Psychiatry’s Biggest Antidepressant Trial Just Got Reanalyzed: “It May Have Misled Treatment for Decades”, Experts Claim

 Overmedication is one of fastest rising problems in psychiatry field worldwide

New findings challenge STAR*D, the 4,000-patient government study that shaped depression treatment guidelines for years. Reanalysis shows no clear benefit of follow-up antidepressants over placebo, and experts weigh in on the need for alternative treatment methods.

 A new analysis published in the Journal of Clinical Psychopharmacology casts doubt on one of the most influential studies in modern psychiatry. When re-evaluated against randomized, placebo-controlled trials, most of the medication strategies used in the STAR*D trial, long seen as the gold standard for stepwise antidepressant care, show no measurable benefit beyond placebo.

The review compared STAR*D’s major treatment steps to real-world randomized controlled trial outcomes. Raising the SSRI dose, switching to another antidepressant, and adding common medications like bupropion or buspirone all failed to outperform placebo in blinded trials. 

The only add-on with consistent clinical benefit was lithium – which is constantly prescribed less and is harder to access due to known toxic effects on, e.g., the thyroid gland and the kidneys.  

“This study is a wake-up call,” said Dr. Hannah Nearney, clinical psychiatrist and UK Medical Director at Flow Neuroscience, a company that develops neuromodulation therapies for depression treatment. “Patients who don’t respond to the first antidepressant are often placed on a carousel of tweaks – higher doses, add-on pills, lateral switches – that produce side effects without providing real relief.”

An estimated 70% of patients with depression do not achieve remission with their first medication. Yet existing guidelines, based heavily on the STAR*D trial, still recommend drug modifications that, as reanalysis revealed, appear scientifically weak.

The new findings suggest these treatment steps may be driven more by expectation and placebo effects than by pharmacological mechanisms.

“This mirrors what we see every day in practice,” added Dr. Kultar Singh Garcha, NHS GP and Flow’s Global Medical Director. “Patients are stuck in trial-and-error cycles, not because we lack alternatives – but because those alternatives haven’t been prioritized in funding or regulation.”

One of those alternatives is transcranial direct current stimulation (tDCS) – a wearable, non-invasive brain stimulation technology backed by clinical trials. Flow Neuroscience, whose CE-certified device is already used in the NHS, says the findings highlight an urgent need to expand access to safe, proven, non-drug interventions.

“While tens of millions continue to cycle through barely effective drug combinations, validated neuromodulation therapies are still being overlooked or overregulated,” added Dr. Nearney. “We must give patients options grounded in science, and it must stay up-to-date. We’re living in a time where depression is becoming the next epidemic.”

The study’s authors argue for a rethinking of depression treatment models. As it claims, not all medications are ineffective – but the common practice of escalating doses or stacking drugs without placebo-controlled evidence may be doing more harm than good.

“This doesn’t mean medication should be abandoned,” Dr. Garcha concluded. “But if we’re going to recommend a new drug step, it has to outperform staying the course – not just look promising in an unblinded study. Otherwise, we’re replacing one flawed approach with another.”

 

Depression history written in the reactions of the brain

 

Scientists have found that the more severely patients have been hit by depression across their lifespan, the less they react emotionally to negative faces during current depression.  The researchers are now working to understand if this means that serious depression changes the way the brain reacts to emotion over time, or if people with stronger emotional responses to negative faces are less vulnerable to long-term depression. Either may have implications for future patient care. This work is presented at the ECNP conference in Lisbon, after recent publication.

Depression is a major mental health burden, but the direct effect on brain activity is only just beginning to be understood. The brains of depressed patients normally show greater activity in certain areas than those of non-depressed healthy people. Now a group of German scientists have discovered that, while still greater than in non-depressed people, brain activity of patients who are currently depressed and have suffered with prolonged and severe depression is lower than that of patients with less severe and prolonged depression. No specific relation is found between brain activity and previous depression in patients where the depression is no longer present.

The researchers worked with 201 seriously depressed patients and 161 patients who had come out of the period of depression (remitted). Each patient was questioned about the duration and extent of their previous depression, which allowed the researchers to build a tailored depression history.  Then during the study, each patient was placed in an MRI scanner, and brain changes were monitored while the patients viewed a series of unsettling images – fearful or angry faces.

Lead researcher Hannah Lemke (University of Münster) said:

“We saw that the unsettling images of negative faces caused activity in certain areas of the brain, mostly the amygdala, parahippocampus PHG and Insula, which are areas where emotions are processed. However the extent of the brain activity was different according to the severity and duration of the depression the patient had already suffered. Those patients where the depression had remitted showed a certain level of activity, but those patients where the depression was current exhibited a reduced activity in these brain areas. This differed for each patient, but in general the more severe the depression history, the less responsive their brains were to the photographs”.

Hannah Lemke continued:
“In those patients where the depression had remitted the brain response was not related to the previous depression history, which may indicate the importance of disease remission to brain health.
Interpreting this needs more work. It’s tempting to think that reduced brain activity is a way the brain copes emotionally with long-term depression, and that maybe the first episode of depression was qualitatively different to the current episode. It seems that underlying brain activity related to the emotional information of serious depression may change over the course of the disease. 

But we also need to consider alternative explanations, for example, it may be that people who process emotions in a certain way are more vulnerable to long-term depression. In either case, we are looking at different faces of depression, with different effects and different outcomes. And perhaps future treatment will need to take this into consideration.

This is a big study, so we can be fairly confident in what we have found. Nevertheless, we now need longitudinal studies, where individual depressed patients are followed over a period of years to see how their brain response changes”.


Commenting, Dr Carmine Pariante, Professor of Biological Psychiatry at King’s College London, said:

“This study confirms how profoundly the brain of patients is affected by major depression. A number of mechanisms can explain these findings, all relevant to the further understanding of depression, as this biological signature could be either a risk factor for, or a consequence of, more severe and chronic depression. Moreover, future studies should clarify if these effects are driven more by the maximum severity of depression, the chronicity of depression, or the exposure to antidepressants; and clarify the molecular mechanisms underpinning these functional changes”.

The 34^th ECNP Annual conference takes place in Lisbon and online from 2-5 October, see https://www.ecnp.eu/Congress2021/ECNPcongress . The European College of Neuropsychopharmacology is Europe’s main organisation working in applied neuroscience.

This press release includes work which appeared in Biological Psychiatry:CNNI, June 2021. see https://www.sciencedirect.com/science/article/abs/pii/S2451902221001488?via%3Dihub  

Digital mental health care pathways are delivering game-changing outcomes in the treatment of depression

Disrupting IAPT: Can digital pathways 'change the game' conference, De Vere Conference Centre, London.

“Digital mental health care pathways are delivering game-changing outcomes in the treatment of depression” according to Rob Brougham, UK MD of Ieso Digital Health, speaking today at Disrupting IAPT: Can digital pathways 'change the game' a national summit, chaired by Jeremy Clarke CBE, bringing together industry leaders to discuss the challenges and opportunities for innovation, ahead of the publication of the new NICE guideline for depression.

Ieso is the UK’s leading provider and award-winning pioneer of clinically validated, digitally-enabled mental health care, available through the NHS, IAPT programme. Ieso is making high-quality therapy accessible, accountable and affordable for the first time by combining the power of technology with personalised care. Ieso works with IAPT services across over 40 CCG footprints.

According to Rob “Many people seeking therapy for mild to moderate depression with the NHS, still face long waiting times, with 1 in 10 having to wait more than a year to be seen leading to minor problems becoming major ones[1]. Nearly two-thirds of people with a known mental condition never seek help from a health professional[2] and yet most of them carry a mobile phone around with them every day. By combining  digital technology with the knowledge and experience of qualified expert clinicians, we are seeing the real-world impact of how Ieso is redefining mental health, removing barriers and stigma by meeting patients where they are; on their mobiles and on PC.”

• 66% of all Ieso therapy sessions now take place out of standard 9-to-5 office hours and at weekends.
• 48% more patients complete Ieso’s therapy, compared to the national average for treatment.
• Greater flexibility of online therapy sessions offered by Ieso is reducing appointment no-shows by 31% compared to average national figures for traditional therapy.

Speaking about the impact that Ieso Digital Health is making, Rob Brougham said: “These new figures provide more evidence showing how Ieso’s digital care pathway is giving patients with depression a much better experience by connecting them to clinicians in real-time and meeting them beyond 9-to-5, enabling them to experience high-quality care, quickly and conveniently, without having to adapt their life to their condition.”

Hormone EPO shown to improve brain sharpness in patients with depression and bipolar disorder

A study has found that EPO (erythropoietin) – best known as a performance-enhancing drug in sport – may improve cognitive functioning in patients suffering from bipolar disorder or depression. This raises hope for the first long-term treatment for this problem, which affects hundreds of millions of patients throughout the world. The work is presented today at the ECNP conference in Vienna*.

The hormone EPO, mostly produced by the kidney, is essential for the production of red blood cells. EPO gives the blood a greater capacity to carry oxygen, and it is this characteristic which makes it attractive as a performance-enhancing drug (the cyclist Lance Armstrong admitted to using EPO to improve physical performance). Medically, recombinant EPO is used for the treatment of anaemia.

Most people think of disorders such as bipolar disorder and depression as conditions which affect mood, but in reality they also affect cognitive function - how quickly and how well a brain functions. This slow-down in thinking can have serious effects on sufferers, making it more difficult to retain a job, pass an exam, or maintain a relationship. Now a group of Danish Scientists have discovered that EPO can help restore cognitive function in patients suffering from these mental disorders.

In two randomized controlled trials, the researchers assessed cognitive function in 79 patients suffering from depression or bipolar disorder. They assigned 40 of the patients to be given EPO for 9 weeks, with the remaining 39 being given a placebo. They found that EPO had beneficial effects on patients’ completion of a range of cognitive tests, including tests on verbal memory, attention span, and planning ability. Tests showed that this improvement was maintained for at least 6 weeks after treatment finished (the longest follow-up time in the trials). 

Lead researcher, Dr Kamilla Miskowiak said:

“EPO treated patients showed a five times greater cognitive improvement from their individual baseline levels compared with placebo treated patients. EPO-treated patients showed 11% improvement while placebo treated patients improved only by 2%. This effect of EPO on cognition was maintained six weeks after patients had completed their treatment”.

In an interesting twist, it was found that patients who performed poorly in neuropsychological tests showed remarkably greater cognitive benefits when given EPO. Dr Miskowiak, commented:

“This is interesting, as it means that we may be able to target patients for EPO treatment –and perhaps other future cognition treatments - based on how they do on neuropsychological tests”.

She continued

“We need bigger studies to confirm that the effects we have seen can be replicated, to confirm dosage, frequency of use and so on. EPO is already used medically, so we know quite a lot about safety. Although EPO is generally safe if patients’ red blood cell levels are controlled regularly, there are certain groups for whom the risk of blot clots is too high – for example people who smoke or who have previously had blood clots. So although these results hold out great promise, EPO treatment is not ready to be rolled out as a treatment just yet and may not be for everyone”.

The WHO estimates that around 350 million people suffer from depression, with a further 60 million suffering from bipolar disorder**, but the drugs normally used to treat depression and bipolar disorders don’t have any major effect on cognition. Up to 70% of patients in remission from bipolar disorder, and up to 40% in remission from depression continue to have cognitive problems. Currently there is no available effective treatment to target cognitive problems in these patients.

Commenting, Professor Eduard Vieta (Chair of the Department of Psychiatry and Psychology at the University of Barcelona Hospital Clinic and treasurer of the ECNP) said:

“The results of this study, albeit preliminary, give hope to people suffering from mood disorders and associated neurocognitive symptoms. Those symptoms are now recognized as a core part of affective disorders and are not appropriately tackled by the currently available pharmacological armamentarium, despite their close association with relevant clinical outcomes such as the ability to return to work”.

Live social media Q&A on diabetes & depression

Diabetes.co.uk is Europe’s largest patient to patient forum which offers people with diabetes a platform where they can talk, support and help each other.

On Thursday 23rd April, Dav Panesar – an expert in the field of Mindfulness based therapies - will be answering any questions from patients and carers of the diabetes community from 7pm-8pm. Users will have the choice of sending in their questions in advance, or can post their questions to the Facebook and Twitter page live on the night.

As part of Depression Awareness Week (20-26 April), Dav will be looking at techniques and tools that the diabetes community can use to deal with depression, anxiety and diabetes related emotional distress including burnout.   Research shows that people with diabetes are three times more likely to suffer depression than the general population and are 29% more likely to have depression compared with people without diabetes - this rises to 53% for those with Type1 diabetes.  Studies have also shown an association between high blood sugars and depression. (IDDT Diabetes – Stress, Anxiety & Depression, January 2013).

As a teacher, facilitator, researcher and consultant with over 20 years of teaching experience, Dav is skilled in incorporating mindfulness within the businesses, education and health sector. His focus and research has been on the application of Mindfulness based approaches for those suffering from diseases such as cancer and diabetes, in addition to mental health including stress, anxiety and depression.

Mindfulness is a technique that teaches an individual to become aware of moment-by-moment thoughts, emotions and physical sensations in a non-judgemental way. The foundations of mindfulness lie in the ancient practice of meditation and in the US, mindfulness is being increasingly used for eating habits and diabetes management. Research has shown that mindfulness enhances clinical effect of glycemic control.

Throughout 2015, Diabetes.co.uk has launched a series of live Q&A’s with experts including doctors, dieticians and nutritionists via their Facebook and Twitter page. Social media users will have the chance to ask any diabetes related questions and receive expert.