Tag: psychosis

Negative symptoms of schizophrenia remain one of the toughest challenges in treatment

These symptoms often include:
🔹 Decreased motivation (avolition)
🔹 Blunted or flat affect
🔹 Reduced emotional range
🔹 Paucity of speech (alogia)

Unlike positive symptoms, negative symptoms respond poorly to antipsychotic medications—even clozapine, our most effective agent for treatment-resistant illness, offers limited relief.

These deficits are often chronic, functionally disabling, and deeply impact quality of life.

Tackling negative symptoms will be the next frontier in improving long-term outcomes in schizophrenia. We need innovative approaches, novel mechanisms, and more research focused on this under-addressed domain.

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Substance-Induced Psychosis vs. Primary Psychosis: Treatment, Prognosis, and the Cannabis Connection

Psychosis can emerge from a range of causes, but distinguishing between substance-induced psychosis (SIP) and primary psychotic disorders like schizophrenia is critical for effective treatment and prognosis. While the clinical presentation often overlaps—hallucinations, delusions, disorganized thinking—the underlying etiology, treatment approach, and long-term outcomes can diverge significantly.

Defining the Two

Substance-Induced Psychosis (SIP) occurs when symptoms of psychosis are directly caused by intoxication with or withdrawal from substances such as cannabis, amphetamines, alcohol, hallucinogens, or synthetic cannabinoids (e.g., spice or K2). The psychosis typically emerges during or shortly after substance use and resolves with abstinence.

Primary Psychosis, on the other hand, refers to psychotic disorders that are not directly attributable to substances or medical conditions. This includes schizophrenia, schizoaffective disorder, and brief psychotic disorder, among others.

Treatment: Overlapping Tools, Different Emphasis

1. Acute Management
Both SIP and primary psychosis are often treated with antipsychotic medications during acute episodes. The initial goals are the same: reduce agitation, manage delusions or hallucinations, and ensure safety.

  • Commonly used antipsychotics include risperidone, olanzapine, haloperidol, and quetiapine. In SIP, short-term use is typically sufficient.
  • In cases involving severe agitation or aggression, benzodiazepines (like lorazepam) may be used adjunctively, especially if stimulant intoxication is suspected.

2. Long-Term Strategy

  • SIP: After stabilization, the primary strategy is abstinence from the offending substance and psychosocial support (e.g., CBT, motivational interviewing, relapse prevention).
  • Primary psychosis: Typically requires ongoing antipsychotic treatment, often for life. Psychosocial interventions, supported employment, and cognitive remediation are also central to recovery.

Conversion to Schizophrenia: What’s the Risk?

One of the key concerns with SIP is whether the episode is a harbinger of an underlying primary psychotic disorder.

  • Approximately 20–50% of individuals with substance-induced psychosis later develop a primary psychotic disorder, such as schizophrenia.
  • Amphetamine- and cannabis-induced psychosis carry the highest risk of conversion, particularly when psychosis occurs in adolescence or early adulthood.
  • A meta-analysis by Niemi-Pynttäri et al. (2013) found that 46% of people with SIP later developed schizophrenia-spectrum disorders over a follow-up of 8 years.

Predictors of conversion include:

  • Younger age at first psychotic episode
  • Family history of psychotic illness
  • Persistent psychotic symptoms after substance clearance
  • Poor premorbid functioning

Do Antipsychotics Work in SIP?

Antipsychotics reduce acute psychotic symptoms in SIP, but their long-term utility is less clear.

  • Studies show rapid resolution of psychosis within days to weeks in most SIP cases when abstinence is achieved.
  • Long-term antipsychotic treatment does not reduce the conversion rate to schizophrenia in confirmed SIP, suggesting their role should be time-limited unless ongoing symptoms or risk factors emerge.
  • A 2020 review in Psychological Medicine emphasized that monitoring over the 6–12 months post-episode is essential for risk stratification and avoiding premature chronic medication exposure.

Cannabis: A Powerful Catalyst

Cannabis has become the most studied and most controversial substance linked to psychosis. Here’s what the evidence says:

  • Daily cannabis users are 3–5 times more likely to develop a psychotic disorder compared to non-users, especially with high-THC strains (≥10% THC).
  • A 2019 Lancet Psychiatry study by Di Forti et al. showed that strong cannabis use accounts for 12% of new psychosis cases in Amsterdam, and 30% in London.
  • Adolescents who use cannabis, particularly those with a family history of psychosis, are at dramatically increased risk.

Mechanistically, THC may dysregulate the dopamine system in vulnerable brains, tipping the balance toward psychosis. Cannabidiol (CBD), in contrast, may be protective, but commercial cannabis typically contains very little CBD.

Final Thought: Clinicians must balance vigilance and restraint—treating psychosis aggressively when needed but also avoiding unnecessary chronic antipsychotic exposure in what may be a reversible, substance-driven episode.

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ARISE Study Phase 3 Results: Understanding Xanomeline’s Setback

What Was the ARISE Study?

The ARISE trial was a Phase 3 clinical study evaluating Cobenfy — a combination of xanomeline (a muscarinic receptor agonist) and trospium chloride (a peripheral anticholinergic) — as an adjunctive treatment for adults with schizophrenia who continued to experience symptoms despite taking an atypical antipsychotic.

What Is a Primary Endpoint, and Why Does It Matter?

In clinical trials, the primary endpoint is the most important outcome researchers are trying to affect — it’s how a drug’s success or failure is officially judged.
In ARISE, the primary endpoint measured the change in symptom severity compared to placebo using a standardized scale for schizophrenia. Meeting this endpoint would have demonstrated clear, statistically significant symptom improvement attributable to Cobenfy.

The Outcome: No Statistically Significant Benefit

According to topline results, Cobenfy did not show a statistically significant improvement compared to placebo when added to atypical antipsychotics. This means the observed difference could have been due to chance and did not meet the pre-set threshold for success.

However, Cobenfy did show a numerical improvement â€” the group receiving the drug combination performed betterthan placebo in symptom reduction, just not to a statistically convincing degree.

Could Anticholinergic Effects Be to Blame?

One possible explanation for this outcome lies in the mechanism of action of both Cobenfy and many commonly used atypical antipsychotics.

  • Xanomeline is designed to activate muscarinic receptors in the brain (specifically M1 and M4), which may help regulate dopamine and reduce psychosis.
  • But many atypical antipsychotics — like olanzapine, clozapine, and quetiapine — also have anticholinergic properties, meaning they block these same receptors.

This sets up a pharmacological tug-of-war: Cobenfy tries to stimulate muscarinic activity, while the background antipsychotic may be dampening it. This conflict could blunt the therapeutic signal, explaining why the benefit didn’t reach statistical significance.

What This Means for the Future

The failure to meet the primary endpoint is a setback, but not the end of the road. The numerical improvements suggest a potential signal, and with refined trial design — perhaps using background medications with lower anticholinergic load — future studies may better reveal Cobenfy’s potential.

Additionally, this trial underscores the importance of considering mechanism compatibility in combination therapies. It’s not just about adding drugs — it’s about how they interact at the receptor level.

Conclusion

While the ARISE study didn’t deliver the result many hoped for, it raised critical questions that will shape future research. A deeper understanding of anticholinergic burden, drug synergy, and precision pharmacology is essential as we continue the search for more effective treatments for schizophrenia.

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🌿 CBD for Psychosis? A Landmark Trial is Underway 🧠

A major new study—the Stratification and Treatment in Early Psychosis (STEP) trial—is set to investigate CBD as a potential treatment for psychosis on a larger scale than ever before. Led by Philip McGuire, MD, professor of psychiatry at Oxford University, STEP will involve 1,000 participants across 30 sites in 10 countries đźŚŤ, making it one of the most ambitious trials of its kind.

🔬 Why it matters:
âś… CBD has shown promise in early studies for psychosis, but large-scale evidence is needed.
âś… STEP will combine three smaller trials to explore effectiveness, biomarkers, and precision treatment approaches.
âś… Nature Medicine named it one of 11 studies that will shape medicine in 2025.

🚀 Could CBD redefine psychosis treatment? The results could change the landscape of psychiatric care. Stay tuned!

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🔍 Suicide & Psychosis: What We Can Learn from Recent Research

A new study sheds light on suicide risk in patients with psychotic disorders, comparing those with recent-onset schizophrenia or other psychotic disorders to those with longer illness duration. The findings offer critical insights for clinicians and mental health professionals.

🚨 Key Takeaways:

đź“Ś Early Illness = Higher Risk: Patients within the first five years of their illness had higher suicide rates, emphasizing the need for intensive early intervention.

đź“Ś Common Risk Factors: Across both groups, depression, prior suicide attempts, and substance use were major red flags.

đź“Ś Different Patterns: Those with recent-onset psychosis were more likely to have rapid illness progression, while those with longer illness duration often had chronic distress and social isolation before suicide.

đź“Ś Missed Opportunities? Many had recent healthcare encounters before suicide, highlighting potential gaps in risk assessment and intervention.

🛑 What This Means for Us:
🔹 Early-phase psychosis care should prioritize suicide prevention.
🔹 Screening for depression, substance use, and prior attempts is essential.
🔹 More proactive intervention is needed, especially after hospital visits.

This study reinforces what many frontline clinicians already suspect—suicide prevention in psychosis requires urgent, tailored strategies. How can we improve early detection and support for at-risk patients? Let’s discuss. 👇

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What HAPPENED to Ulotaront The TAAR-1 Agonist for Schizophrenia?

Back in 2019, during my residency, TAAR-1 agonists were hailed as the future of schizophrenia treatment, generating a wave of excitement and high expectations. Fast forward to 2025, and the once-prominent buzz has all but vanished. What happened to this promising class of drugs that once seemed poised to revolutionize the field?

Ulotaront, an investigational antipsychotic developed by Sumitomo Pharma and Otsuka Pharmaceutical, has recently encountered significant challenges in its clinical development. In July 2023, the drug failed to meet primary endpoints in two Phase III clinical trials aimed at treating acutely psychotic adults with schizophrenia. These studies did not demonstrate a statistically significant improvement over placebo, raising concerns about ulotaront’s efficacy in this patient population.

Given these setbacks, the timeline for ulotaront’s potential approval by the U.S. Food and Drug Administration (FDA) is now uncertain.Consequently, any previous projections for FDA approval will likely be delayed as the developers reassess their clinical strategy.

It’s important to note that ulotaront had previously received Breakthrough Therapy Designation from the FDA in 2019 for the treatment of schizophrenia, reflecting initial optimism about its therapeutic potential.

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Buprenorphine and Psychosis: Unraveling the Risks of Abrupt Discontinuation

This post is inspired by a real case from my practice involving a patient with no significant past psychiatric history but a strong history of substance use, including opioids and cocaine. The patient had been on buprenorphine maintenance therapy for several decades, providing stability in their recovery. However, following an abrupt discontinuation of buprenorphine, the patient developed acute psychotic symptoms. This case highlights an uncommon but important phenomenon clinicians should be aware of when managing buprenorphine discontinuation, especially in individuals with a history of substance use.

Emerging evidence suggests that abrupt discontinuation of buprenorphine may induce psychosis in some individuals, though this appears to be a relatively uncommon occurrence.

Documented Cases

  • New-onset psychotic symptoms have been reported after sudden cessation of buprenorphine in patients with no prior psychosis.
  • Common symptoms include auditory hallucinations, paranoid ideation, and delusions of reference.
  • Psychotic symptoms typically emerge within days to weeks after discontinuation.

Potential Mechanisms

  1. Loss of buprenorphine’s antipsychotic effects through kappa-opioid receptor antagonism.
  2. Interaction between neurobiological vulnerabilities and the stress of withdrawal.
  3. Possible unmasking of latent psychotic disorders.

Risk Factors

  • History of substance use.
  • Early adverse life events.
  • Underlying psychiatric conditions (e.g., bipolar disorder).

Outcomes and Management

  • Symptoms may resolve in weeks to months, though some cases persist longer.
  • Reintroduction of buprenorphine has led to symptom remission in some cases, suggesting a causal relationship.
  • Gradual tapering of buprenorphine might mitigate this risk, though more research is needed.

Clinical Implications

Clinicians should remain vigilant when discontinuing buprenorphine, especially in individuals with risk factors for psychosis. A gradual tapering strategy is recommended to reduce potential risks, though further studies are necessary to guide best practices.

Understanding this phenomenon highlights the importance of individualized care when managing buprenorphine discontinuation in vulnerable populations.

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Clozapine: Unlocking Relief for Negative Symptoms in Schizophrenia

Clozapine has been studied extensively in schizophrenia, particularly for treatment-resistant cases. Its role in managing negative symptoms (e.g., apathy, alogia, anhedonia, social withdrawal) has been investigated in various randomized controlled trials (RCTs).

RCT Evidence for Clozapine in Negative Symptoms

  1. Clozapine vs. Typical Antipsychotics
    • Several studies have shown clozapine’s superiority over first-generation antipsychotics (FGAs) like haloperidol in reducing negative symptoms.
    • Example: A landmark RCT (Kane et al., 1988) demonstrated that clozapine not only reduced positive symptoms but also had beneficial effects on negative symptoms, potentially due to its unique pharmacology (e.g., serotonin-dopamine antagonism, NMDA receptor modulation).
  2. Clozapine vs. Other Atypical Antipsychotics
    • Mixed Results: Some RCTs suggest that clozapine is more effective than other atypical antipsychotics (e.g., risperidone or olanzapine) in improving negative symptoms, while others show no significant difference.
    • A meta-analysis of head-to-head RCTs found that while clozapine had modest effects on negative symptoms, differences between it and other atypicals were small.
  3. Clozapine in Primary Negative Symptoms
    • Challenges: True primary negative symptoms (not secondary to positive symptoms, sedation, or depression) are challenging to isolate in trials.
    • Some RCTs highlight that clozapine’s effects on negative symptoms might be indirect, mediated by improvements in positive symptoms, cognitive function, or overall social functioning.
  4. Adjunctive Therapies
    • RCTs combining clozapine with adjuncts like antidepressants (e.g., fluvoxamine) or cognitive enhancers (e.g., aripiprazole, NMDA modulators) have been conducted. While adjunctive strategies show promise, the evidence remains preliminary and inconsistent.

Potential Mechanism

Clozapine’s effects on negative symptoms may be attributed to:

  • Serotonin-Dopamine Antagonism: Improved dopamine transmission in the mesocortical pathway.
  • Glutamatergic Modulation: Effects on NMDA and AMPA receptors.
  • Anti-inflammatory Properties: Reduced neuroinflammation may play a role in symptom improvement.
  • Sedation Reduction: Lower propensity for extrapyramidal side effects compared to FGAs.

Limitations of Evidence

  • Heterogeneity: Most RCTs mix patients with primary and secondary negative symptoms, confounding results.
  • Measurement Challenges: The assessment of negative symptoms in trials is often subjective and prone to bias.
  • Indirect Effects: Improvements may stem from reductions in positive symptoms or cognitive enhancements rather than direct action on negative symptoms.

Key Takeaway

Clozapine shows some benefit for negative symptoms, particularly when compared to FGAs and in cases with secondary negative symptoms. However, its effects on primary negative symptoms are modest, and it is generally not considered the first-line choice for this domain of schizophrenia. Adjunctive approaches or newer agents might offer additional promise.

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Abrupt Discontinuation of Buprenorphine and Risk of Psychosis: Clinical Considerations

This post is inspired by a real case from my practice involving a patient with no significant past psychiatric history but a strong history of substance use, including opioids and cocaine. The patient had been on buprenorphine maintenance therapy for several decades, providing stability in their recovery. However, following an abrupt discontinuation of buprenorphine, the patient developed acute psychotic symptoms. This case highlights an uncommon but important phenomenon clinicians should be aware of when managing buprenorphine discontinuation, especially in individuals with a history of substance use.

Emerging evidence suggests that abrupt discontinuation of buprenorphine may induce psychosis in some individuals, though this appears to be a relatively uncommon occurrence. Here are the key findings:

Documented Cases

  • New-onset psychotic symptoms have been reported after sudden cessation of buprenorphine in patients with no prior psychosis.
  • Common symptoms include auditory hallucinations, paranoid ideation, and delusions of reference.
  • Psychotic symptoms typically emerge within days to weeks after discontinuation.

Potential Mechanisms

  1. Loss of buprenorphine’s antipsychotic effects through kappa-opioid receptor antagonism.
  2. Interaction between neurobiological vulnerabilities and the stress of withdrawal.
  3. Possible unmasking of latent psychotic disorders.

Risk Factors

  • History of substance use.
  • Early adverse life events.
  • Underlying psychiatric conditions (e.g., bipolar disorder).

Outcomes and Management

  • Symptoms may resolve in weeks to months, though some cases persist longer.
  • Reintroduction of buprenorphine has led to symptom remission in some cases, suggesting a causal relationship.
  • Gradual tapering of buprenorphine might mitigate this risk, though more research is needed.

Clinical Implications

Clinicians should remain vigilant when discontinuing buprenorphine, especially in individuals with risk factors for psychosis. A gradual tapering strategy is recommended to reduce potential risks, though further studies are necessary to guide best practices.

Understanding this phenomenon highlights the importance of individualized care when managing buprenorphine discontinuation in vulnerable populations.

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Family Ties That Bind: When High Expressed Emotion Worsens Schizophrenia

In psychiatry we are always asking patients about social support. The presence or absence of social support can have a major impact on treatment response and ability to remain well once someone leaves the hospital. This usually includes support from family members and friends. 

In 1956 the Medical Research Council Social Psychiatry (MRCSP) London conducted a study regarding the readmission of schizophrenic patients. The research revealed that patients who were stabilized symptomatically and functionally inpatient and subsequently discharged to live with their parents or wives were frequently readmitted for relapse of symptoms compared to those who were discharged to a sibling, or non-family environment. While family involvement is generally a protective factor that helps prevent things like suicide, there are some situations where the over involvement of family can complicate matters and even create worse outcomes.

This usually occurs when a family has high expressed emotion. 

Expressed emotion (EE) has consistently been shown to predict relapse in schizophrenia as well as other psychiatric disorders. Expressed emotion is a measure of the family environment that is based on how the relatives of a psychiatric patient spontaneously talk about the patient. 

It measures 3 aspects of the family environment associated with high expressed emotion:

  1. Hostility (outward anger and frustration towards the patient because the family believes they are choosing to not get better) 
  2. Emotional over-involvement (This is where the family tries to solve all the problems for the patient taking away their ability to be self-reliant). 
  3. Critical comments (where the family views the mentally ill patient as lazy or selfish, not appreciating the difficulty of living with mental illness). 

However, research has shown the following as indications of an environment with low expressed emotion: 

1.    Positivity: (statements that express appreciation or support for the patient’s behavior and gives verbal and nonverbal reinforcement). 

2.    Warmth: (kindness, concern and empathy expressed by the caregiver).

There is such a thing as too much involvement on the part of the families which can lead to complicating family dynamics and exacerbation of an individual’s symptoms of mental illness. Interventions for improving outcomes include reducing contact with high EE caregivers and providing psychoeducation about EE to care givers. Bringing awareness to this behavior may help family members change. 

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