This study aimed to evaluate a novel rTMS protocol for treatment-resistant depression (TRD), using an EEG 10–20 system guided dual-target accelerated approach of right lateral orbitofrontal cortex (lOFC) inhibition followed by left dorsolateral prefrontal cortex (dlPFC) excitation, along with comparing 20 Hz dlPFC accelerated TMS v. sham.

Seventy five patients participated in this trial consisting of 20 sessions over 5 consecutive days comparing dual-site (cTBS of right lOFC followed sequentially by 20 Hz rTMS of left dlPFC), active control (sham right lOFC followed by 20 Hz rTMS of left dlPFC) and sham control (sham for both targets). Resting-state fMRI was acquired prior to and following treatment.

Hamilton Rating Scale for Depression (HRSD-24) scores were similarly significantly improved at 4 weeks in both the Dual and Single group relative to Sham. Planned comparisons immediately after treatment highlighted greater HRSD-24 clinical responders (Dual: 47.8% v. Single:18.2% v. Sham:4.3%, χ2 = 13.0, p = 0.002) and in PHQ-9 scores by day 5 in the Dual relative to Sham group. We further showed that accelerated 20 Hz stimulation targeting the left dlPFC (active control) is significantly better than sham at 4 weeks. Dual stimulation decreased lOFC-subcallosal cingulate functional connectivity. Greater baseline lOFC-thalamic connectivity predicted better therapeutic response, while decreased lOFC-thalamic connectivity correlated with better response.

Our novel accelerated dual TMS protocol shows rapid clinically relevant antidepressant efficacy which may be related to state-modulation. This study has implications for community-based accessible TMS without neuronavigation and rapid onset targeting suicidal ideation and accelerated discharge from hospital.

Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a ‘next-step’. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted.

The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored.

Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to ‘next-step’ treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI.

SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Treatment-Resistant Depression continues to represent a great challenge for clinicians.

We investigated patients with history of resistance, assessing prognostic factors, response to treatments, and remission over time.

We recruited 202 unipolar and bipolar depressed inpatients. According to anamnestic backgrounds, patients were assigned to: A) Non-resistant: responders, with no characteristics of resistance in the current episode. B) Resistant: resistant to two antidepressant trials of adequate doses and duration. C) Pseudo-resistant: non-responders, not classifiable as Resistant because of inadequate trials. During hospitalization, patients were treated by clinical judgment, following a rehabilitation program.

On the day of admission, non-responders were 44.5% of the sample, but 39.3% of them did not meet the Resistant criteria, defining the Pseudo-resistant group. Pseudo-resistant differed from others by younger age, fewer illness episodes, higher rate of personality disorders, and different therapies during hospitalization [Fig.1,2,3]. Pseudo-resistant remission rate, significantly greater than Resistant one, was comparable to Non-resistant [Tab.1]. *Kruskal-Wallis Test **Chi-Squared Test

This study outlines a new group of depressed patients that, apparently drug-resistant, displays the same outcome as responders when treated with first-line drugs during hospitalization, certainly taking benefit from the psychoeducational program. Quick recognition of these patients could be crucial to giving optimal care.

No significant relationships.

Treatment-resistant depression (TRD) presents a significant challenge in clinical practice. Besides antidepressant medications, neurostimulation methods (ECT, rTMS) and ketamine are viable treatment options.

To objectively evaluate the real effectiveness of treatments within interventional psychiatry in the maintenance treatment.

The extensive literature review of the efficacy of ECT, rTMS, and ketamine treatment in the maintenance treatment of TRD and the author’s clinical and research experience will be included in this presentation.

Neurostimulation, particularly ECT and ketamine treatment are usually effective treatments for patients with TRD. However, both of these treatment modalities do not have sustained benefits and after discontinuing treatment the majority of patients relapse. Ketamine has rapid therapeutic effects in depression, but these effects are short-lived. Continuation treatment with ketamine in the form of intranasal ketamine is an option, but concerns over cognitive impairment, interstitial cystitis and significant addictive potential related to longer use of ketamine are significant limiting factors. rTMS is a first-line treatment option for patients with TRD according to the Canadian CANMAT guidelines. However, the majority of patients may relapse following the course of rTMS. The maintenance rTMS over an extended period of time is usually not feasible as it may significantly affect the waiting time for newly referred patients. Portable TMS machine for home use would be an alternative option for a limited number of patients.

Maintenance treatment has been always a big clinical challenge in mood disorder psychiatry. Only well-established multimodal treatment is a realistic option for getting long-term benefits in treating patients with TRD.

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.

Due to its relatively high prevalence and recurrent nature, depression causes a major burden on healthcare systems and societies.

To investigate healthcare resource utilization and costs associated with treatment-resistant depression (TRD) compared with non-TRD depression in Finland.

Of all patients aged 16-65 years and diagnosed with depression in Finland during 2004-2016, persons with TRD (N=15 405) were identified from nationwide registers and matched 1:1 with comparison persons with depression but no TRD. TRD was defined as initiation of a third treatment trial after having failed two pharmacological treatment trials. Follow-up period covered five years after TRD or corresponding matching data (until end of 2018). Healthcare resource utilization was studied with negative binomial regression and average excess costs of TRD with generalized estimating equations, by adjusting for baseline costs, comorbidity and baseline severity of depression.

Persons with TRD (mean age 38.7, SD 13.1, 60.0% women) had more healthcare utilization and work disability (sick leaves and disability pensions), adjusted incidence rate ratio for work disability days was 1.72 (95% CI 1.64-1.80). This resulted in higher total costs for persons with TRD, adjusted mean difference 7572 (95% CI 7215-7929) EUR per patient per year, higher productivity losses (due to sick leaves and disability pensions, mean difference 5296, 95% CI 5042-5550) and direct healthcare costs (2002, 95% CI 1853-2151) compared with non-TRD patients. Mean difference was highest during the first year after TRD (total costs difference 11760, 95% CI 11314-12206).

Treatment-resistant depression is associated with a significant cost burden.

This study was funded by Janssen-Cilag Finland and the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. ML was partly funded by personal grants from the Finnish Medical Foundation and Emil Aaltonen fou

Esketamine is a novel antidepressant approved by the FDA in 2019 in the form of an intranasal spray, recommended for Treatment-Resistant Depression (TRD). The intranasal spray system appears to be more manageable than intravenous ketamine infusion. It contains ketamine’s S- isomer which is four-fold more potent for the NMDA receptor.

The aim of this case series is to describe our clinical experience in the use of Esketamine.

6 TRD patients (3 men; 3 women) were recruited in San Raffaele Turro Hospital from March 2021. All patients (2 bipolar and 4 unipolar) were diagnosed with a Major Depressive Episode according to DSM-5 criteria, resistant to at least two antidepressants. Initially, Esketamine was administrated twice weekly for one month; afterward, it was administrated once weekly for a month; finally, it was administrated once weekly or every two weeks for a month. Clinical scales (HAM-D, YMRS, SSI, HAM-A, MADRS, CADSS) were administrated to assess symptoms and sides effects before and after each administration on a weekly basis.

Three patients out of six showed an improvement in depressive symptoms: two patients had remission (final HAM-D score < 8); one patient had a clinical response (final HAM-D score < 50 % respect baseline value). Three patients withdrew the treatment: two for perceived inefficacy, after 16 and 19 administrations, one for personal reasons.

The use of Esketamine in our TRD patients showed good effectiveness and tolerability but randomized controlled clinical trials are needed to confirm our findings.

No significant relationships.

Vascular endothelial growth factor (VEGF) has been implicated in mediating the effect of antidepressants (AD) and electroconvulsive therapy on depression since it plays a significant role in the neurogenesis. However, the serum VEGF level has not been investigated so far in association with rTMS treatment in patients with major depressive disorder (MDD).

The aim of our study was to compare the effect of the antidepressants and of the repetitive transcranial magnetic stimulation on the serum vascular endothelial growth factor and its association with the responsiveness to the treatments.

A dataset of 50 patients with TRD who were treated with AD (n=33) and bilateral rTMS for 2x5 days (n=17) was analysed (sample ’rTMS&AD’). Montgomery-Asberg Depression Scale (MADRS) was used for monitoring the symptom changes. The serum VEGF levels and symptoms were assessed on the first (V1), on the 14th (V2) and on the 28th day (V3). The VEGF levels were measured by ELISA assay.

The baseline VEGF levels were significantly higher in non-responders both in the rTMS&AD (p=0.04) and AD samples (p=0.02) compared to responders. The MADRS reduction and the changes in VEGF levels between V1 and V3 were significantly associated in responders only in the AD&rTMS sample (p=0.03). The baseline VEGF level has been proven as a significant predictive factor of treatment response in the total sample (p=0.018).

The baseline VEGF level can be a predictive factor to be a non-responder to different treatments. Change of the VEGF level is associated with the improvement of depressive symptoms only due to rTMS.

This study was supported by the FK 131315 grant of the National Research, Development and Innovation Office, Hungary. Authors declare no conflict of interest.

TRD is a highly disabling condition, often responsible for chronic clinical course, high number of relapses and elevated suicide risk. Intranasal esketamine is currently the only available pharmacological therapy specifically indicated for TRD, as add-on therapy to antidepressant treatment with SSRI or SNRI.

The purpose of the study was to evaluate the safety and efficacy of intranasal esketamine associated with CBT in a complex clinical case of TRD, over a six-month follow-up.

A 67-year-old patient with TRD was selected for treatment with intranasal esketamine+CBT as add-on to antidepressant therapy. Before each treatment session the HAM-D rating scale was administered. The patient underwent weekly CBT sessions throughout the 6 months follow-up. The effect on physical well-being and social functioning was evaluated by means of Short-Form-Health-Survey-36.

After the first two administrations of intranasal esketamine the total score on HAM-D decreased by 10 units (from 26 to 16). After 6 weeks of treatment decreased from 26 to 12 with the disappearance of suicidal ideation present at T0. After 6 months the total HAM-D score decreased from 26 to 8. Treatment was well tolerated, with mild adverse effects, confined to the first two hours post-administration. In particular, mild sedation, dizziness, slight transient blood pressure rise were reported, never required medical intervention and resolved spontaneously during the observation period.

Intranasal esketamine add-on therapy + CBT was an effective and safe treatment allowing to achieve and maintain symptomatic remission in a complex case of TRD, improving quality of life, social functioning, and reducing suicidal ideation over a six-month follow-up.

No significant relationships.

Esketamine nasal spray has been developed to treat adults with treatment resistant depression. On Dec.2019, EMA granted a market access approval in this indication.

ESKALE is a descriptive study of treatment resistant depression patients treated with esketamine in France.

Observational retrospective study. 157 patients are included in 3 cohorts depending on their treatment initiation date. This abstract presents the second interim results of patients treated with esketamine and whom data collection ranges from Oct.2019 and Sept.2021.

66.7% of patients were females. Average age was 49 years old with 26 patients > 65 years old. Duration of the current depressive episode was 26.0 months (mean). 48.8% of patient have > 1 suicide attempt during whole life. At esketamine initiation, 78.2% patients were clinically perceived to have severe depression with a MADRS score of 32.4 (median) and a PHQ9 score of 19.5 (median). For the overall sample, esketamine was prescribed in median as a 3rd line and for 40.5% of patients after neurostimulation. The majority of the patient started esketamine at 28 mg or 56 mg and increased the dose to 84 mg. After 4 months of treatment, clinical benefits are the following: decrease of MADRS total score -16.5 points (median) corresponding to 58% of responders and a PHQ9 total score decrease of -8.6 points (median). No new safety signal detected.

This second interim analysis describes patients’ profiles and clinical evolution over a longer period and a broader population than the first interim analysis. The conditions of use are consistent with the ones approved by health authorities.

I (Marie-Alix Codet) works as a full employee at Janssen Cilag

Vagus Nerve Stimulation (VNS) is a neuromodulatory intervention which involves attaching an electrode to the vagus nerve. Studies investigating VNS as an acute treatment method for treatment resistent depression have shown very limited results, however there are data suggesting that VNS might have a beneficial effect on a longer term. There are also studies that suggest that a history of response to ECT might indicate a higher response rate to VNS. VNS was suggested as treatment for a patient who received maintenance ECT for treatment resistant unipolar depression during 9 years. 3 months after VNS was implanted, ECT was stopped due to the Covid-19 pandemic. In this case study we will review the patient’s response to treatment with VNS and the sudden stop of long-term ECT treatment.

To review the response to acute and maintenance ECT and VNS in this patient diagnosed with treatment resistant unipolar depression, and to compare this to the data suggesting VNS as an alternative treatment method for maintenance ECT in patients with treatment resistant depression.

Using the extensive data collected during the patient’s treatment, we will review the clinical response and side-effect burden of this patient to acute and maintenance ECT and to VNS.

The patient showed a vast improvement in depressive symptoms a few months after start of VNS treatment, while long-term maintenance ECT was stopped.

This patient’s response to VNS supports the data suggesting VNS as an alternative treatment method for maintenance ECT in patients with treatment resistant depression.

This patient received VNS treatment as part of a study conducted in our centre (UPC KULeuven) with support of Livanova. Me nor my supervisor (prof. Sienaert Pascal) are directly involved in this study. I have received no financial or other compensation fr

In the last 5 years, R. Hamish McAllister-Williams has received fees from American Center for Psychiatry & Neurology United Arab Emirates, British Association for Psychopharmacology, European College of Neuropsychophamracology, International Society for A

Esketamine nasal spray has been developed for patients with treatment resistant depression.

A cohort Temporary Authorization for Use (ATUc) allowed to collect for a 6-month period the first data in real life

On 02/08/2019 the French National Agency for Medicines and Health Product Safety granted an early access program for Esketamine nasal spray framed by a specific protocol for patients without therapeutic alternatives. Each treatment request was approved based on inclusion and exclusion criteria. Clinical evolution, treatment management and safety were then spontaneously reported by psychiatrists.

From 09/23/2019 to 03/25/2020, 66 patients were treated. The median age was 53 years and 41 (62.1%) were females. At treatment request, 52 patients (79%), presented a severe current depressive episode based on clinical judgment. The median duration of the disease was 12.2 years and the current episode was 2.6 years. Since the beginning of the current depressive episode, all patients (66) were prescribed ≥2 antidepressants (mean 4.2). Esketamine was initiated in a complete hospitalization setting in 27 patients (55.1%) and in day hospitalization in 22 patients (44.9%).Safety profile was consistent with the one described during clinical study. The most frequently adverse events reported (>10%) were dizziness, sedation, sleepiness, anxiety and dissociation. Most of them appeared after treatment administration and were transient.

ATUc ended on 12/18/2019 after Marketing Authorization granted by European Medicines Agency. Data reported by French psychiatrists are the first collected in this specific population and provide descriptive information on patient characteristics, burden of disease; Esketamine management and practical use at hospital level

Data analysis performed by RCTs and poster conception coordinated by Medergy and funded by Janssen

There is a lack of knowledge on utilized pharmacotherapies for treatment resistant depression (TRD).

To investigate the courses of treatment of TRD.

All patients aged 16-65 years and diagnosed with depression in Finland during 2004-2016 were included (identified from nationwide registers for inpatient and specialized outpatient care, sick leaves and disability pensions). New antidepressant users were identified with six-month washout period and followed up for two years to observe the possible emergence of TRD, which was defined as initiation of a third treatment after having two failed pharmacological treatments with adequate duration. Pharmacological treatments were analyzed using PRE2DUP-method.

During follow-up, 177,144 persons had their first registered depression (mean age:39.5, 62.5% women). Of them, 10.9% (N=19,322) met TRD criteria. Among the TRD patients, most common first and second lines antidepressants were as follows: SSRIs (44.6%), mirtazapine (19.0%) and SNRIs (16.5%). As the third line of treatment, 44.2% of TRD patients had antidepressant monotherapy, 32.1% a combination of ≥2 antidepressants, 15.8% antipsychotic or mood stabilizer augmentation and an antidepressant, 4.9% both combination of antidepressants and an augmentation with a mood stabilizer or antipsychotic, 2.7% antipsychotic or mood stabilizer monotherapy and 0.3% ECT monotherapy. Of TRD patients, 36.2% (N=6985) progressed to the fourth line of treatment and most common treatments were antidepressant monotherapy (37.5%), antidepressant combinations (30.8%) and augmentation (20.3%).

Although antidepressant combination and augmentation strategies became more frequent, antidepressant monotherapies were still the most common third and fourth lines of depression treatment.

The study was funded by Janssen and SR is an employee of Janssen.

The deficiency of polyunsaturated fatty acids (PUFAs) and an alteration between the ratio of omega-6 and omega-3 PUFAs may contribute to the pathogenesis of depressive disorders.

To investigate the levels of omega-3 and omega-6 in red cell membranes (mPUFAs) and plasma (pPUFAs) of patients with treatment-resistant (TRD) and non-treatment resistant depression (non-TRD).

TRD and non-TRD consisted of 75 patients enrolled at the Psychiatric and Clinic Psychology Unit of the University of Rome Tor Vergata, Rome, Italy, and met the DSM-IV criteria for major depressive disorder (MDD). A group of healthy controls (HC) matched for agender and age was enrolled. All blood samples were performed in conditions of an empty stomach between 07:00 am and 09:00 am. For each subject were obtained 5 ml of whole blood with the use of tubes for plasma with EDTA as an anticoagulant. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for omega-3 and arachidonic acid (AA) for omega-6 were measured.

Levels of pPUFAs did not differ between the three groups. The mPUFAs were altered in the MDD. TRD and non-TRD had lower EPA and AA values respect to the HC. DHA in red cell membranes was lower in TRD than non-TRD and HC.

Changes in levels of PUFAs in red cell membranes, but not in plasma, may be an important factor to evaluate the resistance to the pharmacological treatment.

Patients unsuccessfully treated by neurostimulation may represent a highly intractable subgroup of depression. While the efficacy of intravenous (IV) ketamine has been established in patients with treatment-resistant depression (TRD), there is an interest to evaluate its effectiveness in a subpopulation with a history of neurostimulation.

This retrospective, posthoc analysis compared the effects of four infusions of IV ketamine in 135 (x̄ = 44 ± 15.4 years of age) neurostimulation-naïve patients to 103 (x̄ = 47 ± 13.9 years of age) patients with a history of neurostimulation. The primary outcome evaluated changes in depression severity, measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). Secondary outcomes evaluated suicidal ideation (SI), anxiety severity, measured by the Generalized Anxiety Disorder 7-Item (GAD-7), and consummatory anhedonia, measured by the Snaith–Hamilton Pleasure Scale (SHAPS).

Following four infusions, both cohorts reported a significant reduction in QIDS-SR16 Total Score (F (4, 648) = 73.4, P < .001), SI (F (4, 642) = 28.6, P < .001), GAD-7 (F (2, 265) = 53.8, P < .001), and SHAPS (F (2, 302) = 45.9, P < .001). No between-group differences emerged. Overall, the neurostimulation-naïve group had a mean reduction in QIDS-SR16 Total Score of 6.4 (standard deviation [SD] = 5.3), whereas the history of neurostimulation patients reported a 4.3 (SD = 5.3) point reduction.

IV ketamine was effective in reducing symptoms of depression, SI, anxiety, and anhedonia in both cohorts in this large, well-characterized community-based sample of adults with TRD.

We evaluated processing-speed and shift-cost measures in adults with depression or attention-deficit hyperactivity disorder (ADHD) and monitored the effects of treatment. We hypothesised that cognitive-speed and shift-cost measures might differentiate diagnostic groups.

Colour, form, and colour–form stimuli were used to measure naming times. The shift costs were calculated as colour–form-naming time minus the sum of colour- and form-naming times. Measurements were done at baseline and end point for 42 adults with depression and 42 with ADHD without depression. Patients with depression were treated with transcranial pulsed electromagnetic fields and patients with ADHD with methylphenidate immediate release.

During depression treatment, reductions in naming times were recorded weekly. One-way analysis of variance indicated statistical between-group differences, with effect sizes in the medium range for form and colour–form. In both groups, naming times were longer before than after treatment. For the ADHD group, shift costs exceeded the average–normal range at baseline but were in the average–normal range after stabilisation with stimulant medication. For the depression group, shift costs were in the average–normal range at baseline and after treatment. Baseline colour–form-naming times predicted reductions in naming times for both groups, with the largest effect size and index of forecasting efficiency for the ADHD group.

The cognitive-processing-speed (colour–form) and shift-cost measures before treatment proved most sensitive in differentiating patients with depression and ADHD. Reductions in naming times for the depression group were suggested to reflect improved psychomotor skills rather than improved cognitive control.

Depression is a disorder that causes disability, with a profound adverse impact on all areas of psychosocial functioning. This is particularly true for those with treatment resistant depression (TRD). However, to date, no systematic assessments of psychosocial functioning for patients with TRD have been conducted.

In the present study, we used the Longitudinal Interval Follow-up Evaluation (LIFE) scale to measure psychosocial functioning in 92 patients with TRD. These patients met formal criteria for TRD and were part of a clinical trial examining the efficacy of lithium augmentation of nortriptyline.

Clinicians rated this sample of patients as experiencing mild to moderate impairment in work-related activities, good to fair interpersonal relations, poor level of involvement in recreational activities, and mild impairment of ability to enjoy sexual activity. Patients and clinicians rated global social adjustment as poor.

Patients with formally defined TRD experience significant impairment in psychosocial functioning. In this sample a tendency existed for both clinicians and patients to assign more severely impaired global ratings when compared with ratings for specific functional areas.