The physical sensations that accompany sadness can feel as undesirable as they are intense – a constriction of the chest, watery eyes and a raw throat, to name a few.
But Norman Farb, an associate professor of psychology at the University of Toronto Mississauga, and Zindel Segal, a distinguished professor of psychology in mood disorders at U of T Scarborough, have discovered that keeping sensation alive in the face of stress is critical for well-being, particularly for those who have recovered from depression.
In the largest neuroimaging study to date of psychotherapy for preventing relapse and recurrence in depression, the researchers linked past depression with a greater tendency to shut down sensory processing when faced with an emotional stressor.
They also found that blocking out sensation is related to a greater risk of depressive relapse.
“We don’t like feeling bad things, (but) we don’t really think about the implications of balancing our short-term relief with our long-term health,” says Farb.
“Our research explains why working to keep feeling is so important. It lays the groundwork for seeing that emotional stress actually robs us of sensation – and to undo stress, one must counter this inhibitory effect.”
The study, published recently in the journal NeuroImage: Clinical, was co-authored by Farb and Segal, along with Ph.D. student Philip Desormeau, in the psychological clinical science graduate department at U of T Scarborough, and Cornell University Professor Adam Anderson.
The study included 166 participants who had recovered from depression but were vulnerable to a future episode. They were divided into two groups. Over an eight-week period, one group underwent cognitive therapy with a well-being focus, while the other group underwent mindfulness-based cognitive therapy.
Between cognitive therapy sessions, 85 participants also had their brain activity measured through a fMRI scan while watching four consecutive clips from TV shows that wouldn’t normally produce an emotional trigger as a baseline – for example, a lifestyle-related show on HGTV – as well as clips from an emotionally charged movie such as 1983’s Terms of Endearment.
For the following two years, researchers followed up with participants every two months.
Farb says he and colleagues discovered something fascinating while studying the brain scans of those who relapsed: they had more of a tendency to “shut down.”
When exposed to the emotionally charged video clips, the parts of their brain that control sensations shut down more often than those who had not relapsed. Researchers also found that those who reported higher feelings of sadness during the movie clips weren’t necessarily more likely to suffer a relapse.
“What actually determined their depression levels was how much that sadness was accompanied by a sensory shutdown,” Farb says.
He adds that when our brains shut out sensory information during a negative mood, we are left with only our thoughts to make sense of what is happening. Often, these thoughts fail to provide a wider view of what is going on—and blocking out bodily sensations locks people into an “echo chamber” of their negative views.
“Our thoughts are there to nail things down so you can hold onto them over time, and that’s fine as long as they keep getting updated—but the thing that updates it is new sensations,” Farb explains.
The researchers say their findings help explain why negative everyday life situations – such as getting criticized at a work meeting or butting heads with your spouse – could cause a relapse in somebody who has recovered from depression.
Segal says such seemingly minor events can trigger deeper feelings of inadequacy and worthlessness in those with a history of depression.
“This negative mood gets tied up with thoughts about themselves and can be easily perpetuated over time, and the person can feel worse,” Segal says, adding that such thoughts often produce bodily sensations.
“If the person suppresses these bodily sensations, their thoughts will compound into more and more depressive reactions.”
Farb adds that the study could help clinical researchers create new assessments around sensory inhibition as a risk marker for depression. It could also contribute to developing targeted therapies that help people recovering from depression become better at noticing their sensations throughout the day, which, in turn, could help them counter negative moods that can shut down sensation and “lock in” depressive thinking.
“We don’t have to wait until the person starts to really spiral, where it takes a lot of resources and time and effort to pull them out,” Farb says.
“You can start to notice if the person is starting to fit the profile of someone who’s getting really sensory-avoidant. We can address it then, before the person stops showing up to work or taking care of their kids.”
Despite the large variety of treatment options currently available for the management of MDD, many patients do not achieve a satisfactory improvement with adequate doses of ADTs given for sufficient duration, and are eventually classified as experiencing treatment resistance.
Besides the basic strategies for detecting, diagnosing, and treating TRD, the French recommendations in this guideline outline the potential for advanced strategies to be guided by the preceding lines of treatment and emphasise the significance of the systematic and rigorous evaluation of previous clinical responses prior to any treatment decision made in resistant/refractory cases.
Comparison between evidence-based and expert guidelines is complex, reflecting differences in methodology, in weight placed on the available evidence and, to some extent, in cultural traditions in treatment, attitudes towards or availability of particular pharmacological agents. The differences mainly concern the advantage given to one pharmacological option over the others and the hierarchical treatment preferences, although strategies (i.e. optimisation, switching, potentiation or combination) are similar.
Experts’ support for using optimisation as a first step following failure to respond to treatment is consistent with most EBGs and with studies on dose increase strategies documenting the efficacy of dose escalation [14,15,16,17]. So far, only the NICE guidelines have displayed some reserve in the general recommendations about dose-escalation . The dose-response relationship varies between pharmacological classes, with beneficial effects reported with TCAs [19, 20], venlafaxine  and the IMAO tranylcypromine [19,20,21]. Evidence supporting the efficacy of dose increase for SSRIs is inconclusive [22,23,24,25,26]. However, optimisation may be a reasonable step, especially due to the inter-individual variability in the plasma concentration of ADT and associated uncertainty about the identification of patients that could probably benefit from high-dose medication.
A switch of the currently administered ADT within or across ADT classes is valuable at each step of the treatment, and our expert panel prioritises a switch across classes for an ADT with evidence of superior efficacy. This strategy is often employed in EBGs in cases of non-response, even though it is not yet fully substantiated by RCTs. Moreover, there is no clear proven advantage of one switch option over the others, even though there may be slightly higher remission rates for between-class than within-class switches . The response rates after switching ADT, including to the same class, shows significant variation between studies (12–70%). A meta-analysis representing 1496 participants compared the switch from an SSRI with either a switch to another class of ADT or a second course of an SSRI, and found slight but significantly higher remission rates for the latter strategy (28% for the across-class switch versus 23.5% for the within-class switch . Similarly, the results of the STAR*D level II study, which enrolled large numbers of patients in “real-world” clinical settings, have shown that citalopram non-responders achieved remission rates between 17.6 and 24.8% after switching to bupropion, sertraline or venlafaxine without any significant differences between the different agents . However, in a large European multicentre study, Souery et al.  found no differences between across-class and within-class switches when analysing response and remission rates. At this point, switching to an ADT with some evidence of higher efficacy is recommended by the CANMAT, BAP, and WFSBP, especially in cases of non-response [14,15,16,17].
The combination of ADTs recommended by the experts is a commonly used strategy in daily clinical practice . However, it should be considered carefully that the evidence for this option in TRD is limited. The literature has focused mainly on the augmentation of SRRIs with TCAs, mirtazapine or mianserin [30, 31], leading several EBGs to recommend concurrent medication with SSRIs or SNRIs and mirtazapine or mianserin. The combination of a TCA with an α2-antagonist recommended by the experts is not documented in the literature and deserves further study. Adding lithium to the ongoing ADT is recommended by the experts as a second intention after a partial response to the first-line treatment, whether it is an SSRI, SNRI or TCA, and in the second intention after non-response to a tricyclic ADT. Its use is consistently supported by treatment guidelines in TRD, and positioned by BAP in the first intention following the failure of the first ADT and in the second intention by the CANMAT after the failure of the first ADT, especially in cases of partial response [14, 15]. These differences are probably the result of a less common use of augmentation with lithium than AAP in clinical routine care, underlined by the need for continuous plasma level determinations and the long-term risks of thyroid, cardiovascular and renal adverse effects . Overall, lithium effectively augments TCAs, although more evidence is needed before such definitive claims about its activity in combination with SSRIs or other first-line ADTs can be confirmed [32, 33].
AAPs were recognised as a second-line strategy in the second intention in partial responders, and as a fourth-line consideration in cases of non-response. The efficacy of the augmentation of ADT with AAP has been the focus of several RCTs and meta-analyses [34, 35]. However, experts’ recommendations were limited to quetiapine in the first intention and aripiprazole in the second intention, despite a high degree of perceived efficacy of other AAPs in several EBGs [14,15,16,17, 36]. Of note, quetiapine is the only AAP to have been previously studied under trial conditions in a head to head comparison with lithium, meaning at least comparable short-term effectiveness between the two treatments . A network meta-analysis of 48 RCTs examined the comparative effects of 11 augmentation agents (aripiprazole, bupropion, buspirone, lamotrigine, lithium, methylphenidate, olanzapine, pindolol, quetiapine, risperidone, and thyroid hormone with each other and with placebo. While only aripiprazole, lithium, quetiapine, and T3 were more effective than placebo, quetiapine and aripiprazole appear to be the most robust evidence-based options . Risperidone has been found to improve ADT responses in two, relatively short, RCT [39, 40] and in a meta-analysis , but has not yet received approval for that indication from the US Food and Drug Administration (FDA). It should also be noted that rather than strictly being an augmentation therapy, it is the proprietary combination of olanzapine and fluoxetine (referred to as OFC) that has been studied as a treatment for TRD and it has not been shown that olanzapine augments other ADTs.
T3 augmentation has not been extensively studied, despite no significant differences with regard to the response rates in comparison to lithium in the STAR*D study . Add-on treatment with lamotrigine proposed by the experts is support by one retrospective chart review suggesting that this strategy could be efficacious and well tolerated . Furthermore it could be for a subset of patients suffering from very severe depressive symptoms .
It is important to note that for most people with TRD, a combination of pharmacological and psychological approaches may be the most effective treatment both in terms of acute response and relapse prevention. Several guidelines propose to consider Cognitive Behavioral Therapy, Interpersonal therapy or Mindfulness-based cognitive therapy [18, 45] and Behavioral activation  in combination or as an alternative to pharmacotherapy in cases of non- or partial response. However, high-quality studies that specifically sought to examine the effectiveness of psychotherapeutic treatments for TRD are scarce. In a recent meta-analysis investigating the effectiveness of psychotherapy for TRD, van Bronswijk and colleagues  found no evidence to conclude that there is a significant benefit of psychotherapy as compared with treatment as usual (TAU) (i.e. pharmacotherapy). However, they reported a moderate general effect size of 0.42 (95% CI 0.29–0.54) in favor of psychotherapy plus TAU. Moreover, there analysis revealed no significant differences in the efficacy between the most frequently investigated psychological interventions (i.e. cognitive behavior therapy, mindfulness-based cognitive therapy, cognitive behavioral analysis system of psychotherapy, and interpersonal psychotherapy). This meta-analysis also provided evidence for a positive association between baseline severity as well as group versus individual therapy format with the treatment effect. Comparisons of different psychological treatments is complex and the choice of a specific type of psychological treatment should notably consider availability and patient preference .
Since little comparative data between these strategies exist, it is important to consider side-effect burden, partial response, and previous medication history when deciding between strategies. According to the British Association for Psychopharmacology and the CANMAT, the decision between switching and adjunctive strategies should be individualised based on clinical factors including the tolerance of the current ADT, the number of previously failed treatment, the severity of the illness, patient preferences and partial/insufficient response on the current ADT [14, 15].
The experts incorporate an additional dimension with consideration of the previous line of treatment. Although their recommendations can meet the clinical needs for most patients, they cannot replace clinical judgement, and tailored choices about care must carefully be considered; the overall characteristics of each individual patient should also be incorporated. Importantly, the availability of ADTs and other compounds investigated as potentiators of ADT varies across countries (i.e., not all agents are benefited from worldwide approval for the treatment of MDD), leading to some discrepancies in daily availability and use patterns.
reference link: https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-019-2237-x
Original Research: Open access.
“Static and treatment-responsive brain biomarkers of depression relapse vulnerability following prophylactic psychotherapy: Evidence from a randomized control trial” by Norman A.S. Farb et al. NeuroImage: Clinical