Drug development
When the drugs don’t work: can pharma keep up with mental health?
From novel diagnoses to psychedelic drug treatments, Chloe Kent explores the pharmaceutical industry’s attempts to keep up with our understanding of mental health and neurodiversity.
Sluggish cognitive tempo (SCT) is not an officially recognised diagnosis, but a clinical construct used to define a group of behaviours encompassing maladaptive daydreaming, brain fog, hypoactivity, sluggishness, vacant staring, inconsistent alertness and a slow working speed.
Absent from both the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD), SCT has been subject to controversy for decades.
While proponents of the diagnosis maintain that the syndrome is a legitimate disorder of cognition related to – but clinically distinct from – attention deficit hyperactivity disorder (ADHD), critics outright dismiss the notion of its existence.
Spearheaded by clinical psychologist Russell Barkley, the term emerged in the 1980s during debate among researchers as to whether predominantly hyperactive/impulsive ADHD and predominantly inattentive ADHD were in fact separate disorders.
The term SCT was coined, according to Barkley, in a University of Georgia student’s dissertation in 1984. While the student in question didn’t look into the category of symptoms he had identified any further, Barkley says: “the rest of us went back and said ‘but those are the people we want to study’.”
In examining the inattentive ADHD subtype, researchers found that certain related characteristics seemed to be different to those typically associated with ADHD. Over time, different researchers found that what was distinct about these patients were their SCT symptoms. They floated the theory that SCT could constitute an entirely distinct disorder to ADHD, rather than there being an inattentive ADHD subtype.
Barkley says: “I’ve often told students, ‘if you want to make a name for yourself in psychology and psychiatry, you’re going to do it with SCT’. We are at the ground floor of discovering another attention disorder and anything you do is publishable because we know so little.
“It’s a very exciting field to me and I’ve been invested for a long time. It’s not yet ready for an official diagnosis in our DSM or ICD, but hopefully by DSM-VI, which is probably another five years out, there’ll be plenty of convincing evidence that we have a second attention disorder here.”
A debated diagnosis
Not everyone is so convinced by the classification of SCT. Duke University emeritus professor and former chair of the department of psychiatry Allen Frances, argues that the DSM already pathologises too many traits that are within the range of normal human experience. He has described SCT as “possibly… the very dumbest and most dangerous diagnostic idea” he has ever encountered.
Frances says that SCT symptoms are associated with a vast number of conditions, from depression and anxiety to the brain fog linked to ‘long Covid’, and that “the last thing our kids need is to be misdiagnosed with ‘Sluggish Cognitive Tempo’ and bathed in even more stimulant meds”.
Despite the controversy over the very existence of SCT, studies have begun to be carried out into potential drug treatments. Nothing is US Food and Drug Administration (FDA) approved yet, but if SCT does end up making its way into the next DSM, this could be set to change.
One study has suggested that an Eli Lilly drug called atomoxetine, brand-name Strattera, could help reduce SCT symptoms, while others have shown that the ADHD drug methylphenidate, brand-name Ritalin, may not work well for those with SCT. But Barkley doesn’t believe any substantial interest is about to pick up just yet.
We certainly wouldn’t get FDA approval to use a drug for something for which there is no official diagnosis.
“I can tell you there’s not a single company, and I consult with all of them from time to time, that has shown an interest in this disorder,” he says. “It took a few years for us to keep beating Eli Lilly over the head before they finally allowed my colleague Keith McBurnett to put a rating scale of SCT into a study they were already doing, looking at Strattera for ADHD and other learning disabilities.”
SCT may or may not make its way into the diagnostic manuals of the future, but it’s a prime example of how our understanding of cognitive conditions is in constant flux. When a novel or disputed diagnosis is proposed, it opens the door to potential pharmaceutical intervention – but also a lot of risk.
Barkley says: “Pharmaceutical companies tend to be conservative. If there’s no official diagnosis and they go out and fund a drug study they are going to get nailed by the government, by the FDA, by social critics of psychiatry who don’t like these medications. We certainly wouldn’t get FDA approval to use a drug for something for which there is no official diagnosis.”
Psychedelic future
It’s not just changing cognitive diagnoses that the pharmaceutical industry has to keep an eye on – the very nature of the drugs used to treat mental health conditions is changing as well. Psychedelic substances are currently being investigated by researchers around the world to treat mental health conditions like depression, anxiety, post-traumatic stress disorder and addiction.
Selective serotonin reuptake inhibitors are the current gold standard for treating most mood disorders, and work by increasing levels of serotonin in the brain. They’re far from a magic bullet and can often induce unpleasant side effects like emotional numbness, changes to heart rate and blood pressure and insomnia. They can even worsen suicidal thoughts in some patients.
A recent review of studies into antidepressants found that their benefits appeared minimal and possibly without any importance for the average patient with major depressive disorder, but that they posed a significant risk of both serious and non-serious side effects.
In 2019, the FDA made the landmark decision to approve Johnson & Johnson’s ketamine-derived nasal spray, Spravato, for treatment-resistant depression. A patient will go to their doctor once or twice a week to receive nasal puffs of a dose of esketamine, remaining at the doctor’s office for two hours afterwards in case they experience any initial disorientation or confusion.
Medical psychedelics company Awakn Life Sciences chief science officer Dr Shaun McNulty says: “Psychedelic therapeutics work by different pharmacological approaches compared to existing therapeutics, they are fundamentally different in their mode of action and often used in combination with psychotherapy.
There is an explosion of interest in bringing psychedelic therapeutics to the market.
"They have already been shown in both preclinical and more significantly in clinical studies to work in patient populations, offering alternative and often far superior outcomes to the existing, marketed therapeutics.
“Whilst research and development of more traditional psychiatric therapeutics is slowing, in part because of poor efficacy, there is an explosion of interest in bringing psychedelic therapeutics to the market.”
Awakn has Phase II trials underway investigating the use of ketamine-assisted psychotherapy for alcohol use disorder and behavioural addictions and MDMA-assisted psychotherapy for alcohol use disorder. It is also investigating new chemical entities which could help treat alcohol, behavioural, opioid and tobacco addictions.
McNulty says: “I believe that as we move forward, first traditional psychedelic compounds, and in time next generation psychedelic compounds with enhanced properties will come to the market, often used in combination with psychotherapy, to treat a broad range of diverse mental health challenges.”
Can pharma keep up with the changes?
With the diagnoses and drugs used to categorise and treat mood disorders and neurodiverse conditions in a state of flux, it’s hard to predict whether or not the pharma industry will be able to keep up with demand.
The role of ‘conventional’ drug therapies for mood disorders has also come under some scrutiny in recent years, despite the skyrocketing prescriptions during the Covid-19 pandemic.
Robert Whittaker, a journalist who has spent much of his career writing critically about psychiatry, recently told Scientific American: “I am not so sure any more that the medications provide a short-term benefit for patient populations as a whole.
“When you look at the short-term studies of antidepressants and antipsychotics, the evidence of efficacy in reducing symptoms compared to placebo is really pretty marginal and fails to rise to the level of a ‘clinically meaningful’ benefit.”
The evidence of [antidepressants and antipsychotics] efficacy in reducing symptoms compared to placebo is really pretty marginal.
It’s also important to note that contemporary activism has reframed the way many individuals feel about neurodiverse conditions – like ADHD or SCT. Instead of a disease to be cured or minimised, many patients and clinicians see these diagnoses simply as different ways of being, which society should seek to accommodate, instead of the affected individual trying to adapt to neurotypical society.
This line of thinking has become increasingly popular when it comes to autism, which is finally being removed from the UK Mental Health Act as a reason a person can be sectioned. Some people who experience auditory hallucinations also seek to reframe their experiences in a similar way.
If something formerly classed as an illness no longer fits that label, then it’s hard to see how the pharmaceutical industry can have any role to play in ‘treating’ it.
McNulty says: “I believe that the pharmaceutical industry will ultimately catch up with our developing understanding of mental health. However, at present, with their traditional research and development approaches, I believe the pharmaceutical industry is not well placed to utilise this understanding to develop next-generation therapeutics.”
Preparing for the challenge ahead
To a large extent then, preparing for vaccine distribution will mean learning from what’s been achieved so far.
“I think some of it has to do with modelling – you can do a lot of simulation around production and distribution logistics,” says Boyle. “You can plan some ‘what if’ scenarios, at least identifying where the weaknesses are in the system and what kind of stressors would bring down parts of it. Then when you start to see the stressor, you already know it’ll cause a breakdown in the system and you already have a contingency plan.”
In practice, this might mean implementing a regional strategy with some redundancy in the supply chain, giving back-up if a certain country ends up in lockdown.
Delivering billions of doses of vaccine to the entire world efficiently will involve hugely complex logistical and programmatic obstacles.
“Everybody wants to operate at minimum inventory levels and maximum cost efficiency levels, but we’re asking now ‘where does lean become too lean?’” says Boyle. “The risk profile of that position has changed and people are going to be re-examining some of their goals. It’s about ensuring resilience of the supply chain and working out what level of risk you’re willing to take.”
With the first vaccines in sight, it is time for logistics providers, governments, airlines, and many more to begin their preparations in earnest. As the speakers emphasised at the IATA teleconference, this is an enormous undertaking that requires careful planning from every stakeholder.
“Delivering billions of doses of vaccine to the entire world efficiently will involve hugely complex logistical and programmatic obstacles all the way along the supply chain,” said Dr Seth Berkley, CEO of Gavi, the Vaccine Alliance. “We look forward to working together with government, vaccine manufacturers and logistical partners to ensure an efficient global roll-out of a safe and affordable Covid-19 vaccine.”
