Is serum copper a "trait marker" of unipolar depression? A preliminary clinical study

Depression is not a homogenous illness and is diagnosed in only one in three persons suffering from this disorder. Besides psychological-psychiatric diagnostic methods (e.g. Hamilton's, Beck's rating scales), some biochemical measures have been introduced as markers of depression. However, the sensitivity of even the best characterized dexamethasone suppression test is as low as 40-50%. A search for better markers is continuously in progress. In the present study, we investigated alterations in serum copper concentrations in depressive patients before, during and after antidepressant treatment and compared these values with the concentrations in healthy volunteers. The serum copper concentration in depression is significantly higher (by 21%) than in the control. However, effective antidepressant treatments (which reduced symptoms by ca. 50% measured by Hamilton Depression Rating Scale) did not affect (did not normalize) this increased copper concentration. The present data indicate that serum copper is a "trait marker" (remains constant regardless of successful treatment) of unipolar depression.     

Clonazepam in the treatment of protracted depression: a hundred-case report]

Clonazepam, which presently is recommended for the treatment of seizure disorders, has been reported to be useful as an adjunctive treatment for depression. The purpose of this paper was to examine the suitable adjunctive dose and the characteristics of clonazepam for the treatment of protracted depression. A hundred protracted depressive patients treated with clonazepam were studies by the retrospective method. A daily dose of 3.0 mg clonazepam as augmentation expressed high effectiveness (78.4%) on protracted depression. Most of the improved patients showed a rapid onset of action within two weeks. Gender, age, phase number, family history of psychosis, and clinical symptoms did not change the effectiveness of clonazepam treatment. A daily dose of at least 3.0 mg clonazepam as augmentation of ongoing antidepressant treatment should be considered for protracted depressive patients with suboptimal improvement. Unipolar depression was significantly more effective than bipolar depression on clonazepam treatment. The clear-cut difference in response to unipolar and bipolar depression suggests that the underlying abnormality in unipolar depression is not the same as that in bipolar depression. A continuance of clonazepam after improvement disturbed the recurrence of depression, and it seems that clonazepam augmentation has a preventive effect.     

Amantadine as an additive treatment in patients suffering from drug-resistant unipolar depression

The paper describes the effect of amantadine addition to imipramine therapy in patients suffering from treatment-resistant unipolar depression who fulfilled DSM IV criteria for major (unipolar) depression. Fifty patients were enrolled in the study on the basis of their histories of illness and therapy. After a 2-week drug-free period, 25 subjects belonging to the first group were treated only with imipramine twice daily (100 mg/day) for 12 weeks, and 25 subjects belonging to the second group were treated with imipramine twice daily (100 mg/day) for 6 weeks and then amantadine was introduced (150 mg/day, twice daily) and administered jointly with imipramine for the successive 6 weeks. Hamilton Depression Rating Scale (HDRS) was used to assess the efficacy of antidepressant therapy. Imipramine did not change the HDRS score after 3, 6 or 12 weeks of treatment when compared with the washout (before treatment). The addition of amantadine to the classic antidepressant reduced HDRS scores after 6-week joint treatment. Moreover, the obtained pharmacokinetic data indicated that amantadine did not significantly influence the plasma concentration of imipramine and its metabolite desipramine in patients treated jointly with imipramine and amantadine, which suggests lack of a pharmacokinetic interaction. The obtained results indicate that joint therapy with an antidepressant and amantadine may be effective in treatment-resistant unipolar depression.     

Ketamine for treatment-resistant unipolar depression: current evidence

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5?mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.     

Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study

A growing body of evidence implicates a derangement of zinc homeostasis in mood disorders. In general, unipolar depression is connected with low blood zinc levels that are increased by effective antidepressant therapy. A placebo-controlled, double blind pilot study of zinc supplementation in antidepressant therapy was conducted in patients who fulfilled DSM IV criteria for major (unipolar) depression. Patients received zinc supplementation (6 patients; 25 mg of Zn2+ once daily) or placebo (8 patients) and were treated with standard antidepressant therapy (tricyclic antidepressants, selective serotonin reuptake inhibitors). Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) were used to assess efficacy of antidepressant therapy, and patients' status was evaluated before the treatment and 2, 6 and 12 weeks after its commencement. Antidepressant treatment significantly reduced HDRS scores by the 2nd week of treatment in both groups, and lowered BDI scores at the 6th week in zinc-treated group. Zinc supplementation significantly reduced scores in both measures after 6- and 12-week supplementation when compared with placebo treatment. This preliminary study is the first demonstration of the benefit of zinc supplementation in antidepressant therapy. The mechanism(s) may be related to modulation of glutamatergic or immune systems by zinc ion.     

Adding lithium to antidepressant therapy: factors related to therapeutic potentiation.

Lithium augmentation of antidepressant drugs was studied in 51 patients with endogenous refractory depression. The remission after 28 days of lithium was obtained in 28 patients (55%). Better effect of lithium was shown in bipolar than unipolar patients, with subjects with lower pre-lithium severity of depression and in those with rapid improvement (within 7 days) on lithium addition. Factors such as age, gender, number of prior antidepressant (or ECT) treatments, type of preceding antidepressant, mean plasma lithium concentration and the results of DST did not show any association with the outcome of lithium augmentation. The 'priming' effect of lithium may contribute to the mechanism of lithium potentiation in a proportion of depressed patients.     

Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Fluoxetine is a new antidepressant which enhances serotoninergic neurotransmission through potent and selective inhibition of neuronal reuptake of serotonin. Metabolism by N-desmethylation occurs in man yielding desmethylfluoxetine, which also inhibits serotonin reuptake. Both the parent compound and metabolite possess elimination half-lives of several days facilitating the maintenance of steady-state plasma concentrations during long term treatment. Fluoxetine has overall therapeutic efficacy comparable with imipramine, amitriptyline and doxepin in patients with unipolar depression treated for 5 to 6 weeks, although it may be less effective than tricyclic antidepressants in relieving sleep disorders in depressed patients. Geriatric patients also responded as well to fluoxetine as to doxepin. The symptomatic improvement in patients with unipolar depression during short term fluoxetine treatment has been satisfactorily maintained when therapy was extended for at least 6 months: the relapse rate was low and similar to that of imipramine. Preliminary data have shown that patients with bipolar depression gained similar therapeutic benefit from fluoxetine or imipramine. Other preliminary trials have indicated that fluoxetine may be useful in obsessive-compulsive disorders. Usual doses of fluoxetine cause significantly fewer anticholinergic-type side effects than tricyclic antidepressants. Nausea, nervousness and insomnia are the most frequently reported fluoxetine-related adverse effects, but these have usually not been severe. Therapeutic doses of fluoxetine do not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease and fluoxetine has been relatively safe in the small number of patients who have taken overdoses. It has not been clearly established whether some types of depression may respond more readily to fluoxetine than other antidepressants, and its overall therapeutic efficacy has not been compared with other second generation antidepressants. Thus, with its different and perhaps improved side effect profile compared with older tricyclic antidepressants, fluoxetine offers properties that could be used to advantage in many patients with depression.     

Specific serotonin and noradrenaline reuptake inhibitors (SNRIs). A review of their pharmacology,clinical efficacy and tolerability

Considerable progress has been made in improving the tolerability of antidepressant drugs. The classical tricyclic antidepressants (TCA) are still, however, the standard for efficacy. The selective serotonin reuptake inhibitors are better tolerated that the tricyclics, but their efficacy in major depression is, at best, equivalent to the earlier compounds and probably inferior in certain cases. Recently a new class of antidepressants has been developed that inhibit selectively the reuptake of both serotonin and noradrenaline with no affinity for the receptors responsible for the adverse effects of the TCAs. These compounds are referred to as the specific serotonin and noradrenaline reuptake inhibitors or SNRIs. This article reviews the pharmacological and clinical characteristics of the two principal compounds of this class, milnacipran (Ixel®) and venlafaxine (Effexor®). This new class of antidepressants, as represented by these two compounds, presents an efficacy comparable to TCAs with a more benign side-effect profile. Certain trials suggest that they may have efficacy superior to SSRIs, especially in more severe depression, with a tolerability which is globally similar. This class therefore appears to offer a potential useful addition to the therapeutic arsenal of antidepressant drugs. © 1998 John Wiley & Sons, Ltd.     

Bupropion and sertraline combination treatment in refractory depression

A sizeable minority of depressed patients, estimated at 15-20%, suffer chronic symptoms which often persist despite appropriate treatment. The search for new, more efficacious pharmacotherapies has included testing existing medications for additional therapeutic effects, such as in combination treatment. Four treatment- refractory patients who presented to the authors for clinical care are described, in which the combination of bupropion and sertraline was effective for a major depressive episode. None of the patients experienced adverse effects. Two carried the diagnosis of unipolar depression, and two, bipolar disorder. All had prior adequate, but ineffective, separate trials of buproprion and a selective serotonin re-uptake inhibitor (SSRI), including sertraline. All had chronic depression with multiple failed medication treatments, arguing against the alternative explanation that their improvement represented a placebo response or spontaneous remission. The efficacious combination of sertraline and bupropion may be due to synergism of its two distinct antidepressant mechanisms involving serotonergic, dopaminergic and noradrenergic systems.     

Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression

Alprazolam is a triazolobenzodiazepine which is related to diazepam and other 1,4-benzodiazepines, and has a similar pharmacological profile. Relative to the newer benzodiazepines, alprazolam has an intermediate half-life of 10 to 12 hours in healthy young subjects. In placebo-controlled and double-blind comparative trials in patients with anxiety, alprazolam was of comparable efficacy to diazepam and generally caused a lower incidence of drowsiness. Alprazolam has antidepressant activity and has been shown to be similar in efficacy to imipramine in the treatment of unipolar depression. Thus, alprazolam may be particularly useful in patients with mixed anxiety/depression. However, its general acceptance as an antidepressant awaits further studies.     

Duloxetine-induced hypomania: case report and brief review of the literature on SNRIs-induced mood switching

Manic switching during antidepressant treatment has been reported with every class of antidepressant drugs. Serotonin-noradrenaline reuptake inhibitors (SNRIs) have been increasingly used for the treatment of unipolar and bipolar depression and are well tolerated and sufficiently effective because of their dual mechanism of action. A case of duloxetine-induced hypomania in a non-bipolar patient is presented, and a brief review of all cases of SNRIs' induced mania and hypomania has been carried out. The available data suggest that SNRIs, especially venlafaxine, can induce mood switching in patients with bipolar depression and in certain patients with unipolar depression, but the potential of duloxetine and milnacipran to induce manic or hypomanic symptoms cannot be disregarded. Switching appears to be dose-related and treatment initiation with lower doses and upward titration when needed may be preferable in selected cases and may help minimizing the risk of mood switching.     

Recent progress in pharmacological and non-pharmacological treatment options of major depression

In spite of recent progress in the pharmacotherapy of depression major issues are still unresolved. These include the non-response rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants and the latency of several weeks until clinical improvement. The only non-pharmacological biological treatment options available so far which exert more rapid antidepressant efficacy are electroconvulsive therapy and, as an augmentation strategy, sleep deprivation. Current pharmacological treatments aim to enhance serotonergic and/or noradrenergic neurotransmission. In spite of emerging knowledge, the crucial mechanisms underlying both non-pharmacological treatments, which are responsible for antidepressant efficacy, are not yet clear so far. In the meantime several new pharmacological principles are under investigation with regard to their putative antidepressant potency. These include 5-HT1A receptor agonists, tachykinin receptor antagonists and various interventions within the hypothalamic-pituitary-adrenal system. While there is evidence for antidepressant properties of these new treatments in animal studies, in case series, in open studies and to some degree also in placebo controlled studies, no definite proof for the antidepressant efficacy of these new pharmacological strategies according to the requirements for evaluation of antidepressant drugs has been furnished so far. In contrast, for the established non-pharmacological treatment strategies including bright light therapy the clinical efficacy has been proven at least in subgroups of depression, but more knowledge of the main mechanisms underlying their antidepressant efficacy is still necessary. In addition new non-pharmacological treatments like repetitive transcranial magnetic stimulation, magnetic seizure therapy and Vagus nerve stimulation are currently under development. Nevertheless, a follow-up of both the new pharmacological strategies and non-pharmacological treatment options is of major importance to provide even better strategies for the clinical management of depression, which also is of great socio-economic impact.     

How long should the lithium augmentation strategy be maintained? A 1-year follow-up of a placebo-controlled study in unipolar refractory major depression

There is compelling evidence from placebo-controlled studies that lithium augmentation is an effective strategy in the acute and continuation treatment of refractory unipolar major depression. Authors prospectively investigated the 1-year outcome of 22 subjects diagnosed with unipolar major depression who had participated in a 4-month placebo-controlled, double-blind continuation study of lithium augmentation without relapse. At the end of the double-blind phase, the blinded medication (lithium in 14 patients, placebo in 8 patients) was tapered off over a 1-week period, while the antidepressant was continued at the same dosage for another 4 weeks. Subsequently, the antidepressant was gradually discontinued over a 4-week period. Clinical status was assessed at regular follow-up visits. During the open 6-month follow-up period, seven subjects suffered an affective recurrence, five of whom had received lithium during the placebo-controlled, double-blind phase of the study. Study data suggest that active medication should be maintained for at least 1 year after successful lithium augmentation in patients with unipolar major depressive disorder.     

Alterations of Amino Acid Level in Depressed Rat Brain

Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of depression. Several studies have demonstrated the potential of amino acids as a source of neuro-specific biomarkers could be used in future diagnosis of depression. Only partial amino acids such as glycine and asparagine were determined from certain parts of rats'' brain included hippocampi and cerebral cortex in previous studies. However, according to systematic biology, amino acids in different area of brain are interacted and interrelated. Hence, the determination of 34 amino acids through entire rats'' brain was conducted in this study in order to demonstrate more possibilities for biomarkers of depression by discovering other potential amino acids in more areas of rats'' brain. As a result, 4 amino acids (L-aspartic acid, L-glutamine, taurine and γ-amino-n-butyric acid) among 34 were typically identified as potentially primary biomarkers of depression by data statistics. Meanwhile, an antidepressant called Fluoxetine was employed to verify other potential amino acids which were not identified by data statistics. Eventually, we found L-α-amino-adipic acid could also become a new potentially secondary biomarker of depression after drug validation. In conclusion, we suggested that L-aspartic acid, L-glutamine, taurine, γ-amino-n-butyric acid and L-α-amino-adipic acid might become potential biomarkers for future diagnosis of depression and development of antidepressant.     

Open questions in current models of antidepressant action

Research on depression and antidepressant drugs is necessary, as many patients display poor response to therapy. Different symptomatic and pathophysiological features have been proposed as end points of the depressive phenotype and of the antidepressant action, including anhedonia, depressed mood, alterations in morphology and activity of some brain areas (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex), modifications in the connectivity between brain structures, changes in neurotransmitters (serotonin, noradrenaline, glutamate and neuropeptides), brain plasticity (neurogenesis, neurotrophins) and abnormal function of the hypothalamic-pituitary adrenal axis. However, few models have been proposed to describe how these end points could induce the depressive phenotype and are involved in the mechanism of action of antidepressants. Here we propose a connectionist-inspired network of depression and antidepressant action, in which the different aetiological factors participating in the release of a depressive episode are represented by input nodes, the different symptomatic as well as pathophysiological end points are represented by an intermediate layer, and the onset of depression or of comorbid disease is represented by the output node. The occurrence of depression and the mechanism of the antidepressant action thus depend upon the weight of the interactions between the different end points, none of them being per se crucial to the onset of a depressive phenotype or to the antidepressant action. This model is heuristic to draw future lines of research concerning new antidepressant therapies, designing new animal models of depression and for a better understanding of the depressive pathology and of its comorbid pathology such as anxiety disorders.     

Circadian rhythms, melatonin and depression

The master biological clock situated in the suprachiasmatic nuclei of the anterior hypothalamus plays a vital role in orchestrating the circadian rhythms of multiple biological processes. Increasing evidence points to a role of the biological clock in the development of depression. In seasonal depression and in bipolar disorders it seems likely that the circadian system plays a vital role in the genesis of the disorder. For major unipolar depressive disorder (MDD) available data suggest a primary involvement of the circadian system but further and larger studies are necessary to conclude. Melatonin and melatonin agonists have chronobiotic effects, which mean that they can readjust the circadian system. Seasonal affective disorders and mood disturbances caused by circadian malfunction are theoretically treatable by manipulating the circadian system using chronobiotic drugs, chronotherapy or bright light therapy. In MDD, melatonin alone has no antidepressant action but novel melatoninergic compounds demonstrate antidepressant properties. Of these, the most advanced is the novel melatonin agonist agomelatine, which combines joint MT1 and MT2 agonism with 5-HT(2C) receptor antagonism. Adding a chronobiotic effect to the inhibition of 5-HT(2C) receptors may explain the rapid impact of agomelatine on depression, since studies showed that agomelatine had an early impact on sleep quality and alertness at awakening. Further studies are necessary in order to better characterize the effect of agomelatine and other novel melatoninergic drugs on the circadian system of MDD patients. In summary, antidepressants with intrinsic chronobiotic properties offer a novel approach to treatment of depression.     

Assessing the Neuronal Serotonergic Target-based Antidepressant Stratagem: Impact of In Vivo Interaction Studies and Knockout Models

Depression remains a challenge in the field of affective neuroscience, despite a steady research progress. Six out of nine basic antidepressant mechanisms rely on serotonin neurotransmitter system. Preclinical studies have demonstrated the significance of serotonin receptors (5-HT_1-3,6,7), its signal transduction pathways and classical down stream targets (including neurotrophins, neurokinins, other peptides and their receptors) in antidepressant drug action. Serotonergic control of depression embraces the recent molecular requirements such as influence on proliferation, neurogenesis, plasticity, synaptic (re)modeling and transmission in the central nervous system. The present progress report analyses the credibility of each protein as therapeutically relevant target of depression. In vivo interaction studies and knockout models which identified these targets are foreseen to unearth new ligands and help them transform to drug candidates. The importance of the antidepressant assay selection at the preclinical level using salient animal models/assay systems is discussed. Such test batteries would definitely provide antidepressants with faster onset, efficacy in resistant (and co-morbid) types and with least adverse effects. Apart from the selective ligands, only those molecules which bring an overall harmony, by virtue of their affinities to various receptor subtypes, could qualify as effective antidepressants. Synchronised modulation of various serotonergic sub-pathways is the basis for a unique and balanced antidepressant profile, as that of fluoxetine (most exploited antidepressant) and such a profile may be considered as a template for the upcoming antidepressants. In conclusion, 5-HT based multi-targeted antidepressant drug discovery supported by in vivo interaction studies and knockout models is advocated as a strategy to provide classic molecules for clinical trials.Key Words: Serotonin, depression, trophic factors, interaction studies, knockout models, preclinical screening, target.     

Affective disorders and biological rhythms

Disruptions of circadian rhythms are described in affective disorders, including unipolar and bipolar disorder, but also seasonal affective disorder. Sleep-wake and hormone circadian rhythms are among the most quoted examples. Depression could be conceptualized as a desynchronization between the endogenous circadian pacemaker and the exogenous stimuli, such as sunlight and social rhythms. Accordingly, Clock genes have been studied and the literature suggests that variants in these genes confer a higher risk of relapse, more sleep disturbances associated with depression, as well as incomplete treatment response. Most of therapeutic interventions in depression have an impact on biological rhythms. Some of them exclusively act via a biological pathway, such as sleep deprivation or light therapy. Some psychosocial interventions are specifically focusing on social rhythms, particularly in bipolar disorder, in which the promotion of stabilization is emphasized. Finally, all antidepressant medications could improve biological rhythms, but some new agents are now totally focusing this novel approach for the treatment of depression.     

The C(-1019)G polymorphism of the 5-HT1A gene promoter and antidepressant response in mood disorders: preliminary findings

Several studies have demonstrated the involvement of 5-HT1A receptors in the pathogenesis of depression and in the antidepressant response to SSRIs. A functional new variant in the promoter region of the 5-HT1A gene was recently reported (-1019 C>G). The aim of this study is to investigate a possible association between this 5-HT1A receptor variant and antidepressant response to fluvoxamine in a sample of 262 mood-disorder subjects (151 major depressed and 111 bipolars) treated with fluvoxamine for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). 5-HT1A variants did not influence antidepressant response in the whole sample and in unipolar subjects. In bipolars, 5-HT1A*C/C genotype carriers showed a better response to fluvoxamine (p=0.036), independently from clinical variables. The 5-HT1A polymorphism effect on antidepressant response was independent from the previously reported effect of the 5-HTTLPR polymorphism. In conclusion, 5-HT1A variants could influence the antidepressant efficacy in bipolar subjects, even if results must be verified on larger samples.