considerable and comparable to that of major medical disorders. The foregoing clinical and biological data have provided the impetus for well-designed pharmacological trials in dysthymia, and a new therapeutic optimism.

This paper reviews the recent literature supporting the hypothesis that reduced neurotransmission in the mesolimbic dopamine (DA) system may sustain some of the symptoms of depressive conditions including dysthymia. Experimental evidences indicate that mesolimbic DA plays a crucial role in controlling incentive, motivation and reward. Additionally, in different models of depression, a reduced DA activity in the limbic system, reversed by chronic antidepressant treatment, is observed. Finally, different antidepressants, irrespective of their acute action on the uptake of norepinephrine or serotonin, have the common property when given chronically to potentiate behavioural responses to DA agonists. The DA hypothesis of depression offers an explanation for the antidepressive effect of drugs such as sulpiride and amisulpride given at low doses, that preferentially block DA autoreceptors and thereby increase DA output.

The results of early therapeutic trials (1960s and 70s) in mild chronic depression (neurotic patients) are difficult to extrapolate to dysthymia. Most studies conducted in the early 1980s showed reference drugs (TCAs and MAOIs) to be poorly effective in chronic mild depression usually defined with RDC. The most recent trials using DSM-III-R criteria for dysthymic recruitment showed TCAs, new MAOIs (RIMA) and SSRI to be effective. AU these compounds have a rather similar pharmacological mechanism of action. It is therefore of both practical and theoretical interest that amisulpride, a benzamide derivative blocking D2 and D3 pre-synaptic receptors, has been found effective in the treatment of dysthymia in different placebo and reference controlled trials. This result is in line with the pharmacological data on animal ‘anhedonic models’.

In order to assess the therapeutic efficacy of amisulpride in dysthymic disorder, two randomised double-blind trials were conducted in France. Both studies included outpatients meeting DSM-III-R criteria for primary dysthymia. Cases of double depressed patients with a mild or moderate major depressive episode superimposed to dysthymia were also eligible. The first study of a three-month duration compared amineptine (200 mg/day) to amisulpride (50 mg/day) and placebo. The second study of a six-month duration compared the therapeutic effects of imipramine (100 mg/day) to amisulpride (50 mg/day) and placebo. Results of the intention to treat analysis and of the end-point analysis were compelling and very similar: significant differences were demonstrated for all primary criteria between amisulpride and placebo and between imipramine and placebo but not between amisulpride and imipramine. For both primary criteria and the responder rate (CGI), statistically significant differences were evidenced between amisulpride and placebo and amineptine and placebo. The same differences were evidenced for SANS subscores. Beneficial effects of low doses of amisulpride in chronic depressive condition can therefore be discussed.

The efficacy and safety of low doses of amisulpride (50 mg/day) and of fluoxetine (20 mg/day) were compared respectively in 139 and 129 outpatients with dysthymia during three months in a multi-centre double-blind trial. No statistically significant difference between the two groups was found in the number of responders at study-end with the Montgomery and Asberg Depressive Rating Scale, which was the main criterion for efficacy. In addition, amisulpride was well tolerated. These preliminary results suggest that low doses of amisulpride may be effective in the treatment of dysthymic patients.

A naturalistic study was conducted in general practice in Portugal on the efficacy and tolerance of low doses of amisulpride in the treatment of dysthymia. A total of 109 patients received low doses (50 – 100 mg) of amisulpride for four weeks. A global evaluation showed good or very good efficacy and tolerance in more than 80% of the patients. The social disability observed at baseline was significantly improved after the four-week treatment period. Few adverse events were observed and only four patients dropped out due to side effects. Our results suggest that low doses of amisulpride might be a safe and effective treatment for dysthymia in clinical practice.