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Background: In recent years, discovery of ketamine's fast and powerful antidepressant effects for treatment-resistant depression (TRD) has led to rethinking of the pathophysiology of depression. Numerous studies in humans and animals have focused on mechanisms of action underlying this effect, producing a number of explanatory pathways., Method: The aim of this article is to summarize the various hypotheses underlying rapid antidepressant action of ketamine and therefore to better understand the mechanisms underlying depression and antidepressant action., Results: Ketamine unique antidepressant properties have led to many studies on its neurobiological grounds. Intracellular signaling pathways such as mTOR, GSK3 or eEF2 seem to play a key role and are associated with an increased synaptic plasticity. Other hypotheses are discussed such as ketamine effects on neuro-inflammation, the role of anterior cingulate cortex in brain changes induced by ketamine, and the potential benefits of analgesic properties of ketamine in depressive disorders., Conclusion: Our review highlights the potential role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Understanding which pathways underlie the fast antidepressant effect of ketamine paves the way for the development of new antidepressants., (Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: The therapeutic efficacy of adding lithium to an ongoing antidepressant in resistant depression is well known. However there is less data concerning the efficacy of giving lithium and antidepressant concurrently from the start of treatment., Methodology: The primary objective of this study was to compare the efficacy of a combination of clomipramine+lithium (C+L) with that of clomipramine+placebo (C+P) in-patients with unipolar major depression, during the first 11 days of treatment. Secondary objectives were the assessment of effectiveness after 6 weeks and assessment of the safety of the combination clomipramine and lithium carbonate. C+L and C+P groups were compared for 6 weeks in a multicenter randomized trial of 141 patients hospitalized with a DSM-IV diagnosis of major depression. Efficacy was evaluated using the standard MADRS and CGI scales., Results: Analysis of the 'as treatment ITT' population showed: the percentage reduction in MADRS scores between D0 and D11 in this population was better in the C+L group but not statistically significant (C+L: 32.1 vs. C+P: 27.4, P=0.07). Nevertheless, the comparison of mean MADRS scores showed a significant difference in the C+L group on days 4 (C+L: 25.1 vs. C+P: 27.8) and 7 (C+L: 18.6 vs. C+P: 21.5), P<0.05, and approaching significance on day 11 (C+L: 14.6 vs. C+P 17.2, P=0.054). On day 7, the number of patients in total remission was threefold higher in the C+L group than in the C+P group (15 vs. 4%, P<0.05) and twofold on day 11 (29 vs. 14%, P<0.05). CGI severity score showed C+L was superior to C+P on days 4, 7 and 11 and CGI improvement score was better in C+L group on day 11 (P<0.05). After 6 weeks of treatment no statistical difference was found between the two groups from the clinical point of view. Safety based upon clinical and laboratory parameters was satisfactory in both groups during the 6 weeks of the study., Limitations: Patients with bipolar disorder, previously treated with clomipramine or with any other mood stabilizers during the previous week; or with suicide attempt during the current episode with a score > or =3 for item 10 of the MADRS were excluded from the study., Conclusion: The results of this study suggests that lithium slightly to moderately potentiates antidepressant treatment in unipolar non-refractory patients with severe major depression in the first days of treatment but not as significantly as for the bipolar population.

Agomelatine (S 20098) has a unique and new pharmacological profile. It is a melatoninergic agonist and selective antagonist of 5-HT2C receptors, and has been shown to be active in several animal models of depression. The aim of this study was to determine the active dose of agomelatine in the treatment of major depressive disorder (DSM-IV criteria). The methodology used was a conventional double-blind design comparing three different doses of agomelatine (1, 5 and 25 mg once a day) with placebo over an 8-week treatment period. Paroxetine was used as the study validator. Seven hundred and eleven patients with a baseline mean score of 27.4 on the 17-item Hamilton Rating Scale for Depression (HAM-D) were included. On the pivotal analysis, the mean final HAM-D total score (Full Analysis Set LOCF) demonstrated agomelatine 25 mg to be statistically more effective than placebo. This was confirmed by other analyses and criteria (responders, remission, subpopulation of severely depressed patients, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression-Severity of Illness). Agomelatine 25 mg alleviated the anxiety associated with depression, as measured on Hamilton Anxiety Scale. Paroxetine was found to be effective on pivotal analysis and most of the secondary criteria used to validate the study methodology and population. Agomelatine, whatever the dose, showed good acceptability with a side-effects profile close to that of placebo. In conclusion, this study demonstrates that agomelatine is efficient in the treatment of major depressive disorder and that 25 mg is the target dose.

Rational and method - Two doses of agomelatine (S-20098), a novel potential antidepressant drug with a new pharmacological profile (melatonin agonist and selective 5HT2C antagonist -MASSA), were compared in a double-blind, randomised, pilot study in order to estimate the antidepressant activity shown in preclinical data. Inpatients suffering from major depressive disorder (DSM III-R criteria) and presenting a minimal score of 25 for MADRS were selected at D -7. After one week of run-in placebo treatment, included patients received one evening dose of agomelatine (either 5 or 100 mg) for 4 to 8 weeks. Hospitalization was required at least for the first 3 weeks. Patients presenting a satisfying response to treatment (MADRS total score<15 or decrease 40% from inclusion score) could be treated as outpatients. A follow up of 2 weeks was performed after stopping the treatment. The total duration of the treatment period could vary, according to investigator's decision, between 7 and 11 weeks. Evaluation criteria included MADRS, HAMD-17, HAM-A, CGI and AMDP 5 at D0, D7, D14 and D28, and, when applicable, at D35, D42, D49 and D56. Safety evaluations included recording of adverse events, ECG monitoring and biology. Results - Thirty inpatients were selected and 28 included (14 per group). There was no major difference between groups at inclusion, neither for demographic nor evaluation criteria. One patient of each group was excluded of the ITT analysis; 19 patients completed the mandatory period up to D28: 10 in the 5 mg group and 9 in the 100 mg group; 10 patients (5 in each group) carried on the study during the optional period, up to D56 for 7 out of them (4 in the 5 mg group, 3 in the 100 mg group). Efficacy criteria showed a significant improvement in both groups, with highly significant within group evolutions (p<0.001 whatever the criteria) and without significant difference between groups. However, better results were observed in the 5 mg group compared to the 100 mg group. Total MADRS scores then decreased from 30.7 3.5 to 14.8 6.4 in the 5 mg group vs a decrease from 31.6 4.7 to 18.6 14.8 in the 100 mg group. Furthermore, significant improvement between D14 and D28 visits were only seen in the 5 mg group. Analysis of somatic complaints (AMDP 5) showed with both treatment a strong decrease of symptoms during the study, especially for items related to sleep disorders (difficulties for falling asleep, interrupted sleep, shortened sleep, early wakening and drowsiness). Acceptability was good for both doses of agomelatine. However, there were slightly more emergent adverse events and severe treatment-related adverse event in the 100 mg group. No modifications of cardio-vascular parameters nor biological abnormalities were observed in both groups. Conclusion - Preliminary clinical data with agomelatine confirm the potential antidepressant effect in accordance with positive preclinical results. There was no significant difference between 5 and 100 mg, both for efficacy and for safety. However, the data suggest that 5 mg could be a at least as effective and slightly better tolerated dose than 100 mg. Further double-blind controlled studies versus active comparators and placebo are required in order to confirm these results.

Unlabelled: Psycho-behavioural inhibition is characteristic of major depressive disorder and frequently recedes after the other depressive symptoms. This may induce an important psychosocial impairment which could be a risk factor for relapse., Methods: The aim of this eight weeks, multicentric, randomized, double blind, placebo controlled trial was to assess the efficacy and safety of sulbutiamine (Arcalion) [600 mg p.d.] on the symptoms of psycho-behavioural inhibition of inpatients with DSM III-R defined Major Depressive Episode (MDE) treated by adjusted doses of clomipramine [75 to 150 mg pd]. Moderate doses of hypnotics and anxiolytics without potential activity on the mood were authorized during the trial. The MDE was assessed with the MADRS, HAM-A and CGI scales. Patients who did not respond adequately to the antidepressant treatment were prematurely withdrawn from the trial. The three Sheehan Disability Scales (SDS), the Norris Visual Analogue Scale (VAS) and the Depressive Psychomotor Retardation Scale (ERD) were used to monitor psycho-behavioural inhibition., Results: The mean intake scores were, as expected, fairly high: MADRS (32), HAMA-A (23), CGI (5) and ERD (27). The SDS and EVA scores showed that the patients felt severely handicapped in their social, professional and family life functioning as well as in their emotional, affective, cognitive and behavioural performances. At four weeks the MADRS, HAM-A and CGI scores indicated that the global improvement of the MDE was comparable in both treatment groups. However, the scores at the EVA and SDS scales showed that the patients treated with sulbutiamine were significantly less incapacitated than the placebo group in all of the various facets (affective, cognitive, emotional, behavioural) of psycho-behavioural inhibition. Furthermore, the safety data shows that both treatment groups were comparable and in particular that sulbutiamine had not induced any inappropriate behaviour, including suicide attempts, or mania., Conclusions: Sulbutiamine has no antidepressive effect but it can hasten the resorption of psycho-behavioural inhibition occurring during major depressive disorder and thereby facilitate the rehabilitation of patients in their social, professional and family life functioning.

The widespread use of antidepressants since the late 1950s and especially the ambulatory treatment of the majority of depressive patients raises the issue of the state of knowledge of the effects of these drugs on cognitive function. This review aims at synthesizing information about differential effects of antidepressants on cognitive function to facilitate good prescription. The first part of this review tries to summarize the main tasks used to explore global reactivity, attention, memory and psychomotor performances. The second part of this work presents the differential cognitive effects of antidepressants with a discrimination between substances which have a sedative impact, antidepressants with no cognitive effect, and drugs which seem to have a positive cognitive action. The differenciation is established for single and repeated administration, for healthy volunteers and depressed subjects. For each substance, the dose, the tasks selected and cognitive effect are discussed and the question of the real benefit of this cognitive impact is raised. The specificity of cognitive effects of antidepressants related to age and to the combination with alcohol are also tackled. Then the discussion raises the difficulty and the biases encountered to perform neuropsychological studies and particularly evaluation of cognitive effects of antidepressants. Finally the conclusion of this review gives some advice to select and prescribe antidepressants according to their cognitive effects.

Distinction between relapse and recurrence is a major difficulty in studies assessing the efficacy of long term antidepressant treatment. A four to six months symptom-free period is required to talk of recovery from depression and plan a preventive treatment, i.e. prevention of recurrence. Compounds are not selected according to their biochemical profile; the most recent antidepressant drugs were studied in that indication through long term controlled trials. In unipolar patients, recent studies favour the prescription of high doses of antidepressant drugs during at least five years. In bipolar patients, combination of long term antidepressant to lithium treatment may be of benefit to patients whose index episode was of depressive type, but appears useless in other cases. In all cases, joint psychotherapy and the quality of the relationship between the patient and the prescribing physician influence compliance and outcome. Dysthymia, panic disorder and obsessive-compulsive disorder constitute other acknowledged cases for long term prescription of antidepressants. These indications remain empirical till controlled trials have not specifically assessed each antidepressant compound.

In this review the authors propose to study the impact of antidepressants on attention, memory and motor functions in healthy volunteers and depressed patients on single and long-term administration. After reviewing the principal cognitive functions, we examine the actual investigation means to conclude that the Critical Flicker Fusion Test (CFFT) is one of the most drug-sensitive tests. It permits a categorization in: sedative antidepressants that in single administration lower CFFT; compounds with no effect on CFFT and no deleterious cognitive effect; and finally substances that raise CFFT and may have psychostimulating properties. On single administration amitriptyline is the most sedative antidepressant on attention or motor level. It seems to produce negative effects on memory level. However, experimental trials give contradictory results. Imipramine in single administration also has sedative effects on memory and car driving capacity. However divergent results of experimental trials do not allow any conclusions of a clearcut negative cognitive effect. Memory impairments with imipramine appear at administration levels of 150 mg. Mianserin has a sedative impact on attention and motor level at low doses (10 mg). Among the tricyclics, nortriptyline has a highly dose dependent sedative effect that has been shown on attention tests (Time Reaction:TR, Digit Symbol Substitution Test: DSST). Among non-tricyclic compounds, doxepine lowers attention and motor performances. Maprotiline (75 mg) lowers CFFT and has a dose dependent effect. Trazodone also has a negative impact on attention tests. Finally viloxazine lowers CFFT but does not impair other attention or motor tests on a 100 mg doses. Buspirone, lofepramine, midalcipran and zimelidine are antidepressants with no effect on CFFT and do not have any positive or negative cognitive effect. On the other hand nomifensine, paroxetine and fluoxetine raise CFFT in healthy volunteers on single administration. Improvement of CFFT performances was found in an isolated manner for nomifensine and paroxetine on 30 mg doses with no other memory or motor effects. MAO-Inhibitors do not impair attention or motor function; thus moclobemide has no negative impact on memory, attention or car driving tests. Cognitive impact of antidepressants in depressive patients seems the same with those of healthy volunteers on single administration. In long-term administration antidepressants have different effects in healthy and depressed subjects. In healthy volunteers cognitive effects of most compounds are normalized after the second week of treatment. However, attention and motor performances with amitriptyline are normalized after 3 weeks of treatment. Sedative motor or cognitive effects of imipramine do not exceed 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

The definition of treatment-resistant depression is variously interpreted. There is no agreement of different authors on its meaning. The present vagueness of criteria for the diagnosis of a refractory depression contrasts with the many studies reporting potentiation of antidepressants by lithium. De Montigny in 1981, after early works by Zall and by Lingjaerde, initiated this approach that still remains poorly understood in terms of biochemical mechanisms. A review of the controlled studies shows that the delay of antidepressant action varies and the term "lithium potentiation" does not seem totally relevant. From a pharmacological point of view, several types of data suggest a synergic potentiation rather than a true potentiation. This effect applies to all classes of antidepressants and improves about 50% of patients who did not respond positively to an adequate treatment received during 4 to 6 weeks. Many questions remain unanswered particularly concerning the lithium levels, factors predicting a positive response and the strategy for the maintenance treatment. Studies are necessary in order to compare the relevance of this potentiation technique with the mere substitution by another antidepressant and to understand the biochemical mechanisms underlying the synergic effect.

The choice of an antidepressant is not necessary during the initial phase of only treatment (acute treatment), it can be reviewed after one or two months (continuation treatment) and a prophylactic treatment may be discussed after a 6 months period (long-term maintenance treatment). Many reasons explain the need to readjust the dosage of antidepressant treatment or to change it: the nature and the gravity of the depression, the family and personal history of affective disorders, the level of side effects and above all the quality of the recovery. Thus the modification of a treatment can be considered according to 4 methods: modification of the psychotropes associated to antidepressant treatment, association of a second antidepressant medication, change of antidepressant medication, institution of a prophylactic treatment. A special aspect concerns the decision and the choice of the antidepressant treatment after recovery by E.C.T. Two types of treatment can be considered: most often a maintenance treatment of antidepressant medication is suggested. Prolongation of ECT may be justified for consolidation: 6 or 8 sessions after recovery, or for prevention of relapse: session every 3-4 weeks after recovery, and for a period of 2-3 years.

Medifoxamine (Clédial TM), a non tricyclic non MAOI antidepressant drug with a dopaminergic and serotoninergic mechanism of action, was compared to imipramine in a multicenter double blind trial. Patients suffering from DSM III-R major depression (without psychotic features), with a minimum inclusion score of 25 at the MADRS after an initial 7-day wash-out period, were randomly assigned to a 4-week treatment by either imipramine or medifoxamine, with flexible doses of at least 100 mg after 2 weeks of treatment. No associated treatment was permitted except for lorazepam 2 to 5 mg per day. Ninety eight patients were recruited by 20 centers throughout France. Eighty four terminated the 4-week protocol. Early terminations were due to serious adverse events (3), death on imipramine (1), protocol violation (1), refusal to continue (1), loss to follow up (1). The 2 groups of patients were comparable on inclusion. In the medifoxamine group (receiving a daily dose of 194 mg at day 28) the percentage of improvement in MADRS scores, the number of patients with a MADRS improvement of a least 50% and a final MADRS score inferior to 8, were not significantly different from the imipramine group (daily dose: 161 mg at day 28). No more difference appeared when several clinical variables were analyzed, in particular the DSM III-R melancholic, the Newcastle endogenous subtypes and the in or out patient status. The two treatment groups were also comparable on other scales (HDRS, HARS assessing anxiety, CGI).(ABSTRACT TRUNCATED AT 250 WORDS)

This review paper deals with the impact of psychotropic drugs on vigilance, awakening and motricity. Antidepressants can be divided into 3 categories, depending on the subject's awakening: sedatives with a strong anticholinergic component, compounds devoid of positive or negative impact on cognition and stimulating antidepressants. The principal effect of lithium is to lengthen the reaction time. Taken acutely, neuroleptics produce alterations of fine motor gestures, but when taken chronically they spare the functioning of cognition. Benzodiazepines act on vigilance in various ways, depending on their half-life and on their plasma peak time after oral administration. The effect of anticonvulsants on cognition is more pronounced with phenytoin and barbiturates than with carbamazepine or valproate sodium. The problems of comparative analysis in this field and the trends in current studies are underlined.

A case of status epilepticus with transient motor deficit is reported in a 66 year old male treated with fluvoxamine. Fluvoxamine is supposed to induce few epileptic seizures. The patient had no previous history of epilepsy. Two factors seem to have favoured the occurrence of epilepsy: presence of an incipient arteriopathic impairment, cortical and subcortical brain atrophy and perhaps drug overdosage causing a tremor in the days before the epileptic fit.

The antidepressant effect of citalopram, a specific inhibitor of the reuptake of serotonin, was explored in an open phase II study involving twenty-one patients hospitalized for depression. Fourteen patients responded, six did not and one was excluded from the study. These preliminary results suggest that citalopram is an effective, well tolerated antidepressant.

The antidepressants can be classified chemically. The standard division is between the tricyclic antidepressants and the chemically heterogeneous MAOIs. Many other compounds can be included among the antidepressants, e.g. the bicyclics and possibly also the beta-stimulants, the alpha-blockers and ions such as rubidium. As regards the mechanisms of action, we have the antidepressants which act selectively upon serotonin and those which act more particularly upon noradrenaline. This notion must be extended. Dopamine may be involved in certain depressive syndromes and also other systems may have a role, such as electrolyte systems, cell permeability and the multiple influences which have a bearing upon the monoamines. Finally, the effect upon receptors and their nature are discussed. A third type of classification refers to the therapeutic spectrum of the drug. We have the sedative antidepressants, active in agitated depression and the stimulant antidepressants which are active in retarded depression. However, the two categories of antidepressants have the same global antidepressant action.

The biochemical features of depressions able to guide the prescription of antidepressants are seen through a review of the literature. The papers were mainly focused on the peripheral catabolites of brain monoamines. Depressions characterized by low levels of 5 HIAA in the C.S.F. would predict a better efficacy of the antidepressants acting on the re-uptake of serotonin. The dosage of urinary MHPG seems to be a valuable index for the choice of the drug. Subjects with low levels response better to IMI, DE-IMI and NT, and those with normal levels to AMI. COMT activity and platelet MAO activity are may be a valuable index for the predictivity of the therapeutic results. Finally, the dexamethasone suppression test can be useful in order to guide the length of the treatment.