I’m Sorcha, a PhD student at Imperial College London leading the PsilOCD study – which explores the use of a low dose of psilocybin to treat obsessive-compulsive disorder (OCD). Psilocybin is a naturally occurring psychedelic compound found in several species of mushroom, eliciting gentle emotional and perceptual changes at the dose we’re administering. As well as assessing clinical symptoms, we’re studying an array of different outcomes related to OCD’s specific cognitive features, which I'm going to talk about in this article.
OCD: Driven By Anxiety or Cognitive Deficits?
Characterised by anxiety-inducing thoughts (‘obsessions’) and mental or physical attempts to quell the anxiety they generate (‘compulsions’), OCD has traditionally been viewed as an anxiety-spectrum disorder. Neurobiologically, anxiety is at the crux of OCD, evident in overactivity of the amygdala (a brain region strongly involved in fear processing), and the comorbidity between OCD and other anxiety conditions is undeniable. Although its manifestation can range from contamination-centric worries to concerns about harming others, patients always fear specific thoughts, feelings, and outcomes.
But recently, research has shifted towards focusing on OCD’s cognitive underpinnings, which might represent more influenceable – and therefore targetable – elements of the condition.
Cognitive Inflexibility: Entrenched Thought Patterns & Perspectives
The main cognitive deficit seen in OCD is cognitive inflexibility, the decreased ability to adapt and switch between different tasks, strategies, or perspectives. While anxiety naturally makes attention more rigid, patients also display this deficit in psychological tasks.
A subdomain of cognitive flexibility is ‘set-shifting’, describing the ability to shift focus between different ‘sets’ of stimuli. OCD patients score notably poorly, accompanied by reduced connectivity between two involved brain regions. OCD patients’ unaffected relatives also score poorly in set-shifting tasks– pointing to it as a potential inherent genetic trait or ‘endophenotype’.
Reversal learning - the ability to modify behavioural strategies following feedback – is also affected. It is subserved by the orbitofrontal cortex (OFC), one of the core brain regions affected in OCD. Patients display prominent deficits, reflected in abnormal activity in the lateral OFC that is also seen in their unaffected relatives.
Compulsions Prevail: A Tendency to Form Habits
Another cognitive hallmark of OCD is the dominance of the brain’s habit-formation system. Although compulsions are habit-like, patients are also prone to developing compulsive habits in generic tasks. The habit theory of OCD is neurobiologically plausible – goal-directed control relies upon two key brain regions affected in OCD: the caudate nucleus and medial orbitofrontal cortex.
One study reported abnormally high activation of the caudate nucleus in OCD patients during habit learning, which correlated significantly with their urge to perform these behaviours. The OCD brain may be less efficient at starting and maintaining purposeful ‘goal-driven’ actions, allowing habitual compulsive behaviours to prevail.
Decreased Confidence Hinders Decision-Making
The third core cognitive feature seen in OCD is decreased confidence, concerning not only the individual’s specific fears, but also their performance in unrelated tasks. They exhibit lowered confidence across diverse cognitive areas like memory, perception, and action. Naturally, this disparity between competence and confidence hinders decision-making; by causing them to seek unnecessary additional information, it raises their decision-making threshold.
Can Psychotherapy Treat the Cognitive Features of OCD?
Exposure Response Prevention (ERP) is the gold-standard intervention for OCD, granting about 60% of patients significant symptom reduction. Participants expose themselves to their triggering thoughts, symptoms, and situations, while ‘accepting’ their feared outcomes and refraining from performing compulsions.
Effective ERP represents active ‘re-learning’: it tests and ultimately disproves the brain's irrational hypotheses (the outcomes it believes will transpire if compulsions are not performed). Only then can 'fear extinction’ occur, involving part of the prefrontal cortex receiving contextual ‘safety’ signals, and, in turn, inhibiting the amygdala’s fear response.
Interestingly, ERP’s effectiveness may be attributable to its ability to improve confidence. One group of researchers suggest that invasive deep-brain stimulation (DBS) works by increasing self-confidence, and ERP seems to do this under normal circumstances. When successful, it weakens dysfunctional beliefs, as well as normalising patients’ excessive feelings of responsibility and confidence in their memory.
During ERP, the patient temporarily dares to ‘test’ whether negative outcomes can occur. The brain generates prediction errors when they don’t, prompting it to reappraise previously feared thoughts, sensations, and outcomes as unthreatening and/or irrelevant. Initial discomfort is always part of ERP; the amygdala needs to be ‘online’ for the cortex to start suppressing it, and compulsions – mental or physical – preclude this process.
Do Established Medications Treat OCD’s Cognitive Features?
Viewing OCD through a cognitive framework sheds light on why current pharmacotherapy is less effective than ERP. The most widely prescribed medications for OCD are serotonin reuptake inhibitors (SSRIs), which enhance synaptic serotonin concentrations. This increases serotonin’s effects on its receptors, including those involved in OCD.
However, only 40-60% of patients respond adequately. SSRIs are often viewed as tools to dampen anxiety, but serotonin is a highly multifaceted neurotransmitter with roles far beyond emotion regulation. Serotonin seems to aid reversal learning, with one study finding medicated patients to change strategies more nimbly. But, SSRIs can also blunt cognition – with chronic use potentially impairing reversal learning in healthy humans.
SSRIs might not precisely or reliably target OCD’s cognitive features, potentially explaining their modest efficacy.
New Directions for OCD Pharmacotherapy
The newest wave of exploratory pharmaceuticals mainly act on glutamate, the brain’s major excitatory neurotransmitter – which is dysregulated in OCD. Biohaven Ltd. is conducting research on a glutamate-modulating drug called troriluzole. And another glutamatergic drug, topiramate, can be helpful for compulsions– but may also induce OCD-like symptoms.
Ketamine, a short-acting anesthetic, blocks the activity of glutamate across the brain and causes various nuanced downstream effects. It can improve performance in set-shifting and reversal-learning tasks in animal studies, but its impact on human OCD symptoms is less clear. One study deemed it ineffective for OCD while another reported immediate symptom improvements.
Another possible candidate to target OCD’s cognitive features is psilocybin, which we’re exploring in PsilOCD. Psilocybin has shown promise in treating various psychiatric conditions and a small 2006 study reported low-moderate doses to be safe and effective for OCD. It primarily interacts with 5HT2A serotonin receptors, enriched in the cortex. This temporarily weakens the brain’s entrenched models of the world, priming it to revise them in line with incoming information.
Collectively, psilocybin’s brain effects highlight it as a potential tool to support ERP– potentially by tapping into OCD’s cognitive aspects. By making beliefs temporarily more malleable, psilocybin could facilitate the neural process by which patients’ confidence is increased – possibly via enhancements in cognitive flexibility.