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Take a look at a selection of our recent media coverage:

Flexible-dose subcutaneous ketamine safe and effective in treatment-resistant depression

20th July 2023

A flexibly dosed, twice-weekly subcutaneous injection of ketamine over four weeks led to higher levels of clinical remission compared to midazolam in patients with treatment-resistant depression, according to a new phase III trial.

The trial by Australian researchers, which was published in the British Journal of Psychiatry, compared racemic ketamine with midazolam in two patient cohorts: one with fixed dosing and a second with a more flexible regimen.

The trial was initially designed to compare twice-weekly subcutaneous racemic ketamine (0.5 mg/kg) or midazolam (0.025 mg/kg) for four weeks, with at least three days between treatments. Data for these findings were referred to in the study as cohort one.

The dosing schedule was revised after a Data Safety Monitoring Board recommendation to flexible-dose ketamine 0.5–0.9 mg/kg or midazolam 0.025–0.045 mg/kg, with response-guided dosing increments. Data for these findings were referred to in the study as cohort two.

The primary outcome was remission, characterised by a Montgomery-Åsberg Rating Scale for Depression score of less than 10, after four weeks of treatment.

Subcutaneous ketamine and treatment outcomes

The final analysis comprised 68 patients in the fixed-dose cohort one and 106 in the flexible-dose cohort two.

Ketamine was found to be significantly more efficacious than midazolam in cohort two at achieving remission (odds ratio, OR = 12.1, 95% CI 2.1 – 69.2, p = 0.005). However, there was no significant different between the two treatments when given as a fixed dose in cohort one (OR = 1.3, 95% CI 0.2 – 8.2, p = 0.76).

In terms of safety, serious adverse events were rare and most were unrelated to the study drug. For instance, in cohort one, there were two serious adverse events in the midazolam group – a suicide attempt and mood deterioration – but both unrelated to the study medications. There were no serious adverse events in the ketamine group.

Among those in cohort two, there were three serious adverse events in the midazolam group: a suicide attempt, increased suicidal ideation and a wrist injury, which, again, were unrelated to the study treatments. In contrast, there were two serious adverse events in the ketamine group: one major dissociative episode and auditory hallucination, both of which were deemed to be related to treatment. No deaths were reported throughout the study. 

Failing to respond to an adequate course of two or more treatments is referred to as treatment-resistant depression, and ketamine is a novel highly effective and rapidly acting treatment. It is available as an intravenous infusion of a racemic mixture and as a commercially developed single enantiomeric intranasal spray containing S-ketamine.

Esketamine nasal spray superior to quetiapine XR for treatment-resistant major depressive disorder

3rd April 2023

An Esketamine nasal spray achieved remission from week 6 onwards compared to extended-release quetiapine in treatment-resistant depression

Data presented at the 31st European Congress of Psychiatry (EPA 2023) showed that in patients with treatment-resistant major depressive disorder, esketamine nasal spray achieved significantly higher rates of remission as early as 6 weeks after starting therapy compared to the use of extended-release (XR) quetiapine.

In the World Health Organisation European Region, depression is estimated to affect roughly 4.3% (or 40 million people) of the population. In addition, a US study of 36,309 adults reported that the 12-month and lifetime prevalence’s of major depressive disorder were 10.4% and 20.6%, respectively

Treatment-resistant depression (i.e., failure to respond to ≥2 treatments) affects 10-30% of those with major depressive disorder, and is associated with considerable morbidity and mortality. Esketamine nasal spray has been found when used in conjunction with an antidepressant to induce a significantly higher reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) score compared to placebo and an antidepressant.

Furthermore, antipsychotics are a potentially useful adjunct in treatment-resistant depression with a 2019 Cochrane review concluding that addition of an antipsychotic such as quetiapine to current antidepressant therapy, improved depressive symptoms over the short-term. But how esketamine compares to agents such as quetiapine is unclear and the subject of the study presented at EPS 2023.

The findings presented at EPA 2023 are from the ESCAPE-TRD trial which directly compared esketamine with quetiapine XR in addition to a selective serotonin re-uptake inhibitor/serotonin-norepinephrine re-uptake inhibitor (SSRI/SNRI), in patients with treatment-resistant major depressive disorder, over 32 weeks.

In the trial patients were randomised 1:1 to either esketamine or quetiapine plus an antidepressant and examined the effect of both on remission (defined as a MADRAS score < 10) and response (defined as a > 50% improvement in MADRAS score from baseline).

Esketamine nasal spray and treatment outcomes

A total of 676 patients were randomised to either quetiapine (340) or esketamine.

At Week 32, 55% of esketamine and 37% of quetiapine patients achieved remission. However, a significantly higher proportion of patients given esketamine achieved remission from week 6 (p = 0.008) onwards and a response from day 15 (p < 0.001).

The most common adverse effects from esketamine leading to treatment discontinuation were dizziness, dissociation and vomiting.

The authors concluded that an esketamine nasal spray use in patients with treatment-resistant depression led to a higher response and rate of remission over time compared to quetiapine XR.

Citation
Reif A. et al., Esketamine nasal spray shows higher remission and response rates over 32 weeks of treatment compared with quetiapine extended-release in patients with treatment resistant depression: Results from ESCAPE-TRD, a randomised, phase IIIb clinical trial. Presented at EPA 2023, March 25-28. Poster PO0067 (under oral communication 8).

Meet the Expert: Andreas Reif on treatment-resistant depression

3rd February 2023

Andreas Reif is Head of the Department of Psychiatry, Psychosomatic Medicine and Psychotherapy at the University Hospital, Frankfurt. He spoke to Hospital Healthcare Europe about treatment-resistant depression and innovations in the management of the condition.

Andreas Reif’s main clinical areas of interest are mood disorders with a focus on bipolar disorders, suicidality, therapy-resistant depression and adult ADHD. From a research perspective, he is interested in personalised medicine in psychiatry as well as the neurobiology of mental disorders, with a focus on improving diagnosis and treatment. He was involved in establishing the German National Centre for Affective Disorders and sits on its board of directors.

Establishing the National Centre for Affective Disorders

Professor Reif described how the main reason for establishing the national centre (along with seven other institutions in Germany) was to ‘create a research and clinical studies network of centres of excellence for mood disorders.’ He believed that such a network was lacking in Germany, especially considering how ‘depression is the most prevalent disorder in the field of psychiatry and there are only a few hospitals that really specialise in mood disorders.’

The overarching aim he felt, was really to bring together existing expertise in the fields of neurostimulation, neuroimaging, genetics and psychopharmacology and therefore ‘create a network that leverages existing studies that are able to build up cohorts for research purposes as well as providing an existing network for both academic and industry sponsored studies on mood disorders in a larger network.’

Defining treatment-resistant’ depression

Professor Reif described how unfortunately there is no single universally accepted definition, though existing ones are similar and vary slightly. He mentioned that the current definition used for regulatory purposes is ‘the failure of two antidepressant treatments that have been provided with an adequate dose and duration.’ This he explained was a rephrasing of the criteria for treatment-resistant schizophrenia which was used after the introduction of clozapine.

Despite this somewhat straight forward definition, Professor Reif noted that in practice, it was more difficult to interpret. For instance, non-medical treatments such as psychotherapy, and CBT are not included and there was some uncertainty over what constituted an adequate dose and duration of treatment. As he said, the current definition ‘gets messier and messier the longer you think about it.’ Nevertheless, he feels that at least two-thirds of the patients he sees in outpatient clinics have treatment-resistant depression.

In contrast, there are others who have been suboptimally managed with either an inadequate dose of treatment or the way in which the drug had been used was not guideline compliant. Fortunately, in such cases, treatment could be easily modified and patients discharged back into primary care.

Underlying mechanisms and patient impact

Professor Reif thinks that there is still much to be learnt about the underlying causes of treatment-resistant depression. He mentioned how there was a known relationship with certain factors such as ‘co-morbidity with anxiety disorder, ADHD, early onset depression, melancholic features such as early suicide attempts,’ however, but these were merely associated risk factors and not causative.

Delving into the neurobiology has also failed to provide satisfactory explanations, particularly in relation to genetics, with no obvious differences between those who have can be considered to have regular depression and those who eventually display treatment-resistant depression. It has been postulated that there is some degree of neurological imbalance between pro-inflammatory and anti-inflammatory markers or a disturbance in the connections between the limbic system and the prefrontal cortex.

Nevertheless, he thinks that a better understanding of possible mechanisms would arise from prospective studies that followed up on depressed patients and to identify those who enter remission and those who go on to become treatment-resistant, though sadly, there is an absence of such studies. Although inadequate adherence may be a factor in treatment-resistant depression, this could easily be identified with therapeutic drug monitoring.

Professor Reif feels that the burden upon both the individual and healthcare systems is enormous. Treatment-resistant patients have a higher level of hospitalisations and suicide attempts but there is also an economic impact. As he said, ‘individually, often these patients are unable to work or work with reduced ability’ and there is a high level of unemployment combined with a huge negative impact on their quality of life.

Management of treatment-resistant depression

Currently, there are several recommended approaches. First, the patient’s existing therapy can be augmented with an atypical antipsychotic such as quetiapine or lithium. Another approach is to combine an SSRI or SNRI or a tricyclic with mirtazapine or trazadone. Treatment switches can also be effective but this is only recommended once. For instance, if patients have already been changed from an SSRI to a SNRI, there is no benefit from any further switches. Both transcranial magnetic stimulation or ECT have also been used and in some cases prove to be very effective. Finally, the addition of psychotherapy to the current medical treatment can also be tried.

Professor Reif said that the efficacy of these approaches, at least from an examination of the current evidence, is that between 20% to a third of patients should be helped. He is not overly convinced by these figures but this probably reflects how in practice he deals with more severely ill patients. Despite this, he does believe that with the combination of high-density psychotherapy, optimised medical treatment and neuro-stimulatory techniques, ‘over 90% of patients will ultimately remit.’ For those patients who fail to remit with such combination therapy, he thinks that experimental approaches such as deep brain stimulation or invasive vagus nerve stimulation are likely to be more successful.

Innovations in management

Professor Reif mentioned the ESCAPE-TRD study in which nasal esketamine was compared to augmentation therapy with extended-release quetiapine in patients with treatment-resistant depression. Esketamine represents a first-in-class treatment targeting the glutamate system although Professor Reif had already been using the drug experimentally at his centre for severely ill patients and found it to be very effective.

While there were studies demonstrating that esketamine was effective, esketamine had only been compared to placebo plus newly initiated oral antidepressants, hence it has not been possible to determine whether it is more effective than any of the existing therapies. As he said, ESCAPE-TRD was really the first head-to-head study comparing esketamine with an active treatment, a move he thinks was ‘quite brave for Janssen because they could have failed.’ ESCAPE-TRD was conducted over 32 weeks and which he says, was a sufficiently long time to determine its effectiveness.

He described how the study found that ‘esketamine was significantly better in all outcomes but most importantly, met its primary outcome of remission at week eight in an acute setting.’ In fact, there was an almost 10% difference in the remission rate compared to quetiapine.

A further and relevant finding was in relation to the main secondary outcome, which found that a significantly higher proportion of patients given esketamine, who achieved remission achieved at week eight, maintained relapse free through to week 32. When asked to summarise the findings, he said that the overall conclusion was that ‘esketamine was superior to quetiapine in achieving remission in treatment-resistant depression.’

Next steps for treatment-resistant depression

Professor Reif thinks that much more needs to be achieved in the management of treatment-resistant depression and believes that there are at least three initial steps required. Perhaps the immediate priority, he feels, is to ensure access to esketamine given how currently, few centres provide the drug.

Secondly, with only around a quarter of patients achieving remission after eight weeks, it was necessary to explore the development of relevant biomarkers, to identify those patients likely to respond, since this was impossible from a clinical perspective.

Thirdly, is the acknowledgement that depression is actually a heterogenous disorder with many underlying pathologies and the introduction of a wide range of therapies, affecting different biochemical pathways, would enable the treatment of a higher number of patients.

Finally, Professor Reif believes that a wider adoption of esketamine is needed, together with its incorporation into management algorithms. While accepting that the drug is not a panacea, he says that it represents a valuable addition to psychiatry’s therapeutic armamentarium and is hopeful that because of this innovation, the pharmaceutical industry will be spurred on to develop more effective treatments in psychiatry.

Psilocybin effective for treatment-resistant major depression

21st November 2022

Psilocybin given as a single dose is effective in patients with treatment-resistant major depression in as little as three weeks

The use of a single dose of psilocybin leads to a significant improvement in symptoms among patients with treatment-resistant major depression according to the findings of a study by an international team of researchers.

Treatment-resistant depression (TRD) is a subset of major depressive disorder which does not respond to traditional and first-line therapeutic options. The estimate of TRD varies although according to a 2021 US study, among 8.9 million adults treated for major depression, 2.8 million (30.9%) had TRD. Psilocybin is the major psychoactive alkaloid of some species of mushrooms distributed worldwide and a known hallucinogen.

Interest in the use of psilocybin to help with the depression and anxiety associated with advanced stage cancer, revealed a positive trend toward improved mood and anxiety. More recently, two doses of the hallucinogen given to patients with major depression in the context of supportive psychotherapy, suggested that psilocybin combined with therapy is efficacious in the treatment of major depressive disorder.

To date, only a single, open-label feasibility trial has examined the value of psilocybin for the treatment of patients with treatment-resistant depression, offering support for its safety and efficacy and serving as the basis for further trials.

Consequently, in the present study, researchers recruited adults with TRD across 22 sites in 10 countries randomised them 1:1:1 to a single dose of psilocybin (10 mg, 25 mg) or 1 mg which served as a control. The treatment was given with a support session lasting6 to 8 hours and participants followed up for 12 weeks.

The primary endpoint was the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score which ranges from 0 to 60 with higher scores reflecting more severe depression. The researchers examined the change in scores for the 10 and 25 mg doses compared to the 1 mg dose. Secondary outcomes included a response, defined as a > 50% decrease from baseline to week 3 in the MADRS score and a sustained response, i.e., continuing from week 3 to 12.

Psilocybin and treatment response

A total of 233 individuals with a mean age of 39.8 years (52% female) were included and randomised to each arm of the study (ranging from 75 to 79 participants). At baseline, 68% of the entire cohort had a MADRS score indicating severe depression.

The reduction in MADRS scores were -6.6 (95% CI -10.2 to -2.9) for the 25 mg dose (p < 0.001 vs 1 mg dose) and -2.5 (95% CI -6.2 to 1.2) for the 10 mg dose (p = 0.18 vs 1 mg dose).

At 3 weeks, a response was also more likely in those given 25 mg compared to 1 mg (Odds ratio, OR = 2.9, 95% CI 1.2 – 6.6) but this was not significant for the 10 mg dose (OR = 1.2, 95% CI 0.5 – 3.01). However, the response to treatment was not sustained at 12 weeks for either dose.

Adverse effects included headaches (24%) and nausea (22%) and were much more common in the 25 mg dose group, although suicidal ideation or behaviour or self-injury was seen in each of the groups.

The authors concluded that psilocybin given as a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects, prompting the need for further studies of the treatment.

Citation
Goodwin GM et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Eng J Med 2022.

Treatment-resistant depression trials show large placebo response

6th October 2021

In trials of treatment-resistant depression, researchers have identified a large and consistent placebo response to all modalities.

Treatment-resistant depression (TRD) can be defined as a major depressive disorder (MDD) in adults who failed to respond to at least two different antidepressant treatments in their current moderate-to-severe depressive episode. It is a common problem with a prevalence estimated from one analysis to affect 30.9% of patients.

Although the efficacy of an antidepressant in clinical trials is assessed by comparison against placebo, a common problem is the large and positive placebo response often observed. The magnitude of average placebo response in studies of major depression has been found to be 29.7%, but ranged between 12.5 and 51.8%.

Moreover, in an analysis of 252 antidepressant controlled trials with 26,324 patients assigned to placebo, a placebo response was seen in 35 to 40% of patients, although the analysis did not specifically examine treatment-resistant depression.

However, what remains uncertain, is the magnitude of the placebo response in patients with TRD who are exposed to a range of different modalities. This prompted a team from the Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada, to not only assess the size of the placebo response in patients with TRD, but to also identify relevant factors associated with the placebo response.

The team undertook a comprehensive literature search and included studies that were parallel-arm, double-blind and placebo-controlled, specifically recruiting patients with treatment-resistant depression. They set the primary outcome as the Hedges g value, which is a measure of the effect size, for the placebo response.

The value of Hedges g indicates the extent to which two groups differ, based on the size of the standard deviation, e.g., a value of 1 indicates that groups differ by one standard deviations, 2 denotes two standard deviations and so on. As a secondary outcome, the team used meta-regression to explore potential moderators of the placebo effect.

Findings

A total of 50 clinical trials with 3228 patients, with a mean age of 45.8 years (20.7% women), where included in the final analysis. The placebos included pills, liquids, parenteral injections and several sham procedures such as sham transcranial magnetic stimulation, transcranial direct current stimulation or invasive brain stimulation.

The pooled placebo effect size for all treatment modalities was large (Hedges g = 1.05, 95% CI 0.91 – 1.1) although this did vary with the type of placebo intervention. For example, with pill placebos, g = 1.14, parenteral placebo, g = 1.33. The pooled placebo response rate in all trials was 21.2% with a pooled remission rate of 13%.

In the TRD trials, meta-regression revealed that industry-sponsored trials, year of publication and studies with an open-label prospective phase before randomisation, all had a significantly higher placebo effect.

Discussing these findings, the authors felt that their results offered future researchers a benchmark for expected placebo responses in TRD trials. They concluded by calling for more consistent reporting of data, an agreement on the definition of TRD, and an assessment and reporting of participant’s expectations and experiences within a clinical trial.

Citation

Jones BDM et al. Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis. JAMA Netw Open 2021.

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