The Integrative Management of Treatment-Resistant Depression: A Comprehensive Review and Perspectives

Abstract

Background: Major depressive disorder is a prevalent and disabling illness. Notwithstanding numerous advances in the pharmacological treatment of depression, approximately 70% of patients do not remit after first-line antidepressant treatment. Methods: The MEDLINE/PubMed, EMBASE and ClinicalTrials.gov electronic databases were searched from inception to October 1, 2013, for randomized controlled trials (RCT), relevant open-label trials, meta-analyses and ongoing trials of pharmacological and psychotherapeutic approaches to treatment-resistant depression (TRD). Results: Switching to a different antidepressant is a useful option following nonresponse to a first-line agent. Although widely used in clinical practice, there is limited evidence to support antidepressant combination for TRD. Notwithstanding evidence for lithium or T₃ augmentation to be successful in TRD, most studies were carried out when participants were treated with tricyclic antidepressants (TCA). Of the available strategies to augment the response to new-generation antidepressants, the use of some atypical antipsychotics is best supported by evidence. Several novel therapeutic options are currently discussed. Evidence suggests that cognitive therapy (CT) is an effective strategy for TRD. Conclusions: The success of switching to a different antidepressant following a first-line agent is supported by evidence, but there is limited evidence for effective combination strategies. Lithium and T₃ augmentation of TCA have the strongest evidence base for successful treatment of TRD. The use of augmentation of newer-generation antidepressants with atypical antipsychotics is supported by a growing evidence base. Current evidence supports CT as an effective strategy for TRD. There is a need for additional large-scale RCT of TRD. The development of new antidepressants targeting novel pathways opens a promising perspective for the management of TRD.

Olanzapine augments the effect of selective serotonin reuptake inhibitors by suppressing GABAergic inhibition via antagonism of 5-HT6 receptors in the dorsal raphe nucleus

“…These results suggest that olanzapine and 5-HT 6 receptor antagonists disinhibit serotonergic neurons in the DRN, resulting in increased extracellular 5-HT levels. Combination therapies with conventional antidepressants and atypical antipsychotics such as olanzapine are reportedly effective for the treatment of refractory depression (Nelson and Papakostas, 2009;Carvalho et al, 2014). Consistent with these reports, the present findings suggest that olanzapine enhances the effects of SSRIs on serotonergic function via 5-HT 6 receptor antagonism.…”

“…These reported differences in 5-HT 6 receptor affinity are consistent with the present results showing that olanzapine and clozapine, but not quetiapine and haloperidol, increased extracellular 5-HT levels in raphe slice cultures. However, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 combination therapies with quetiapine and conventional antidepressants are also effective for treatment of refractory depression (Nelson and Papakostas, 2009;Carvalho et al, 2014). Because the dose of quetiapine for adjunctive therapy is relatively high (200e600 mg/day) (McIntyre et al, 2007) compared with that of olanzapine (1e6 mg/kg) (Corya et al, 2006), it is possible that the quetiapine concentration used in the slice cultures in the present study was insufficient to induce an increase in 5-HT.…”

Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A Systematic Review

“…There are anecdotal reports on the use of clonazepam and other benzodiazepines or mood stabilizers, which, however, need to be properly tested [15,50,59,62,72]. Another neglected area of research is concerned with the role of withdrawal symptoms in assessing switching strategies that are increasingly utilized in the treatment resistance of mood and anxiety disorders [86,91]. Drug effects are attributed without adequate consideration of the confounding role of withdrawal symptoms.…”

Mood and Anxiety Disorders as Early Manifestations of Medical Illness: A Systematic Review

“…The occurrence of affective prodromes should be particularly suspected in patients having an onset of mania later than the expected age and when standard psychiatric treatments do not lead to an improvement in psychological symptoms. In fact, affective symptoms due to a medical illness tend not to fully respond to antidepressant drugs, even when properly administered [107,108], but rather to the proper treatment of the underlying medical disorder. Indeed, many patients dismissed as suffering from a mood or anxiety disorder, with an adequate follow-up, may later present with a medical illness responsible at least in part for it [109].…”