TREATING severe and chronic depression can be extremely difficult. Over the years, medicines have been developed to treat mood disorders, from tricyclics in the 1950s to SSRIs (selective serotonin reuptake inhibitors) in the 1970s.
However, it can take time for these drugs to have an effect (and in an estimated 30 per cent of cases, they don't work at all); with SSRIs, it's between four to eight weeks.
But could a new drug that's just been approved by the Food & Drug Administration (FDA) in the United States be the answer?
Called Auvelity (generic name AXS-05), it has been hailed a game-changer as research suggests it rapidly reduces symptoms within a week of starting treatment, with some patients experiencing 'remission' - in other words, no symptoms of depression at all - by 'week two', according to a spokesman for Axsome Therapeutics, the pharmaceutical company that developed it.
The FDA approval for the twice-daily pill comes just three months after the publication of positive results of a clinical trial, where it was compared against a placebo.
Published in May in the Journal of Clinical Psychiatry, the GEMINI trial showed that patients with severe depression who took the drug for six weeks were significantly more likely to report improved symptoms than those taking the placebo, with 39.5 per cent experiencing remission compared to 17.3 per cent in the placebo group.
(This high rate of effectiveness in the placebo group is not unusual - multiple studies show placebo pills can help lift depressive mood, possibly because patients have a high level of expectation of improvement and they get extra support during a trial.)
Perhaps not surprisingly, Axsome's share price soared with the drug's approval, rising by nearly 40 per cent in just one day.
"At the moment, most drugs used to treat depression take up to eight weeks to have any effect on symptoms, which can be very distressing for people in a mental health crisis, as well as making it more difficult for them to stick to their drug regimen," says Maurizio Fava, psychiatrist-in-chief at Massachusetts General Hospital and a professor of medicine at Harvard Medical School, who co-authored the report of the GEMINI trial.
The new oral drug works in a completely different way from current ones; it triggers the production of glutamate, a chemical messenger in nerve cells in the brain. The claim is that this prompts the brain to form new neural connections, allowing for more positive thought pathways to develop.
And it also contains dextromethorphan, an ingredient found in medicines such as Benylin Dry Cough and Robitus-sin Dry Cough Medicine. It's a morphine-based drug, known as a N-methyl-d-aspartate (NMDA) receptor antagonist, which has sedative and dissociative (where you feel disconnected from thoughts and feelings) properties. In cough syrups it acts on the brain to suppress coughing.
(It works in a similar way to ketamine, used as an anaesthetic in surgery and has been tested as a nasal spray to treat depression. However, the UK drugs watchdog has rejected its use in the NHS.)
Auvelity also contains bupropion, already prescribed to treat depression (although not in the UK) and to help people stop smoking because it reduces smoking satisfaction. Importantly, it boosts blood levels of dextromethorphan by reducing the amount that gets processed by the body, so 'supercharging' the effectiveness of dextromethorphan.
The maker claims Auvelity is the first new oral drug for severe depression with a new mechanism in decades. It's been approved in the US for treating major depressive disorder (MDD) - defined as having symptoms of depression most of the time for at least two weeks that typically interfere with one's ability to work, sleep, study and eat.
"Depression is a difficult-to-treat condition with potentially devastating consequences for patients and their families," said Professor Fava. "Based on the [trial] results and its novel oral NMDA antagonist mechanism, AXS-05 may represent an important new treatment option for patients with depression."
As well as "significant improvements in depressive symptoms compared to [a] placebo", the drug was well-tolerated, with only 6 per cent of people leaving the trial early due to side-effects, he said.
That's important as current antidepressants are often poorly tolerated, causing side-effects such as sexual dysfunction (reported in over 70 per cent of patients in one 2016 study), withdrawal symptoms and weight gain, as well as feeling emotionally numb. These were not seen in the Auvelity study: the most common side-effects were dizziness, nausea, headache, sleepiness and dry mouth.
As many as 20 million adults in the US experience a major depressive disorder each year, according to pre-Covid figures. In the UK, as many as 17 per cent of adults were affected by moderate to severe depressive symptoms in the two years up to August 2021, Office for National Statistics figures show.
Estimates vary as to how many people in the UK have severe depression but one study by Public Health England (now the UK Health Security Agency) found that over 12 months in 2014, 6.6 per cent of the population had suffered from it.
The maker of Auvelity is seeking approval from the European Medicines Agency; it's not clear when they will apply for it in the UK.
So is this drug the Holy Grail for severe depression? Auvelity was granted 'Breakthrough Therapy' designation by the FDA - meaning its approval was fast-tracked.
Earlier this year, an expensive new dementia drug, Aduhelm, was controversially granted this fast-track approval, on the basis that it reduced amyloid plaque build-up in the brain, linked to dementia, without showing it improved patient outcomes.
After the European regulator commented on the lack of evidence, the manufacturer withdrew its application for approval in Europe. And already some experts have expressed doubts about just how reliable the evidence for the new 'wonder drug' for depression is.
"It appears to have been evaluated against placebo in only one trial involving 327 patients, and against bupropion-treated patients in one other - not against the best treatments currently available for depression," says Dr Mark Horowitz, a training psychiatrist and an honorary clinical research fellow at University College London.
"Although it has been branded as fast acting because it shows a difference from placebo after one week, after six weeks that difference on a depression scoring system, while statistically significant, is not likely to cause much of a change," he adds, explaining that for people with severe symptoms, clinicians would expect a score that's at least nearly twice as high "for the minimum noticeable improvement".
Another concern is the length of the GEMINI trial, which lasted just six weeks. This is not long enough to get an accurate view on the drug's true efficacy, explains Dr Horowitz. "Lots of drugs can boost your mood for six weeks, including many recreational drugs, but in the longer term they can cause significant side-effects and trouble with mood because the effects wear off," he says.
"The drugs in this study include a cough-suppressant medication which is described as a dissociative drug - in other words, it can make you feel slightly 'out of it'.
"This could produce enough of an effect to make you feel slightly better for a short time before you got used to it - at around six weeks.
"This also means that the study could not have been blinded - where patients are unaware whether they were given the active drug or the placebo - because the group taking the drug instead of the placebo sugar pills would have noticed they felt 'out of it' and immediately correctly assumed they were the drug group.
"So it will have a strong, amplified placebo effect - people will know they are on the drug, expect to feel better and we know that this itself has a large effect on mood scores, perhaps explaining the improvement in the drug group."
Dr Horowitz argues that drug companies searching for new antidepressants are trying to simplify complex issues.
"The idea that a complex condition like depression, which is caused by many social and environmental factors, can be cured by increasing levels of one or more neurotransmitters [such as serotonin or glutamate] is far-fetched," he says.
"The human brain is responsive to environment, upbringing, poverty, physical ill-health and relationship breakdowns, to name a few. There is no drug that can affect these things. What helps is relevant support and non-drug therapies that can be helpful.
"NICE [the National Institute for Health and Care Excellence] lists eight non-drug therapies for severe depression, that include mindfulness, counselling and problem-solving therapy, all of which have lesser side-effects and equal effectiveness to medication in the short term.
"We know learning skills to manage our mood is more helpful in the long-term than covering up emotions with drug effects, especially since we now understand that these drugs [in the case of SSRIs and NMDAs] do not correct the underlying chemical problem."
Dr Horowitz has co-authored a review that found there is no evidence depression is linked to a chemical imbalance of serotonin.
Andrew Miller, a professor of psychiatry and behavioural sciences at Emory University School of Medicine in the US, also said caution is advisable: "It's a little early to tell, but unfortunately the study and the pharmaceutical industry continue to make the same mistakes: they assume depressed patients are a homogeneous group, which they are not, and that medications should work across all patients, which they don't."
He adds: "Based on the relatively small differences between placebo and drug in this study (albeit large enough to be clinically significant by definition), we can only assume some patients are responding well and others not so much.
"More work needs to be done to identify which patients are most likely to respond. Also, without comparing the drug to both bupropion and dextromethorphan alone, it is hard to know whether the combination drug is significantly better than either drug alone. It is no surprise that something is better than nothing."
Professor Fava agrees that there is not a one-size-fits-all solution for severe depression.
He says we have known for some time that major depressive disorder is very heterogenous and it is not simply due to a "lack of serotonin", despite the fact that a number of standard antidepressants work on serotonin levels. He adds that other factors, including counselling, will continue to play an important role alongside medication.
"Many studies have shown greater efficacy of the combination of antidepressants with forms of therapy such as cognitive behavioural therapy than either treatment alone, but medication must also be available as a front-line treatment," he says.
"There is a sequential model of treatment where medications are started first among patients with severe forms of depression and therapy is added later in order to maximise the benefits of therapy."
Other experts suggest older-style antidepressants, tricyclics, still have their place.
David Healy, a psychiatrist and a professor in the department of family medicine at McMaster University, in Canada, says these drugs - which prevent the reabsorption of serotonin and another chemical messenger, norepinephrine - can help some people.
"If you want effective antidepressants, the old tricyclics are more effective than anything else," he says. "In all trials where they are compared to SSRIs they beat them."
Another newer approach to treating depression involves tackling inflammation - the idea is that the body's natural process of fighting infection might be at the root cause of depressive illness, and that using an anti-inflammatory could be a way to treat it.
Several studies have shown non-steroidal anti-inflammatory drugs, including ibuprofen, can cut depressive symptoms.
Professor Miller says anti-inflammatories may help by reducing anhedonia - the loss of pleasure and motivation to engage in activities. "Anhedonia is the most disabling of the symptoms of depression," he says.
Carmine Pariante, a professor of biological psychiatry at King's College London, has been looking into the use of anti-inflammatories for depression for the past 20 years and his team has established that molecules produced by the immune system that increase inflammation (such as IL-1 and IL-6 ) can reduce the formation of new brain cells.
He explains: "This affects the brain, disrupting the connection between the different neurons, and this is what creates depressive symptoms."
He says anti-inflammatories (such as minocycline, an antibiotic with anti-inflammatory properties) have been shown to reduce symptoms of depression in patients and may prove to be safe alternatives to other drugs.
Professor Pariante also published a study involving data from 500,000 people that found those who were depressed had raised levels of a molecule known as C-reactive protein, a marker for inflammation.
"This is the largest ever study on this and unequivocally confirms that inflammation is present in depressed people," he said. But Professor Healy says "people with inflammatory states may have depressive symptoms but the idea that 'depression is caused by inflammation' is absurd".
Professor Miller agrees anti-inflammatory drugs are not ready for prime time in the treatment of psychiatric disorders and "there is not enough well-controlled data to guide their use, and many of the most effective anti-inflammatory drugs are also powerful immuno-suppressants". But he believes they are a promising field of further research.
Rather than focusing on one 'cure-all', Edward Bullimore, a professor of psychiatry at the University of Cambridge, says: "It is not going to be any one drug that works to cure people from depression, but a range of much more individualised treatments.
"At the moment, it is very much one-size-fits-all when it comes to antidepressants, but I hope that is going to change in future."
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