The lack of a standardised definition for the concept of TRD and an adequate criteria for therapeutic response make difficult the management of patients with MDD who do not achieve remission with one or more courses of treatment. All classifications suggested to define TRD are arbitrary, partially evidence-based, subordinated to the pharmacological findings of the time in which they are written and with serious inconsistencies, making it difficult to construct a universal and enduring diagnostic system.

Considering that the most important goal in treating a patient with Major Depressive Disorder (MDD) should be remission and return to previous functionality, the search for a standardised, evidence-based classification system will allow timely and effective interventions leading to the reduction of this devastating condition.

Bibliographic review

The proposed therapeutic algorithm arises from the combination of several fundamental principles for the management of treatment-resistant depression: the different classification systems of the concept, as well as the concepts of response, relapse, recurrence and remission; the scientific evidence found in the current literature, routine clinical practice, knowledge of switching and augmentation strategies, the new pharmacological targets and neurobiological hypothesis discovered, without forgetting finally the different clinical profiles of depressive symptomatology and the specific indications of each antidepressant.

Resistant depression is difficult to treat successfully and is not a uniform entity. Recently there has been a move to characterise treatment-resistant depression as ‘difficult-to-treat’ depression on the basis that the former description implies that depression treatments are normally effective and that non-response is therefore somehow abnormal.

No significant relationships.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory treatment option, which is used in a variety of neurological and psychiatric diseases. It is approved for depression treatment and recommended in international guidelines. A significant reduction in treatment duration was achieved by using theta burst stimulation (TBS) protocols, which are practicable and non-inferior to conventional TMS.

To analyse the efficacy and safety of intermittent theta burst stimulation (iTBS) of left DLPFC in inpatients with treatment-resistant depression.

We evaluated n=44 inpatients with treatment resistant major depressive disorder (n=37) and bipolar depression (n=7), who were treated with the 5 Hz intermittent TBS once daily for 3-6 weeks according to clinical decision. A total of 600 pulses and 200 bursts were applied in each treatment session. Clinical and response data were obtained by chart review.

Mean age at time of first stimulation was 54 years. 61,3 % of patients were female. On average, the current episode started 21 months before the first stimulation. In total, 924 treatment sessions were performed. On average, patients received 21 sessions. The mean MADRS Score pre-treatment was 27.2. Post-treatment, there was a clear reduction in depression severity (MADRS 18.3). No severe adverse events and no seizures occurred in this clinical observational analysis.

Intermittent TBS is efficacious and safe in patients with chronic and refractory depression.

No significant relationships.

Introduciton: Repetetive transcranial magnetic stimulation (rTMS) is an effective and safety noninvasive technique for treatment of major depression disorder (MDD). There is a body of increasing evidences on the potential molecular mechanisms underlying its effectivity even in case of treatment resistant depression (TRD), however, the exact mechanism is still not clarified. Among multiple biological systems, inflammation can be a target of rTMS in MDD (Tian et al. 2020; Tateishi et al. 2020).

Here we analysed serum cytokine levels in TRD before and after rTMS interventions.

We used bilateral stimulation (15Hz for left DLPC and 1Hz on the right side) in 18 patients with TRD (5 men and 13 women; mean age=47.7±12.1 year) for 2x5 days. Blood samples were collected before the first (V1) and after the last inetrevntion (V2). Phenotypic changes were measured by Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Snaith–Hamilton Pleasure Scale (SHAPS), Insomnia Severity Index (ISI) and Stroop Color-Word Test (SCWT) modified by Golden. Inflammatory cytokines were assessed by ELISA assays.

Change of BDI and BAI scores between V1 and V2 is associated with difference of TNFalpha levels (p=0.043; adj.R2=0.42 p=0.011; adj R2=0.43). Decrease on SHAPS score has been depended on IL-6 level (p=0.027) and the interaction of TNFalpha and IL-10 (p=0.005; adj R2=0.63). Sleep disturbance and neurocognitive function was not associated with cytokine levels.

Our results confirmed the association between depressive, anxious and anhedonia symptom improvement and inflammatory mechansims during rTMS treatment. The study was supported by the OTKA 151513 grant.

Globally, depression affects millions of individuals. A third of depression patients meet the criteria for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor antagonist, ketamine, improved depressive symptoms in a span of 24-hours. Recently, the FDA approved esketamine, an enantiomer of ketamine for TRD.

To determine the effectiveness of ketamine and esketamine in TRD, and observe their role in suicidality.

Individual systematic searches were conducted on the PubMed database following the PRISMA protocol (Figure 1). Inclusion criteria included randomized clinical trials (RCT). Search strings were (i) “ketamine” OR “esketamine” AND “treatment-resistant depression” (ii) “ketamine” OR “esketamine” AND “suicide.” Eleven studies were included for depression and five studies for suicidality (Table 1). Comparison analysis for suicide appeared trivial because of only one inclusion eligible esketamine RCT. This review was submitted for registration at PROSPERO. Randomized odds ratios, 95% confidence interval (CI), and heterogeneity were obtained.

The comprehensive meta-analysis, version 3.0, was used for analysis. Ketamine improved TRD symptoms and reduced suicidality by a nine-fold and three-fold odds, respectively (OR 9.01, CI 4.89–16.6, p<0.001 and OR 2.9, CI 1.67–5.06, p<0.001). Esketamine also improved TRS symptoms (OR= 2.61, 95% CI= 1.56–4.37, p<0.001). The heterogeneity ranged from 11% to 60% between the three groups. Sensitivity analysis did not alter the results.

Findings must be cautiously interpreted as the primary endpoint differed. The primary endpoint was set at 24-hours and 28-days for ketamine and esketamine, respectively. Esketamine’s effectiveness over 28 days appears promising for TRD. Current aim should consist of structured guidance for clinicians in esketamine administration.