Antidepressant-resistant Depression Research Articles

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT1A, 5-HT2A and adrenergic a2 receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.

Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus

Electroconvulsive therapy is the most effective treatment for antidepressant-resistant depression, although its mechanism has not been fully elucidated. Previous studies have demonstrated that electroconvulsive seizures (ECS) induce expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus. However, in contrast with mature BDNF (mBDNF) known to have antidepressant effects, its precursor (pro-BDNF) has harmful effects on neurons. We therefore hypothesized that efficient processing of pro-BDNF is a critical requirement for the antidepressant effects of ECS. We found that single administration of ECS rapidly increased not only hippocampal levels of pro-BDNF but also those of prohormone convertase 1 (PC1) and tissue-plasminogen activator (t-PA), which are proteases involved in intra- and extracellular pro-BDNF processing, respectively. Interestingly, pro-BDNF and t-PA levels were increased in hippocampal synaptosomes after single ECS, suggesting their transport to secretory sites. In rats receiving 10-d repeated ECS, accumulation of pro-BDNF and a resultant increase in mBDNF levels were observed. While t-PA levels increased and accumulated following repeated ECS, PC1 levels did not, suggesting that intracellular processing capacity is limited. Finally, chronic administration of imipramine significantly increased mBDNF levels, but not pro-BDNF and protease levels, indicating that the therapeutic mechanism of imipramine differs from that of ECS. Taken together, these results suggest that, while intra- and extracellular proteases are involved in pro-BDNF processing in single ECS, t-PA plays a dominant role following repeated ECS. Such efficient pro-BDNF processing as well as strong induction of BDNF expression may contribute to the antidepressant effects of ECS.

Investigation on the Mechanisms for the Suppression of Cell Proliferation in the Dentate Gyrus of the Hippocampus in ACTH Treated Rats

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.

Antidepressant-Resistant Depression and Antidepressant-Associated Suicidal Behaviour: The Role of Underlying Bipolarity

The complex relationship between the use of antidepressants and suicidal behaviour is one of the hottest topics of our contemporary psychiatry. Based on the literature, this paper summarizes the author's view on antidepressant-resistant depression and antidepressant-associated suicidal behaviour. Antidepressant-resistance, antidepressant-induced worsening of depression, antidepressant-associated (hypo)manic switches, mixed depressive episode, and antidepressant-associated suicidality among depressed patients are relatively most frequent in bipolar/bipolar spectrum depression and in children and adolescents. As early age at onset of major depressive episode and mixed depression are powerful clinical markers of bipolarity and the manic component of bipolar disorder (and possible its biological background) shows a declining tendency with age antidepressant-resistance/worsening, antidepressant-induced (hypo)manic switches and “suicide-inducing” potential of antidepressants seem to be related to the underlying bipolarity.

Placebo-Controlled Study of Relapse Prevention With Risperidone Augmentation in Older Patients with Resistant Depression

The effect of risperidone augmentation of citalopram for relapse prevention in older patients with antidepressant-resistant depression was evaluated. Patients with major depression aged > or =55 years who had failed at least one adequate trial of an antidepressant received citalopram monotherapy (20-40 mg) for 4 to 6 weeks to confirm nonresponse (<50% reduction in Hamilton Rating Scale for Depression [HAM-D] scores). Those who achieved remission (HAM-D score < or =7 or Clinical Global Impressions severity score 1 or 2) after 4 to 6 weeks of open-label risperidone augmentation (0.25-1 mg) then entered a 24-week double-blind maintenance phase during which they received citalopram augmented with risperidone or placebo. The patients' mean age was 63.4 +/- 7.9 years; 58% were women; 61% had received two or more antidepressants during the current episode; 93 met the criterion for citalopram nonresponse and entered open-label risperidone augmentation. Of the 89 patients who completed risperidone augmentation, 63 achieved symptom resolution and entered the 6-month double-blind maintenance phase: 32 received risperidone augmentation and 31 received placebo augmentation. The median time to relapse (Kaplan-Meier estimates) was 105 days in the risperidone group and 57 days in the placebo group (Wilcoxon chi(2): 3.2, df = 1, p = 0.069). Overall, 18 of 32 (56%) from the risperidone group and 20 of 31 (65%) from the placebo group relapsed. Treatment was well tolerated. In older patients with resistant depression and poor response to standard treatments, risperidone augmentation resulted in symptom resolution in a substantial number of patients and a nonsignificant delay in time to relapse.

Lithium addition in antidepressant-resistant depression: Effects on platelet 5-HT, plasma 5-HT and plasma 5-HIAA concentration

The efficacy of the addition of lithium to an established course of antidepressant treatment can be explained by a synergistic effect of the two drugs on central 5-HT neurotransmission. In the present study we investigated the effect of lithium addition on the 5-HT concentration in plasma and platelets and the concentration of 5-HIAA. Thirty-nine depressed inpatients who fulfilled the DSM-IV criteria for major depressive disorder and who did not respond to monotherapy with either imipramine or fluvoxamine participated in this study. Concentration of 5-HT in both plasma and platelets did not change significantly during lithium addition. The 5-HT ratio (plasma concentration/platelet concentration) shows a small non-significant increase after 3 weeks lithium addition. The mean concentration of 5-HIAA shows a significant increase during lithium addition; with no difference between the imipramine and the fluvoxamine sample. The increments in 5-HIAA concentration during lithium addition are indicative of an increased 5-HT turnover.

治療抵抗性うつ病に奏効する薬剤の創薬を目指して&lt;/br&gt;&amp;mdash;電気けいれん療法の有用性と脳由来神経栄養因子（BDNF）の関与&amp;mdash;

In recent years, depression studies have focused on morphological changes associated with depression. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that plays an important role in the morphological changes associated with depression and the mechanisms of antidepressants. On the other hand, hyperfunction of the hypothalamic-pituitary-adrenal axis has been link to pathophysiology of depression. In our previous studies, ACTH-treated rats served as a valuable animal model of tricyclic antidepressant-resistant depressive conditions. However, few neuroanatomic studies have been done. In the present study, we investigated mechanisms underling ACTH-treated rat serving an imipramine treatment-resistant depression model using c-Fos as a marker. The c-Fos immunohistochemical study indicated that the medial prefrontal cortex is an action site of imipramine in ACTH-treated rats. Electroconvulsive therapy is considered an effective treatment for treatment-resistant depression. However, the mechanisms causing treatment-resistant depressive conditions are unknown. We investigated the effect of repeated electrical convulsive shock (ECS)-treatment using the forced swim test, a screening method for antidepressant-like activity, and hippocampal BDNF protein levels in ACTH-treated rats. Findings showed that repeated ECS treatment decreased the immobility time during forced swim test. Furthermore, the ECS treatment also markedly increased the hippocampal BDNF levels in the rat tricyclic antidepressant-resistant depression model. In addition, the repeated ECS treatment showed long-lasting effects on forced swim test and increased of hippocampal BDNF levels in normal rats. These findings suggest that BDNF plays a key role in the antidepressant-like effect of ECS and that increased BDNF may be involved in promoting the long-lasting effect.

Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression

There is evidence to indicate that peripheral glucocorticoid receptor (GR) function is reduced in major depression, and a possible molecular explanation for this is the impact of raised pro-inflammatory cytokines. The topical steroid vasoconstriction assay provides a convenient probe of peripheral GR function. The present study sought to assess the sensitivity of peripheral GRs in antidepressant-resistant major depressives and investigate the association between GR sensitivity and circulating plasma cytokines. Nineteen antidepressant-resistant depressives together with age- and sex-matched healthy controls underwent the steroid vasoconstriction assay using three commercial preparations of corticosteroids containing clobetasol propionate 0.05%, betamethasone valerate 0.1%, and clobetasone butyrate 0.05%, corresponding to very potent, potent, and moderately potent steroid creams respectively. The pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assays. The severity of the depressive episode was assessed using the Hamilton Depression Scale (HAMD). Depressed subjects had a significantly reduced vasoconstriction response across all three strengths of steroid. They also had significantly higher concentrations of TNF-alpha and IL-6. There was a significant inverse correlation between TNF-alpha concentration and vasoconstriction response and also between the HAMD score and vasoconstriction response. These findings suggest that cutaneous GR function is abnormal in antidepressant-resistant depression, that circulating TNF-alpha may play a significant role in this abnormality and that the efficacy of topical steroids in antidepressant-resistant depressives is reduced.

Efficacy and Tolerability of Tranylcypromine Versus Phenelzine

The aim of this study was to examine whether phenelzine is a suitable alternative to tranylcypromine in antidepressant-resistant depression. A total of 77 severely depressed in-patients, meeting the DSM-IV criteria for major depressive disorder, who failed to respond to fixed plasma level treatment with either tricyclic antidepressants or fluvoxamine were withdrawn from psychotropic medication and included in a double-blind flexible-dose 5-week comparison of tranylcypromine and phenelzine. Of the 77 patients, 67 (87%) completed the trial, of whom 35 (52%) responded. No significant differences in response between both drugs were observed. Seventeen (44%) of 39 patients responded to tranylcypromine and 18 (47%) of 38 to phenelzine (> or = 50% reduction in Hamilton Rating Scale for Depression [HAM-D] score). The mean reduction in HAM-D score was 10.4 +/- 8.3 for the tranylcypromine sample versus 8.3 +/- 8.4 for the phenelzine-treated patients. Only a few patients (10%) used concomitant psychotropic medication. A substantial number of patients experienced severe side effects, mainly dizziness, agitation, and insomnia; the incidence was the same in both samples (21%). No difference in efficacy was observed between both monoamine oxidase inhibitors in a sample of patients with severe antidepressant-refractory depression. Phenelzine appears to be a suitable alternative to tranylcypromine.

Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test

The problem of antidepressant-resistant depression has necessitated finding ways of augmenting the actions of currently existing antidepressants. The present studies investigate the possibility of synergistic interactions between nitric oxide (NO) synthase inhibitors and antidepressants in the mouse forced swim test (FST), a pre-clinical test of antidepressant activity. Treatment with a behaviourally subactive dose of the NO synthase inhibitor N G-nitro- l-arginine ( l-NA) (3 mg/kg) augmented the behavioural effect of the tricyclic antidepressant imipramine. In a similar fashion l-NA (3 mg/kg) augmented the effect of the selective serotonin re-uptake inhibitor (SSRI) fluoxetine but not the noradrenaline re-uptake inhibitor, reboxetine in the FST. The interaction observed between l-NA and fluoxetine generalised to other selective serotonin re-uptake inhibitors, namely, sertraline and citalopram in the FST. Treatment with a subactive dose of the neuronally selective NO synthase inhibitor, 7-nitroindazole (30 and 50 mg/kg), augmented the behavioural effects of imipramine and fluoxetine, respectively. Thus inhibition of NO synthase enhances the activity of antidepressants that work via a serotonergic mechanism in the FST. The results of the present investigation support a view that antidepressant effects, or enhancement of such effects in the FST, may be elicited via NO synthase inhibition. Furthermore, these data raise the possibility that inhibition of NO synthase could be used as a strategy to enhance the clinical efficacy of serotonergic antidepressants.

Predictors of response to lithium augmentation in tricyclic antidepressant-resistant depression

Background: The efficacy of lithium augmentation in therapy-resistant depression has been shown in a series of well-designed, placebo-controlled studies. However, little is known about the predictors of a good response to this treatment strategy. Methods: We retrospectively examined the predictive value of 20 demographic, clinical, biochemical and endocrinological variables using a two-step logistic regression. Seventy-one in-patients with depression refractory to tricyclic antidepressants had received lithium augmentation as part of a standardised treatment protocol. Results: Within 4 weeks 37 patients (52%) responded to lithium augmentation. Five variables with predictive value were found. Responders were more severely depressed according to the Bech–Rafaelsen Melancholia Scale. The duration of their index episode was shorter. Triiodothyronine serum levels were lower and neuroleptic co-medication and co-diagnosis of personality disorder were less frequent. Limitations: This was an open, retrospective study. Conclusions: Severity of depression is a predictor of response to lithium augmentation. This result conflicts with recent studies but is similar to results found in studies of other pharmacological antidepressant strategies.

Open pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression

Background: Recently, a dopamine hypothesis of depression was put forward, and several studies have demonstrated that direct and indirect dopamine agonists have antidepressant effects. Methods: Using Clinical Global Impressions, we evaluated the efficacy of 4-week treatment of pergolide as an antidepressant adjuvant involving 20 unipolar depressed patients who were refractory to standard treatment with antidepressants. Results: One patients (5%) were very much improved, seven (35%) much improved, four (20%) minimally improved, six (30%) no change or worse, and two (10%) not assessed. There was no significant difference in any clinical factors between the pergolide responder and non-responder group. Limitations: This study was a non-blind open trial, and pergolide was added to tricyclic and heterocyclic antidepressants. Conclusion: Pergolide may be useful as an antidepressant adjuvant, suggesting a potential role for dopamine-2 stimulation in the antidepressant response.

Pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression

Pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression

Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression

Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression

Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression

Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression