As depression exerts a growing grip, remedies from microdosing psychedelics to getting active are in the spotlight. By Nicky Pellegrino.
If ever there was a year to induce anxiety and depression, it has been 2020. Even those who have never experienced a mood disorder before may have found themselves struggling. Has the Covid-19 pandemic sparked a depression epidemic? Science is still playing catch-up, but the early signs are that lockdowns, financial worries and fear of the virus have taken a heavy psychological toll on many of us.
A first-of-its-kind study from the Boston University School of Public Health found 27.8 per cent of adults had depression symptoms in mid-April, compared with 8.5 per cent before the pandemic, with money worries the most common cause. An analysis of a number of Asian studies puts the prevalence of depression at seven times higher than before. And if you are unfortunate enough to become sick with Covid-19, it significantly ups your risk of developing a mood disorder, according to a recent UK study published in the Lancet.
In New Zealand, the effect appears to have been worst on younger people. A survey in April conducted by University of Otago researchers found that almost half of those aged between 18 and 24 experienced moderate to severe psychological distress during the lockdown.
Dr Susanna Every-Palmer emphasises that the survey was only a snapshot in time. Her team from the department of psychological medicine has continued to collect data and next year should be able to tell us more about how we are coping with the new normal. But what the snapshot suggests is about a third of New Zealanders experienced psychological distress in lockdown, well above the levels measured in previous population surveys.
"From our research we identified a number of vulnerable groups," says Every-Palmer.
"Those included young people, people in living situations they weren't happy with, people who had lost their jobs and people with a past history of mental illness or pre-existing health conditions that put them at risk."
It is not as though we were doing well before the pandemic. Mental well-being was already on a downslide, with young people in particular suffering, especially those who are female, Māori, Pasifika or among the rainbow community. And although the mental-health sector got an almost $2 billion boost in last year's Budget, we are still struggling to understand what is going wrong, never mind come up with effective strategies for prevention and intervention.
Even medication doesn't necessarily help, with up to a third of people unable to find any drug that eases their symptoms. Auckland psychiatrist Wayne Miles says some of his treatment-resistant patients have been struggling for a long time. Typically they will have had their first experience of mental unwellness in late adolescence or early adulthood, although possibly at the time it wasn't recognised as depression.
"Some are desperate," says Miles. "Some are resigned to the fact they will have to put up with it. These people have had between five and 20 years of depression. Some have had multiple episodes and some only one but have never recovered properly."
In recent years, there has been renewed interest into the therapeutic use of psychedelics for mental health. Scientists around the world have been looking at how MDMA (Ecstasy) might help patients with severe post-traumatic stress syndrome (PTSD), how a South American plant-based psychoactive tea called ayahuasca might be used to treat depression and how LSD may be helpful for addiction and severe phobias. Psilocybin, the active ingredient in magic mushrooms, is also being investigated as a potential breakthrough drug for hard-to-treat mental-health problems.
In New Zealand, the psychedelic medicine that is being considered most seriously for depression is ketamine. Categorised as a dissociative anaesthetic, it has been seen as a potential breakthrough for a while but handbrakes have been concerns about addiction, side effects and the scope for abuse.
Ketamine is an old drug – it was discovered in the 1960s and was the most common battlefield anaesthetic in the Vietnam War. Under the moniker Special K, it has since been popular as a party drug. There is little doubt that it is helpful for depression but one big question has been whether it can be effective in doses that are too low to create the psychedelic experience of hallucination or dissociation.
Miles is involved in a major drug study, the BEDROC trial, being conducted by New Zealand company Douglas Pharmaceuticals here and overseas. It is focused on a slow-release ketamine pill that is designed to be difficult to abuse – it can't be crushed to enable snorting or liquidised for injecting – and early results suggest it is effective and fast. Within a week of starting to take it, three-quarters of treatment-resistant patients have been showing benefits and a compassionate-use programme allowing those who have responded to remain on the drug – provisionally called R107 – has seen those benefits persist for many people.
Eighteen of Miles' patients are enrolled in the BEDROC trial. "To be involved, they have to have tried traditional treatments and failed with those," he says.
In the first week, everyone is given the active medication, before doses are randomised so they might get a placebo or ketamine.
"Not everyone responds and not everyone stays well, but it's been quite impressive," says Miles, who can tell by watching a person walking down the corridor on the way to see him that something has changed. "You'll get a beaming smile, when the week before they struggled to smile. For some people it's mood that has improved and for others it's their energy level; they feel like they can do things they weren't previously managing. One patient told me his wife almost fell off her chair when she saw him painting the house."
Research into R107 is happening in Australia, Singapore and Taiwan as well as five New Zealand centres, and the project is about halfway through. Ketamine works differently from SSRI anti-depressants, which raise levels of the brain chemical serotonin. A University of Auckland trial that gave patients an intravenous infusion of ketamine and then used EEG imaging to observe brain electrical activity demonstrated that it triggers changes in neural plasticity, increasing the brain's ability to form new connections, something that appears separate from the action that produces "highs".
In with the old
Humans have a long history of using psychedelics. In South America, shamans have used ayahuasca in traditional healing rituals and ceremonies for centuries. And the heyday of use of the class-A drug LSD was the 1960s, when the US psychologist and writer Timothy Leary urged people to take an acid trip to "turn on, tune in, and drop out".
More recently, the trend has been to self-medicate with psychedelics by microdosing, taking tiny amounts of LSD or magic mushrooms to not get high but to improve mood. The trend is associated with tech-industry denizens of Northern California's Silicon Valley who swear by microdosing to boost creativity and focus, improve sleep and help stress. The few laboratory studies that have tried to replicate those results, however, haven't come up with much.
Now, Dr Suresh Muthukumaraswamy, at the University of Auckland, is about to conduct a world-first trial of microdosing and its effect on well-being. It will involve 40 healthy male participants, females having been excluded to avoid the hormonal fluctuations of menstruation complicating the results. They will take tiny amounts of pharmaceutical-grade LSD or a placebo as they go about their daily lives and complete nightly questionnaires about mood, well-being, concentration and any negative effects.
Muthukumaraswamy has the funding and ethics-committee approval to go ahead, but the pandemic has delayed things. The trial is just a first step, with the chance it won't uncover any benefits, and even if it does, these will need to be replicated in other groups.
Many of those who work in mental-health care will tell you that there is still a significant stigma despite more people speaking out about their experiences. The list of high-achieving men who have admitted to problems with anxiety and depression is growing.
What started with rugby's Sir John Kirwan and comedian Mike King has continued with politician Todd Muller and young royal Prince Harry. In recent months, former TVNZ reporter Jehan Casinader and Alistair Campbell, former aide to UK Prime Minister Tony Blair, have released books detailing their own battles and ways of surviving them.
Some people are more at risk of developing a psychiatric disorder than others and geneticists are only just beginning to understand why. Although it is clear there is no one single depression gene, there may be a common genetic architecture that lies behind a range of mental illnesses. Recent work at the University of Auckland's Liggins Institute has shed more light on this. In a two-year study, molecular biologist Evgeniia Golovina identified 61 biological pathways that play a role in schizophrenia, anxiety, bipolar disorder, depression and attention-deficit hyperactivity disorder that may explain why the conditions can overlap.
This is not as deterministic as saying that if you have the genetic variants that affect a particular biological pathway you are going to get a mental illness.
"But we all have a certain predisposition and where we sit on that spectrum is partly down to our genetics and also partly down to your environment," says study co-author Justin O'Sullivan. "There are a whole lot of things that can impact on it. So I'd never argue that this is completely biologically determined. It is only one part of the puzzle."
What the geneticists are hoping to do is help us understand why one individual might respond to a drug that boosts serotonin while another does better on a medication that gets different parts of the brain talking to each other. Or why in some cases taking antidepressants is counter-productive, doubling the rate of suicidal thinking.
"We know that if we treat everybody the same way, they don't all respond the same way," says O'Sullivan. "The beauty of this is you can start to identify why people differ. Each of us has our own genome, we have different combinations of these variants that affect the way some of these pathways are working. It may predispose you to one combination of conditions or another combination. If we can understand that, then what we can start to do is predict how people might respond to treatments or how their conditions might develop."
Stop taking the pills
The future will be about precision medicine, individualised treatments and hopefully better outcomes. In the meantime, however, in a year when more of us are struggling with low mood and panic, and while the difficult circumstances seem set to remain for some time to come, Bruce Arroll would discourage GPs from reaching too quickly for their prescription pad when faced with a newly distressed patient.
Arroll is a professor at the University of Auckland, a specialist in primary healthcare and a practising GP. He doesn't even like to use the word depression, preferring "stuck". His clinic no longer offers a depression programme, but instead wellness support.
"I discourage GPs from labelling patients because those labels can affect you for the rest of your life and may prevent you from getting jobs," says Arroll.
His preferred method of treating those with mood disorders is known as Fact (focused acceptance and commitment therapy) and can be used by GPs or nurses for those with mild to moderate depression. The approach is being used in general practices and marae clinics within the Counties Manukau District Health Board area and has been successful in increasing access to mental-health support for Māori.
Arroll says that many patients arrive in his surgery not even realising their problem is a mood disorder. "They'll come complaining of lethargy, sleep problems or vague aches and pains that don't make any biological sense," he says. "While you've got to make sure you're not missing a cancer somewhere, it's usually a sign of distress. Or 'distress with reduced motivation'."
Tackling the lack of motivation is the key, says Arroll. "You've got to get them exercising, connecting with friends, going to work, cutting down their substance abuse and not spending all day in bed, because that's what people do when they get de-motivated. They hide in bed, which feels nice temporarily but messes up your circadian rhythm. Then you can't sleep at night, which makes it worse."
Arroll doesn't even like the term antidepressant. "'Mood helpers' for some of the population would be better," he says.
For those with mild to moderate depression, the existing drugs are particularly ineffective. And across the board the placebo effect appears to be far stronger than any genuine drug response. Behavioural activation helps about 40 per cent of people feel better within two weeks, which in Arroll's view makes it the winner.
The problem, of course, is that if you are feeling "stuck", the last thing you want is to get out and exercise or catch up with friends. "So you have to trust your experience and do the opposite of what your mind is telling you," says Arroll, who pushes his patients to get moving.
He sees behavioural activation as the first line of defence, and medication as a follow-up option only if it doesn't work. "Keeping fit is the road to mental health and, of course, it's one of the first avoidance behaviours people get into."
It is well known that high-intensity exercise such as running releases the body's endorphin feel-good chemicals. But there is also evidence that lower-intensity effort sustained over time supports nerve cell growth and new connections in the brain, and it may be this improvement in brain health that is making us feel better.
There is also science to show that other lifestyle factors can strongly affect depression. A recent analysis of data from 85,000 people by Western Sydney University found that physical activity, healthy diet, optimal sleep (seven to nine hours) and less screen time are protective of a depressed mood.
Whether it is a drug or a therapy, no single solution is ever going to suit every person who is struggling with anxiety and low mood. But either way, one of Arroll's favourite aphorisms does seem fitting. "You cannot sit there and make yourself feel better. You have to start doing things."