The role of the opioid pathway in schizophrenia and bipolar I disorder
Psychiatry has spent decades focused on dopamine, serotonin, norepinephrine, and glutamate. These key neurotransmitters – known to regulate mood, behaviour, and bodily functions – have served as the foundation for diagnostic frameworks, development of treatments, and education of generations of clinicians. Psychiatrists have been taught to view mental illness almost exclusively through the lens of these systems.
However, the opioid pathway, a heavily studied physiologic pathway inextricably intertwined with behaviour and reward, rarely receives attention within psychiatric practice. Although the opioid system is primarily associated with substance misuse and overdose, its role in psychiatry is much broader and includes effects on serious mental illness (SMI).
It is widely accepted that μ-, κ- and δ-opioid receptors regulate appetite, impulsivity, reward, stress responsivity, metabolic signals, and dopamine release itself. All of these are highly relevant to the symptomology and comorbidities that complicate SMI. Nevertheless, when clinicians think about schizophrenia or bipolar I disorder (BD-I), they rarely think about these receptors. Now, real-world clinical experience is helping the field better understand the role of these systems and the impact they have on the patient experience.
Opioid pathways in SMI
The role of the opioid system in schizophrenia has been demonstrated in the literature for several decades. Findings, such as reduced μ-opioid receptor availability and increased κ-opioid receptor activity in people living with this complex condition, show up consistently in the literature. These receptors are closely tied to dopamine regulation, so when κ activation increases, there are downstream effects on dysphoria, stress sensitivity, and dopamine release itself. Clinically, this maps onto what is seen every day in clinical practice among schizophrenia patients: high rates of alcohol use disorder (AUD) (roughly one-third of patients), non-suicidal self-injury in as many as 44%, gambling problems in about a third, and risky sexual behaviour in nearly 40%. Opioid use disorder is also far more common in this patient population than is typically acknowledged, with some studies reporting rates close to 50%.
In BD-I, the opioid system is similarly relevant. Research suggests a bidirectional relationship where mood disorders can increase vulnerability to opioid misuse, while opioid exposure may worsen or precipitate mood symptoms, including mania. The literature shows that abnormalities in μ-, κ- and δ-opioid receptors can influence impulsivity, reward-driven behaviour, and mood instability – areas that are profoundly altered in BD-I. The epidemiology reflects this biology: about 70% of patients live with AUD, more than half engage in some form of self-harm, nearly half report risky sexual behaviour, and many struggle with gambling or opioid use.
These comorbidities are common in schizophrenia and BD-I, yet, they remain absent from standard conversations about the neurobiology of these conditions. Nevertheless, when interpreted through the lens of opioid-mediated reward, stress, and impulse regulation, many commonly observed clinical patterns can be understood within a more coherent biologic framework.
This broader understanding of the role of the opioid system in SMI has also led to the development of additional treatment options.
Treatment approaches that engage the opioid pathway
Olanzapine has long been one of the most effective antipsychotics for the treatment of schizophrenia or BD-I, but side effects, including weight gain and metabolic impacts, have limited its use over time. Samidorphan, a μ-opioid receptor antagonist, was designed to help mitigate some of the weight and metabolic impacts of olanzapine alone. LYBALVI (olanzapine and samidorphan) is a once-daily, oral atypical antipsychotic that combines olanzapine and samidorphan. LYBALVI is approved to treat schizophrenia in adults. It is also used to treat manic or mixed episodes that happen with bipolar I disorder, either alone for short-term (acute) or maintenance treatment, or in combination with valproate or lithium.
In the FDA pivotal trial data on LYBALVI, the most common reported change after switching from olanzapine to the combination was decreased appetite. From a clinical perspective, this suggested that patients may experience appetite, reward, and intake differently when opioid-receptor modulation is part of treatment. While the exact mechanism of action is unclear, the pharmacology of samidorphan further reinforces this – the molecule has approximately five-times greater affinity for the μ-opioid receptor and 30-times greater affinity for the δ-opioid receptor compared to other commonly used opioid receptor antagonists. It also produces substantial μ-receptor blockade, so an individual would require far more opioid exposure for comparable receptor activation than if no antagonist were on board.
Real-world studies have also shown that patients living with schizophrenia or BD-I taking olanzapine/samidorphan tend to have fewer emergency room (ER) visits, fewer hospitalisations and shorter in-patient stays compared with patients taking other oral atypical antipsychotics or olanzapine alone. These findings do not establish causation, but they align with clinical observations that the combination may address several factors known to drive acute care utilisation, including metabolic burden, impulsive or compulsive behaviours, urges, self-injury, addictive patterns, risky sexual behaviour, and gambling – all behaviours heavily influenced by opioid-receptor signalling. These behaviours frequently underlie psychiatric crises and ER presentations, so any treatment approach that engages this biology is clinically meaningful.
I’ve had many representative cases showing how the opioid pathway intersects with real-world risks in schizophrenia and BD-I. For example, two of my patients were 21-year-old college students living with BD-I. Neither had a pattern of regular substance use. One was stable on olanzapine 5 mg whereas the other was stable on olanzapine/samidorphan 5 mg/10 mg. They attended the same party where fentanyl was unknowingly laced into the drugs they both took. The patient receiving olanzapine died of an accidental opioid overdose, while the patient receiving olanzapine/samidorphan survived.
This case is not presented as evidence of treatment effect, but rather to present how the opioid pathway plays a significant and often under-recognised role in the symptoms, behaviours, and vulnerabilities seen in people living with schizophrenia and BD-I. It is my humble opinion that incorporating opioid-receptor antagonism, such as olanzapine/samidorphan, may be relevant when considering the risks and vulnerabilities associated with accidental opioid exposure.
Reframing SMI through the opioid pathway
Psychiatry is at a point where we can no longer ignore the broader biology driving the complexity of schizophrenia and BD-I. The opioid system is tied to reward processing, stress responsivity, self-injury, urges, cravings, and impulsivity; therefore, opioid-receptor signalling may play a meaningful role in the symptoms and comorbidities that shape the course of these diseases. Leaving this system out of the conversation leaves the neurobiologic model for these disorders incomplete.
The opioid pathway explains why many destabilising behaviours associated with schizophrenia and BD-I fall outside traditional dopamine- or serotonin-based frameworks. For clinicians, it provides a physiologic context for the urges, compulsive behaviours, and episodic substance use that complicate care. For researchers, it highlights the importance of studying how μ-, κ- and δ-receptor activity interact with symptoms and comorbidities that drive outcomes. And for educators, it underscores that psychosis and mood instability are only part of the story that providers should understand. Patients deserve a clinical understanding that reflects the complexity of their lived experience and the opioid pathway needs to be part of that discussion.
About the author
Dr Richard L. Price is a psychiatrist in Monsey, New York and is affiliated with multiple hospitals in the area, including New York-Presbyterian Hospital-Columbia and Cornell and Montefiore Mount Vernon Hospital. He received his medical degree from Lewis Katz School of Medicine at Temple University and has been in practice for more than 20 years. Dr Price has expertise in treating bipolar disorder, depression, anxiety disorders, among other conditions.
