Antidepressants In Treatment-resistant Depression Research Articles

Lithium – Fifteen Years Later

Background. The 75th anniversary of introducing lithium into modern psychiatry is recognized, attested by the 1949 paper of John Cade. About this event, my editorial in the special 2010 issue of Neuropsychobiology was titled “Lithium: Sixty Years Thereafter”. Since then, fifteen more years have brought further information about lithium. This paper makes a narrative review of the most important articles published in this period. Summary. The selected key literature of 2010-2024 addressed lithium prophylactic efficacy in bipolar disorder (BD), including pediatric, recurrent depression, and lithium augmentation of antidepressants in treatment-resistant depression (TRD). Novel data have been obtained for lithium adverse effects (kidney, thyroid) and beneficial outcomes of long-term lithium administration (anti-suicidal, neuroprotective, antiviral, and others). The results on the mechanisms of lithium action covered genetic investigations of the ConLiGen, and in vitro studies with induced pluripotent stem cells and lymphoblastoid cell lines. The underutilization of lithium nowadays was emphasized, and the ways to overcome it were considered. Key Messages. Lithium remains the choice drug for recurrence prevention in BD, also in adolescents, and a significant option for augmentation of antidepressants in TRD. The adverse side effects should be carefully followed and managed according to current guidelines. There are also beneficial lithium impacts, of which anti-suicidal and anti-dementia seem the most important. Most of the results of neurobiological studies on lithium mechanisms may be related to lithium response and some (e.g. immunomodulatory) to the pathogenesis of BD. Better education about lithium could make more patients the beneficiary of this drug.

Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = −17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = −14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = −13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = −37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = −42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = −34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299

A qualitative investigation of the Montgomery-Åsberg depression rating scale: discrepancies in rater perceptions and data trends in remote assessments of rapid-acting antidepressants in treatment resistant depression.

Despite the development of many successful pharmaceutical interventions, a significant subset of patients experience treatment-resistant depression (TRD). Ketamine and its derivatives constitute a novel therapeutic approach to treat TRD; however, standard tools, such as the Montgomery-Åsberg Depression Rating Scale (MADRS) are still being used to measure symptoms and track changes. The aim of this study was to review item-level differences between rate of data change (MADRS score) and rater-weighted perception of the most useful items for assessing change in symptoms while remotely conducting the 10-item version of the MADRS in TRD in a clinical trial of rapid-acting antidepressants. Two studies of rapid-acting antidepressants in the treatment of TRD were used to identify item-scoring trends when MADRS is administered remotely and repeatedly (733 subjects across 10 visits). Scoring trends were evaluated in tandem to a rater survey completed by 75 raters. This was completed to gain insight on MADRS items' perceived level of helpfulness when assessing change of symptoms in rapid-acting antidepressant trials. MADRS items 'Reduced sleep', 'Apparent sadness', and 'Pessimistic thoughts' were found to have the greatest average data change by visit, while raters ranked 'Reported sadness', 'Lassitude' and 'Apparent sadness' as the most helpful items when assessing symptom change. The diversion between rate of data-change ranking and rater perception of helpfulness could be related to difficulty in assessing specific items, to the novel treatment itself, and/or to the sensitivity to symptom change to which raters are accustomed in traditional antidepressant treatments.

Antiviral, immunomodulatory, and neuroprotective effect of lithium.

Currently, in psychiatry, lithium is a drug of choice as a mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most important psychiatric use of lithium is probably increasing the efficacy of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium exerts antisuicidal, antiviral, immunomodulatory, and neuroprotective effects. The goal of the review is to describe the experimental and clinical studies on the last three properties of lithium. Antiviral effects of lithium pertain mostly to DNA viruses, especially herpes viruses. The therapeutic effects of lithium in systemic and topical administration on labial and genital herpes were demonstrated in clinical studies. There is also some evidence, mostly in experimental studies, that lithium possesses antiviral activity against RNA viruses, including coronaviruses. The immunomodulatory effect of lithium can mitigate "low-grade inflammatory" conditions in bipolar illness. The neuroprotective properties of lithium make this ion a plausible candidate for the prevention and treatment of neurodegenerative disorders. A favorable effect of lithium was shown in experimental models of neurodegenerative disorders. On the clinical level, some preventive action against dementia and moderately therapeutic activity in Alzheimer's disease, and mild cognitive impairment were observed. Despite promising results of lithium obtained in animal models of Huntington's disease and amyotrophic lateral sclerosis, they have not been confirmed in clinical studies. A suggestion for common mechanisms of antiviral, immunomodulatory, and neuroprotective effects of lithium is advanced.

Augmentative Pharmacological Strategies in Treatment-Resistant Major Depression: A Comprehensive Review.

Treatment resistant depression (TRD) is associated with poor outcomes, but a consensus is lacking in the literature regarding which compound represents the best pharmacological augmentation strategy to antidepressants (AD). In the present review, we identify the available literature regarding the pharmacological augmentation to AD in TRD. Research in the main psychiatric databases was performed (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles in English with the main topic being pharmacological augmentation in TRD and presenting a precise definition of TRD were included. Aripiprazole and lithium were the most investigated molecules, and aripiprazole presented the strongest evidence of efficacy. Moreover, olanzapine, quetiapine, cariprazine, risperidone, and ziprasidone showed positive results but to a lesser extent. Brexpiprazole and intranasal esketamine need further study in real-world practice. Intravenous ketamine presented an evincible AD effect in the short-term. The efficacy of adjunctive ADs, antiepileptic drugs, psychostimulants, pramipexole, ropinirole, acetyl-salicylic acid, metyrapone, reserpine, testosterone, T3/T4, naltrexone, SAMe, and zinc cannot be precisely estimated in light of the limited available data. Studies on lamotrigine and pindolol reported negative results. According to our results, aripiprazole and lithium may be considered by clinicians as potential effective augmentative strategies in TRD, although the data regarding lithium are somewhat controversial. Reliable conclusions about the other molecules cannot be drawn. Further controlled comparative studies, standardized in terms of design, doses, and duration of the augmentative treatments, are needed to formulate definitive conclusions.

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial.

Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing. We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054). To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).

Repetitive transcranial magnetic stimulation as an augmentative strategy for treatment-resistant depression, a meta-analysis of randomized, double-blind and sham-controlled study.

BackgroundDozens of randomized controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) treatment, but there has not been a meta-analysis report which evaluates the efficacy and tolerability of rTMS used as an augmentative strategy for antidepressants in treatment-resistant depression (TRD) treatment. We thus conducted this meta-analysis, aimed at clarifying whether rTMS enhances the efficacy of TRD.MethodsWe searched MEDLINE and Cochrane Central Register of Controlled Trials for RCTs for studying the efficacy of rTMS versus (vs) sham condition when combined with antidepressants in TRD treatment, and screened the references of the previous meta-analysis about the rTMS for MDD treatment. Response rates and NNT were chose as the primary outcomes, and remission rates, change from baseline of HAMD scores, dropouts were used as secondary outcomes. For dichotomous data, an intention-to-treat analysis principle was applied; for continuous data, we calculated the standard mean difference between groups with a random-effect model. Sensitivity analysis was done to explore the source of heterogeneity and the factors which potentially impact the efficacy.ResultsSeven RCTs were finally included in the meta-analysis. The total sample size was 279, with 171 in the rTMS group and 108 in the sham group. The pooled response and remission rate for the rTMS and sham group was 46.6% and 22.1%, respectively; the pooled odds ratio (OR) was 5.12 [95% confidence interval (CI) 2.11-12.45, z = 3.60, p = 0.0003, and the associated number needed to treat (NNT) was 3.4. rTMS group achieved a significant reduction of HAMD score than the sham group, the pooled SMD of change from baseline was 0.86 [95% confidence interval (CI) 0.57-1.15, z = 5.75, p < 0.00001]. Because of the small number of included RCTs, the preplanned sensitivity and subgroup analyses were finally abandoned. The dropouts in both groups were relatively low, indicating the high acceptability of rTMS.ConclusionsFor TRD patients, augmentative rTMS after the failure of medications significantly increases the effect of antidepressants, and rTMS was a safe strategy with relatively low adverse events and low dropout rate, suggesting that augmentative rTMS is an effective intervention for TRD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-014-0342-4) contains supplementary material, which is available to authorized users.

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.

Is there a role for switching antidepressants in treatment‐resistant depression?

AbstractThis extract has been taken from Treatment‐resistant Depression By Siegfried Kasper and Stuart Montgomery (eds)Wiley‐Blackwell 2013

Augmentation Treatments with Second-generation Antipsychotics to Antidepressants in Treatment-resistant Depression

Various classes of antidepressants have been used in the treatment of major depressive disorder (MDD); however, the efficacy of these treatments remains uncertain. A number of well-controlled clinical trials, meta-analyses and practical clinical studies have found that approximately 30 % of MDD patients remit following antidepressant treatment, leaving approximately 70 % of patients with significant residual symptoms. In these latter patients with what is considered treatment-resistant MDD, typical antipsychotics have sometimes been administered in order to augment the antidepressant effects but safety and tolerability concerns significantly reduce their usage in MDD patients. The advent of second-generation antipsychotics (SGAs), which have diverse pharmacodynamic profiles relative to antidepressants, has dramatically increased the usage of such drugs for patients with MDD. Recently, SGAs such as aripiprazole, quetiapine and olanzapine in combination with fluoxetine have been approved for the treatment of MDD, especially in the case of treatment resistance. This article reviews the efficacy and tolerability of SGA augmentation when added to antidepressant therapy for treatment-resistant MDD patients in acute phase studies published to date.

Effect of co-treatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test

BackgroundSeveral clinical reports have postulated a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants in treatment-resistant depression. MethodsThe present study aimed to examine the effect of treatment with fluoxetine or mirtazapine, given separately or jointly with risperidone, on active behavior and plasma corticosterone level in male Wistar rats subjected to the forced swim test (FST). ResultsThe obtained results showed that fluoxetine (5mg/kg), mirtazapine (5 and 10mg/kg) or risperidone (0.05 and 0.1mg/kg) did not change the active behavior of rats in the FST. However, co-treatment with fluoxetine (10mg/kg) and risperidone (0.1mg/kg) induced an antidepressant-like effect in that test because it significantly increased the swimming time and decreased the immobility time, while combined treatment with mirtazapine at 5 and 10mg/kg and risperidone at 0.05 and 0.1mg/kg evoked a significant increase in the swimming time and also climbing, and decreased the immobility time. WAY 100635 (a 5-HT1a receptor antagonist) at a dose of 0.1mg/kg inhibited the antidepressant-like effect induced by co-administration of fluoxetine or mirtazapine and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined treatment with fluoxetine or mirtazapine and risperidone failed to enhance the exploratory activity of rats. Co-treatment with fluoxetine or mirtazapine and risperidone did not reduce the stress-induced increase in plasma corticosterone concentration in animals subjected to the FST. ConclusionThe obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of fluoxetine and mirtazapine in the FST (but does not normalize the stress-induced increase in corticosterone level in these rats), and that 5-HT1a receptors may play some role in these effects.

Citalopram versus desipramine in treatment resistant depression: Effect of continuation or switching strategies. A randomized open study

Objectives. Evidence in favour of switching between selective serotonin reuptake inhibitor (SSRI) and tricyclic (TCA) antidepressants in treatment resistant depression has been tested in a few studies only, consequently a prospective study was undertaken to evaluate the impact of switching strategies. Methods. One hundred eighty-nine patients who failed to respond to a previous antidepressant were randomised to four arms: firstly they received citalopram or desipramine for a 4-week period; secondly, those who failed to respond were treated for a further 4-week period with the same antidepressant (citalopram-citalopram and desipramine-desipramine arms) or switched to the alternate one (citalopram-desipramine and desipramine-citalopram arms). Results. There was no difference in the first 4-week phase between patients receiving citalopram versus desipramine in Hamilton Rating Scale for Depression (HRSD), Montgomery–Asberg Depression Rating Scale (MADRS), and Clinical Global Impression (CGI) scores. In the second 4-week phase remitter rates were higher among non-switched patients (P = 0.04). Moreover, considering HRSD and MADRS, switched patients reported significantly higher scores (P ≤ 0.02 for both scales at each time-point). Conclusions. This study supports the thesis that switching from an SSRI to a TCA (and vice versa) in non-responders to a 4-week trial of an SSRI/TCA is not associated with improved response. The result goes in the opposite direction to that predicted by current guidelines.

Bipolarity and inadequate response to antidepressant drugs: Clinical and psychopharmacological perspective

The reason why depression may respond poorly to treatment with antidepressant drugs may be connected with the features of bipolarity. Evidence to this effect has accumulated in recent studies of various kinds of depression in mood disorders. Additional evidence for such a connection may be the efficacy of mood-stabilizing drugs in the augmentation of antidepressants in treatment-resistant depression. This review is based on clinical and psychopharmacological research performed over the past five years. The clinical investigation was based on the response to antidepressants of bipolar depression or to symptoms of hypomania, assessed mainly by the Mood Disorder Questionnaire (MDQ) and the Hypomania Checklist-32 (HCL-32). The psychopharmacological research tested the efficacy of augmentation of antidepressants in treatment-resistant depression by mood-stabilizing drugs of the 1st and 2nd generations. A number of studies have pointed to an association between bipolar depression, or symptoms of hypomania and an inadequate response to antidepressants. Such a connection was also found in the Polish TRES-DEP study which included 1051 depressed patients. Pharmacological studies have demonstrated the efficacy of first generation mood-stabilizing drugs (lithium, carbamazepine) and second generation drugs (quetiapine, olanzapine, risperidone, ziprasidone, lamotrigine) for augmentation of antidepressants in treatment-resistant depression. Some evidence has been presented that mixed depressive episodes may also belong to this category. The results of these clinical and psychopharmacological studies appear to confirm an association between bipolarity and a poor response of depression to treatment with antidepressant drugs.

RESEARCH: Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ)

The low rate of response to antidepressants in treatment resistant depression (TRD) justifies studies of next-step therapies following a treatment failure. In TRD clinical trials, it is important to verify the accurate diagnosis of treatment resistance for all enrolled subjects using a reliable and valid instrument. Self-rated scales can reduce the impact of investigator bias and reduce the time burden for clinical researchers. The Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) is a self-rated scale used to determine treatment resistance in major depressive disorder (MDD). The ADAPT-A study is a multi-center double-blind, placebo-controlled study of low-dose aripiprazole adjunctive to ADT among outpatients with TRD. At the screening assessment, potential subjects completed the MGH ATRQ. The ADAPT-A medical monitors subsequently performed remote patient interviews and obtained detailed medication histories. The data obtained from the MGH ATRQ and by the medical monitors were compared for congruency. Of the 186 patients enrolled by the local sites, no subjects deemed treatment resistant by the MGH ATRQ were found to be nonresistant by the medical monitors. In 76.3% (n = 142) of the subjects, the number of failed adequate antidepressant trials reported by the MGH ATRQ was concordant with the data collected by medical monitors. In 16.1% (n = 30) of all cases, the medical monitors found a greater number of failed trials; in 7.5% (n = 14) of cases, the medical monitors found fewer failed medication trials. The discrepancy was by more than one medication trial in only 4.0% (n = 7) of cases. We found the MGH ATRQ to be relatively concordant in its assessment of treatment resistance in depression compared with independent clinical researchers. Although the MGH ATRQ tended to underreport the number of unsuccessful treatment trials relative to the clinical interviews, its accuracy in cases it detected was confirmed by raters.

Bipolar mood disorder and treatment-resistant depression

Two lines of evidence point to the relationship between bipolar mood disorder and treatment-resistant depression. First, the frequency of suboptimal response to antidepressant drugs is significantly higher in bipolar than in unipolar mood disorder. Secondly, the first and the second generation mood stabilizing drugs are efficacious for augmentation of antidepressants in treatment-resistant depression. Short-term non-response to antidepressant drugs has been significantly higher in bipolar and in unipolar mood disorder. A significant percentage of unipolar depressed patients resistant to antidepressant drugs reaches a diagnosis of bipolarity during a specific screening or during follow-up. In the Polish all-country DEP-BI study including 880 depressed outpatients treated with psychiatrists, it was found that the percentage of treatment-resistant depression was significantly higher in bipolar than in unipolar mood disorder, especially so, in bipolar spectrum disorder where the features of bipolarity are most easy to overlook. Recent Polish TRES-DEP study included 1051 depressed patients (569 with treatment-resistant and 482 with treatment non-resistant depression). Using Hypomania Check List-32 (HCL-32) scale, it has been found that the percentage of ≥ 14 score on HCL-32, indicating bipolarity, was significantly higher in patients with treatment resistant than in treatment-nonresistant depression (44% vs 30%, respectively). Lithium, the prototypic mood stabilizer, has been the most frequent modality used for the augmentation of antidepressants in treatment-resistant depression, and the efficacy of lithium in this respect has been confirmed by a number of meta-analyses. Our study has shown that such effect of lithium is significantly better in bipolar than in unipolar depression. Out of the first generation antidepressant drugs, also some efficacy of carbamazepine, and to less extent, valproate, has been found for the augmentation of antidepressants. Lamotrigine, new generation anticonvulsant and mood-stabilizer, demonstrated its antidepressant efficacy both during acute episode and in prophylaxis of depression in bipolar illness. It has been also effective for augmentation of antidepressant drugs in treatment-resistant depression. In our study we found that the overall efficacy of lamotrigine was similar to that of lithium, however, both drugs were more efficacious for augmentation of venlafaxine than paroxetine. In recent years, there have been numerous studies on the efficacy of second generation antipsychotic drugs (some of them can be qualified also as second generation mood stabilizers) for the augmentation of antidepressants in treatment-resistant depression. While the clear antidepressant effect of quetiapine as monotherapy has been demonstrated, the majority of second generation antipsychotics proved their efficacy in augmentation of antidepressants in treatment-resistant depression, and aripirazole, obtained an official approval for such indication.

P01-75 - Quetiapine XR or lithium combination with antidepressants in treatment resistant depression

ObjectivesCompare quetiapine+antidepressant (AD) with lithium+AD, and quetiapine monotherapy with lithium+AD in open, rater-blinded treatment.MethodsPatients with treatment resistant depression (Thase et al 1997 stage 1 and 2) with severity of MADRS ≥25 received: quetiapine XR 300mg/day plus AD (SSRIs or venlafaxine) (n=229), lithium (monitored to between 0.6 to 1.0 meq/l) plus AD (n=221) or quetiapine XR alone (300mg/day) (n=225) for 6 weeks. Primary efficacy measure was change from baseline in MADRS total score. The pre-specified non-inferiority limit was 3 points on the MADRS.ResultsFewer patients discontinued on quetiapine+AD (15.2%) than lithium+AD (20.5%) and quetiapine monotherapy (21.5%). Quetiapine+AD and quetiapine monotherapy, were not inferior to lithium+AD in the primary (per protocol) analysis with a mean difference (97.5%CI) on the MADRS of -2.32 (-4.6 to -0.05) favouring add-on quetiapine and -0.97 (-3.24 to 1.31) favouring quetiapine monotherapy. This mandated superiority testing on the modified ITT population showing no significant difference at endpoint.In a post hoc analysis discounting multiplicity, quetiapine+AD was significantly more effective than lithium+AD on the MADRS change from baseline, p=0.046. The advantage was observed at day 4 (p=0.007) and persisted throughout. Efficacy was supported by CGI-I (p=0.07). Quetiapine+AD showed a numerically greater advantage over lithium+AD in those with two failed treatments (Stage 2) rather than one (Stage 1).ConclusionsQuetiapine+AD and quetiapine monotherapy, were non-inferior to lithium+AD in treatment resistant depression. There was an early significant and persistent efficacy advantage on MADRS for quetiapine augmentation compared with lithium augmentation of SSRI or venlafaxine treatment.

The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression

Meta-analysis of all available trials of Venlafaxine in the treatment of major depressive disorders, including treatment resistant depression and long-term relapse prevention. We conducted a meta-analysis comparing venlafaxine and tricyclics, or selective serotonin reuptake inhibitors (SSRIs), in major depression. We also included trials comparing venlafaxine and alternative antidepressants in subjects with treatment resistant depression, or compared with placebo in long-term relapse prevention. Trials were identified through searches of Medline, Embase, Cochrane Library and through accessing unpublished trials held by the manufacturer. Results based on intention to treat analyses where available, were pooled using theoretically exact conditional maximum likelihood methods for fixed effects (primary analyses), and numerical simulation using a Gibbs sampler for full random effects. Compared to all SSRIs for the treatment of major depression (fluoxetine, paroxetine, sertraline, citalopram, escitalopram and fluvoxamine), venlafaxine was associated with a greater response [odds ratio 1.15 (95% CI 1.02-1.29)] and remission [odds ratio 1.19 (95% CI 1.06-1.34)]. Overall drop out rates appeared similar for SSRIs and venlafaxine. Compared to tricyclics, response to venlafaxine was estimated to be greater by exact method, odds ratio 1.21 (95% CI 1.03-1.43), but not statistically significantly different, using a full random effects method odds ratio 1.22 (95% CI 0.96-1.54). We observed no difference in remission rates (odds ratio 1.06 (95% CI 0.74-1.63)). Tricyclics were less well tolerated with higher overall drop out rates. Compared to alternative antidepressants in treatment resistant depression (trials included comparison with sertraline, bupropion, fluoxetine, citalopram, and one with a range of agents-mostly SSRIs), the odds ratio for response was 1.35 (95% CI 1.19-1.54). The odds ratio for remission was 1.35 (95% CI 1.20-1.52). Compared to placebo the odds ratio for relapse prevention with venlafaxine was 0.37 (95% CI 0.27-0.51). This meta analysis provides evidence of the clinical efficacy of venlafaxine in achieving therapeutic response and remission in patients with major depression. Venlafaxine appears more effective than SSRIs, and at least as effective as tricyclic antidepressants, in the treatment of major depressive episode. Venlafaxine appeared more effective than comparators in treatment resistant depression. In addition, venlafaxine effective in reducing relapse when given long term after major depressive episode.

Aripiprazole Augmentation of Selective Serotonin Reuptake Inhibitors for Treatment-Resistant Major Depressive Disorder

Due to their favorable side effect profile, atypical antipsychotic agents offer important therapeutic advantages in mood disorders. Aripiprazole, an atypical antipsychotic agent with partial dopaminergic and serotonin 1A receptor agonist activity, may be particularly useful when used in conjunction with standard antidepressants in treatment-resistant depression. The purpose of this study was to test this hypothesis in depressed outpatients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor (SSRI). 12 patients (mean +/- SD age = 46.6 +/- 11.3 years, 66.7% female) with major depressive disorder (MDD) diagnosed by use of the Structured Clinical Interview for DSM-IV-Axis I Disorders, who had failed to experience a clinical response following an adequate trial of an SSRI, were treated with open-label aripiprazole in addition to their SSRI for 8 weeks. Clinical response was defined as a 50% or greater decrease in depressive symptoms during the course of the trial (baseline-endpoint) as measured by the 17-item Hamilton Rating Scale for Depression total score. Data were collected from August 2003 to July 2004. 9/12 (75.0%) patients completed the trial. Using a completer analysis, 5/9 (55.6%) patients were classified as responders. An intent-to-treat (ITT) analysis resulted in 7 responders (58.3%). The overall proportion of remitters was 3/9 (33.3%) using a completer analysis and 5/12 (41.7%) using the ITT analysis. Aripiprazole administration appeared safe, with no severe adverse events observed in any of the study participants. These results suggest a possible augmentation role for aripiprazole when used in conjunction with SSRIs in SSRI-resistant MDD.

The effect of lithium on the immune system

A substantial amount of data point to antiviral and immunomodulatory effects of lithium both in vitro and in vivo. Antiviral effect of lithium, particularly against herpes viruses, was demonstrated both in affective patients taking lithium for prophylactic purposes and in non-affective subjects. Modulatory effects of lithium on many parameters of cellular and humoral immunity were also found in clinical studies with affective patients. These findings have been paralleled by new information indicating a possible pathogenic role of viral infection and immune dysfunction in affective illness. A hypothesis is proposed that the antiviral and immunomodulatory action of lithium may have relevance to the prevention by this ionic drug of the recurrences of affective episodes and the potentiation of antidepressants in treatment-resistant depression. Copyright © 1999 John Wiley & Sons, Ltd.