A fresh understanding of OCD is opening routes to new treatments

We all have compulsions and habits.  we have to channel both to benefit ourselves.  It is just how you learn mastery.

 Chewing nails is a famous bad habit shared by folks with high nervous energy.  Then one day as age arrives, it goes away.  did it ever matter?

Planned habits are well worth acquiring, think about that to see if it goes somewhere.

A fresh understanding of OCD is opening routes to new treatments

We're finally pinning down the mechanisms that drive obsessive-compulsive disorder, revealing a complex combination of imbalanced brain networks, the immune system and even gut microbes

By Anthea Rowan

11 September 2024

When my daughter was young, she washed her hands a lot. We might have poked what we thought was gentle fun at her, saying she was “a little bit OCD”. Later, she began to disclose “bad thoughts”, which I assumed were the typical products of a child’s imagination. I told her we all had thoughts like that, and if we ignored them, they went away.

Hers didn’t. At 21, they were out of control and out of proportion to anything like reality. She was diagnosed with obsessive-compulsive disorder and I finally realised there was nothing “a little bit” about this condition.

OCD is complex and commonly misunderstood, with a limited number of treatment options. But in recent years, the mechanisms in the brain and body that drive it are finally being pinned down, revealing an elaborate picture involving genetics, various brain networks, the immune system and even the bacteria in our gut. In turn, this growing understanding is opening up new possibilities of tackling this life-sabotaging condition.

Around the world, between 1 and 3 per cent of people are estimated to have OCD, which typically begins during adolescence or early adulthood. As its name suggests, it is characterised by obsessions – or intrusive thoughts – and compulsions, which are habits you can’t stop. “Compulsive thoughts capture attention and take over because they’ve become a compulsive habit,” says Barbara Sahakian at the University of Cambridge.

OCD symptoms

The obsessions are unwanted ideas, images or impulses that dominate people’s thoughts and defy efforts to control them. They typically involve themes of danger or harm, such as excessive fears about contamination, an extreme concern with order and symmetry or worries about losing important things.

Compulsions can take many forms: excessive washing, lock checking or superstitious behaviours like touching an object a certain number of times to prevent something bad happening. “The symptoms are very disabling and unpleasant,” says Trevor Robbins, also at the University of Cambridge.

I have witnessed the physical manifestation of my daughter’s thought process on a loop in her repeated hand-washing – yet the intrusive thoughts aren’t silenced by soap and water or reassurance that thoughts are just thoughts.

This highlights one of the problems with our understanding of OCD, because obsessive thoughts and compulsive actions are part of everyday life, to some degree. We go back to check that we did indeed lock the front door, and can’t stop our mind wandering to the stressful event coming up next week. Indeed, many symptoms of OCD represent distortions of useful behaviours or defence mechanisms – such as avoiding contaminated substances or checking that a fire is out – intended to ensure safety.

But when obsessive thoughts become frequent or intense, or compulsive rituals become so prominent that they interfere with an individual’s functioning, that is when a diagnosis of OCD is made. In severe cases, people may not be able to leave their home, as they are performing their rituals for as long as 12 hours a day, says Robbins.

Currently, the front-line treatment for OCD is a specialised form of cognitive behavioural therapy (CBT) called exposure and response prevention, in which the individual is gradually exposed to situations that trigger them and learns ways to cope with their distress. Drugs called selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression and anxiety, can also be used. But around a third of people with OCD don’t respond to these, so the hunt is on for alternatives.

OCD causes

One line of enquiry that researchers have pursued since the 1990s is to try to understand the brain mechanisms that drive OCD. An increasingly clear picture is emerging of its underlying circuitry. This research has highlighted the importance of certain neuronal networks that help prioritise information and decide which bits we should act on. Known as frontostriatal loops, these connect the front of the outermost part of the brain, the cortex, with an inner region called the striatum (see OCD brain networks, below).

One of these loops is related to goal-directed behaviour, where we deliberately weigh up information and decide on certain actions to achieve a particular objective. Another is involved with our habit system, where we carry out actions automatically. There is constant interplay between these systems, with the goal-directed network able to inhibit the habit ones.

Going back to check a lock repeatedly is a common symptom of OCD

Both systems can be impaired in OCD, says Naomi Fineberg at the University of Hertfordshire, UK. “There’s poor inhibitory control.” For instance, under-connectivity in the goal-directed loop and hyper-connectivity in the habit network are both associated with stronger OCD symptoms.

A third loop acts as a control circuit that arbitrates between the goal-directed and habit systems and allocates control “This mainly enables flexible switching between the goal-directed and the habit system,” says Robbins. “If this system is impaired, which also appears to be the case in OCD, then you will have a scenario where it is difficult to disengage from the habit system, leading to repetitive behaviour, which may be a driver of compulsive behaviour.”

The importance of this arbitration loop was highlighted earlier this year in a study by Jun Soo Kwon at Seoul National University, South Korea, and his colleagues, in which people with and without OCD had their brains scanned while carrying out cognitive tests. The researchers found that reduced connectivity in the brain network involved with arbitration was linked to the severity of compulsive symptoms.

Another piece of the puzzle of OCD in the brain is the role of the neurotransmitters that drive and direct the activity in neural networks. A major leap forward in our understanding of this came last year in a study that looked at the levels of two key neurotransmitters in the brains of people with and without OCD: glutamate, an “excitatory” neurotransmitter that enhances communication between neurons, and GABA, which dampens it.

Using a powerful scanning technique, Marjan Biria, who is now at University College London, Robbins and their colleagues focused on two specific brain regions: the anterior cingulate cortex and the supplementary motor area, which are both involved in controlling the balance between conscious goals and more automatic habits. They found that people with OCD had higher levels of glutamate and lower levels of GABA in the anterior cingulate cortex, compared with people who don’t have the condition.

The study also found that the severity of OCD symptoms and a tendency towards compulsive behaviour were related to higher glutamate levels in the supplementary motor area. The dominance of excitatory neurotransmitters in these regions may make them hyperactive, which, in turn, allows compulsive behaviour to dominate.

These findings lend weight to a surprising alternative view of OCD that has emerged over the past decade. The traditional explanation for the condition is that obsessive thoughts drive compulsive rituals, which are carried out to control or reduce distress. The alternative hypothesis turns this on its head: the idea is that obsessions may arise as a post-hoc rationalisation of compulsive behaviour. In other words, compulsive habits may be the driver of the irrational beliefs and worries, not the other way round.

Compulsive thoughts take over because they have become a compulsive habit

Crucial evidence for this came from a 2014 study in which participants with and without OCD were trained to develop new habits in the lab. To avoid getting a shock to their wrist, they pressed a pedal when they saw a square on a computer screen. Later, the shocker was disconnected from their wrist, so there was no longer a need to press the pedal to avoid pain. Strikingly, those with OCD – but not those without – continued to press on the pedal when they saw the square, even though they said they knew it could no longer harm them.

When questioned about their persistence in pressing the pedal, some volunteers with OCD invented explanations for their behaviour such as “I thought it could still shock me somehow” even though they earlier said that they knew they wouldn’t be hurt. One rationale for this disconnect is that when we carry out an action that no longer makes sense, our brains can invent a story that makes our behaviour seem more logical.

This still begs the question of why some people are more prone to OCD than others. Here, too, the underlying factors are becoming clearer. We have long known that genetics plays a strong part, because OCD tends to run in families, with the immediate relatives of affected individuals having a four to eight times higher risk of developing the condition.

In fact, half of the risk of developing OCD is down to our genes. A paper from March that has yet to be peer-reviewed pinpoints some of the finer details. This examined the genomes of nearly 40,000 people with OCD and identified 15 genetic signatures associated with the condition, including ones for proteins that influence brain function and development. Intriguingly, one of the other signatures identified was associated with the genes for the major histocompatibility complex, a region of DNA that plays an important role in the immune system and has also been linked to other mental health conditions such as schizophrenia and bipolar disorder.

This finding fits with a growing body of evidence that the immune system is one of the factors driving OCD. It seems to have this effect by influencing certain brain networks that, in turn, enhance compulsive behaviours. A case in point is two related conditions called PANS and PANDAS in which children can suddenly develop OCD symptoms, anxiety or tics seemingly in response to infection.

The immune system and OCD

“In PANS/PANDAS, severe OCD symptoms can present within hours and from nowhere,” says Fulvio D’Acquisto at the University of Roehampton, London. It appears that an immune reaction may cause inflammation and impair a brain region heavily implicated in OCD called the basal ganglia, of which the striatum is part.

Further support for the role of the immune system in OCD comes from the 2023 discovery by a team of researchers, including D’Acquisto, that people with the condition have increased activity levels in a gene for a protein produced by immune cells called immuno-moodulin, or Imood.

D’Acquisto and his colleagues had found this protein by chance a few years earlier while working on mice that exhibited high levels of compulsive digging, and discovered that this behaviour was linked to high levels of Imood. Their soon-to-be published research will set out a proposed mechanism for the protein’s effect: an infection leads to temporary increases in Imood, which then accumulates in the brain, altering the functioning of neuronal cells, says D’Acquisto.

What’s more, antibodies against Imood reduce the compulsive behaviours in mice, raising the possibility that they might work in humans too. Efforts to develop a human version of the Imood antibody are currently under way, with the aim of testing them as potential new treatments for OCD.

But this is just one of many avenues being explored in the hunt for new ways to tackle the condition. These include brain stimulation techniques, phone apps and even changes to diet, as there is emerging evidence that gut microbes play a part in the condition too (see Do microbes cause OCD?, below).

New medications

One of the many new ideas is to use ketamine. This anaesthetic and rave drug causes feelings of disassociation, and is undergoing a surprising conversion to being used to treat brain and mental health conditions. For instance, a randomised controlled trial carried out by Carolyn Rodriguez at Stanford University in California and her colleagues found that taking ketamine resulted in a rapid improvement in OCD symptoms. In a study due to be published soon, the researchers found that a single intravenous infusion relieves symptoms for about three weeks. Rodriguez is now exploring the biochemical mechanisms through which this drug works.

However, the addictive nature of ketamine and its side effects mean it is no magic bullet. “These things give me pause. I’m not advocating people with OCD rush to use ketamine,” says Rodriguez, who is a strong proponent of CBT treatment for OCD. To use an analogy, if a person broke their arm, they would need a cast to support it in recovery, she says. “I think of CBT as the plaster cast and ketamine, in the short term, to alleviate pain while doctors cast the break.”

The psychedelic drug psilocybin is in clinical trials for treating OCD

Ketamine is thought to work because it increases neuroplasticity – the brain’s ability to remodel itself – and, in so doing, it loosens the characteristically rigid thinking that accompanies OCD and makes those with the condition more receptive to CBT.

For similar reasons, the psychedelic drug psilocybin – the active ingredient in magic mushrooms – is also in clinical trials for OCD in the UK and the US. In the body, it is converted into a molecule that binds to a specific receptor in the brain for the neurotransmitter serotonin, so it can act in similar ways to SSRIs and, in turn, may help unstick thought patterns. “If you boost serotonin, it makes you more flexible,” says Robbins.

We are also seeking fresh treatments by looking at existing drugs designed to treat other mental health conditions, especially those that work on the brain’s glutamate pathways, which we now know are implicated in OCD. A case in point is the drug riluzole, approved by the US Food and Drug Administration (FDA) to treat motor neuron disease. Early studies found it helpful in treating OCD that is resistant to treatment with SSRIs and CBT.

A patient undergoing transcranial magnetic stimulation, which can help alleviate OCD

Now, the pharmaceutical company Biohaven is working to develop a related drug, troriluzole, with fewer side effects. It is in a phase III trial in humans and is, according to Rodriguez, “the closest we’ve been since the 1990s to a new FDA-approved drug” for OCD.

New treatments are sorely needed because, for the 10 per cent of people with severe OCD whose symptoms don’t respond to CBT or SSRIs, invasive surgical procedures are currently the main alternative. These include anterior cingulotomy, when a permanent lesion is made in area deep in the brain involved with OCD behaviours. Alternatively, deep brain stimulation (DBS), where thin electrodes are inserted into this part of the brain to deliver electrical currents, is a less permanent way to mimic these lesions and disrupt information flow.

Brain stimulation

Around two-thirds of people receiving DBS for OCD see a marked reduction in symptoms. However, it is a last-resort treatment as it is invasive and comes with risks such as infection, seizures or bleeding. But this may change if a newly developed non-surgical technique to stimulate neural activity deep in the brain called transcranial temporal interference stimulation (TTIS) proves to be a viable alternative. In this, electrodes attached to the scalp deliver signals at different frequencies to a particular deep brain region.

When these signals interfere with each other, they alter neural activity. A randomised trial in May found this technique could selectively target the striatum.

Meanwhile, a number of other non-invasive techniques to alter the neural pathways in outer parts of the brain – through magnetic or electrical stimulation – are becoming increasingly common, with the first such device approved by the FDA for OCD in 2017.

Just like for TTIS, these devices are composed of electrodes or electromagnetic coils that are placed on top of the skull. The effect – felt as a buzz – can be tailored to the brain circuitry of the individual, something that can be done with ever greater precision now that we have a clearer understanding of the brain networks associated with OCD symptoms.

A 2023 meta-analysis of 25 trials of so-called transcranial magnetic stimulation (TMS) found that it “exhibited a moderate therapeutic effect… on OCD symptom severity”. The effects are small, says Fineberg, but it has value “perhaps in helping to loosen the brain up so you can do your CBT”.

However, Robbins is more optimistic about the potential of TMS, especially since studies are under way to establish the best brain areas to target and the optimum doses for alleviation of symptoms. “The exciting thing about TMS is that it adjusts the so-called excitatory/inhibitory balance in the cortex, which we’ve recently shown is affected in OCD,” he says.

The upshot of all these investigations into the mechanisms underlying OCD is that, in future, clinicians should have some much-needed new tools to treat this distressing and sometimes intractable condition. “OCD is not a neurodegenerative disease where you’re losing the brain,” says Robbins. “It’s just that the brain has been modulated – it’s not in the right state. I think it could be made to function better.” Rodriguez is also optimistic for the future. “I’m so hopeful for the patients I have now for when they are older,” she says. “The technology is coming on in leaps and bounds.”

When I ask my daughter what she thinks about these new possibilities she, too, is hopeful. “Knowing there may be things within my reach that can ease OCD symptoms is really helpful,” she says. “It makes me feel more in control.”

Do microbes cause OCD?

Evidence is mounting that the microbes in our gut play an important role in mental health conditions, and new research is revealing that this is the case for obsessive-compulsive disorder too.

Key evidence comes from a study published this year, in which a team at Shanghai Jiao Tong University, China, transplanted faecal gut microbiota from humans with OCD into mice. Two weeks later, the mice began to exhibit repetitive behaviours and signs of anxiety compared with animals that didn’t receive a transplant. The researchers also found inflammation in a key brain area implicated in OCD called the medial prefrontal cortex, probably due to the accumulation of a substance called succinic acid driven by the proliferation of transplanted microbes.

This not only indicates that gut microbes might be a causative factor in OCD, but opens up potential routes to treating the condition through diet or manipulation of the types of microbes in our digestive system.