We’ve all seen it: PTSD that won’t budge. Patients try sertraline or paroxetine—the so-called “gold standards”—and walk away with little more than side effects and a sense of failure.
Enter a new contender: brexpiprazole + sertraline.
A recent Phase 3 randomized controlled trial might finally offer something real for those stuck in the PTSD trenches.
🚨 The Results
In a study across 86 sites with over 550 adults, adding brexpiprazole (2–3 mg) to sertraline (150 mg) led to a 5.6-point greater reduction on the CAPS‑5 (the gold-standard PTSD measure) compared to sertraline + placebo. That’s not a marginal win—it’s a clinically significant shift, especially in a treatment-resistant population.
Responder rates tell the story even clearer:
68.5% of patients on the combo had ≥30% reduction in symptoms
Compared to 48.2% on sertraline alone
That’s a +20% absolute response rate boost
And the improvements weren’t just short-lived. Benefits held through 12 weeks, even during a post-treatment observation period. No relapse, no rebound—just stability.
🧩 More Than Symptom Checklists
It wasn’t just about PTSD symptoms. This combo also:
Improved psychosocial functioning (B-IPF scores)
Reduced anxiety and depression (HADS)
Lowered global illness severity (CGI-S)
Helped with all symptom clusters, including reexperiencing, avoidance, and hyperarousal
That’s rare. Most meds in psychiatry hit one or two domains and leave the rest hanging. This one made a dent where it counts: function, resilience, and real-world relief.
⚠️ What About Side Effects?
Brexpiprazole is still an atypical antipsychotic, so there’s baggage. But the trial data suggest it’s relatively well-tolerated:
Fatigue: 6.8%
Weight gain: 5.9%
Somnolence: 5.4%
Discontinuation due to AEs? Just 3.9%, vs 10.2% in placebo.
No new safety signals. No psychosis worsening. Not perfect, but not the metabolic disaster zone we see with other agents.
🚀 What’s Next?
The FDA is reviewing this combo
For those of us treating chronic PTSD, this may be a real tool—not just a shiny new molecule with good marketing.
Until then, it’s worth paying attention. Because when sertraline alone doesn’t cut it—and we know it often doesn’t—this combo could offer a lifeline.
🧠💡 CBT Confirmed—Again: Landmark Meta-Analysis Reinforces Clinical Value Across Diagnoses A massive meta-analysis in JAMA Psychiatry (2025) reaffirms what many of us observe in day-to-day care: Cognitive Behavioral Therapy (CBT) is one of the most effective, versatile, and enduring treatments for adult psychiatric conditions.
🔬 Study at a Glance
Pooled data from hundreds of RCTs
Assessed CBT’s efficacy across depression, anxiety disorders, PTSD, and eating disorders
Found significant, lasting effects across diagnostic categories
Highlighted condition-specific variation in effect sizes, but overall CBT consistently outperformed inactive controls
📚 Real-World Relevance Imagine a patient with chronic panic disorder who’s failed two SSRI trials and prefers non-pharmacologic interventions. CBT remains a frontline solution—equally relevant for the young adult with bulimia or the veteran with PTSD. These aren’t just data points—they’re the cases we see every day.
🔄 How Does CBT Stack Up Against Other Therapies? While the study primarily focused on CBT, it reinforces existing literature suggesting that CBT often matches or outperforms alternative modalities like psychodynamic therapy or interpersonal therapy in short-term efficacy—especially when structure, time-limited treatment, and measurable goals are critical.
🛠 Implications for Clinical Practice ✅ Why prioritize CBT?
It’s highly adaptable
Supported across diverse populations
Scalable via group therapy, digital tools, and telehealth
🚧 Barriers to Access:
Limited availability of trained therapists
Insurance coverage gaps
Patient preference for “talk therapy” without structure
✅ Strategies to Overcome Them:
Integrate CBT-informed principles into brief med management visits
Refer to digital CBT platforms when face-to-face access is limited
Advocate for reimbursement parity and expanded training programs
📎 Bottom Line This study isn’t just academic—it’s a call to action. Prioritizing CBT in treatment planning can lead to better outcomes, broader reach, and more durable recovery. As clinicians, it’s on us to ensure our systems support its accessibility.
Research into the therapeutic potential of cannabis for mental health disorders has grown in recent years, with mixed findings from randomized controlled trials (RCTs).
Anxiety Disorders
CBD (Cannabidiol) has shown promise in reducing anxiety symptoms in RCTs, particularly for social anxiety disorder (SAD). For instance, a small RCT found that a single dose of 300 mg of CBD reduced anxiety levels in participants undergoing a simulated public speaking test.
Some RCTs suggest that CBD may be anxiolytic without causing impairment or euphoria, making it preferable for anxiety compared to THC-dominant cannabis products, which may exacerbate anxiety in some users.
Post-Traumatic Stress Disorder (PTSD)
RCTs exploring THC and CBD combinations in PTSD have had mixed outcomes. Some studies indicate that THC may reduce nightmares and improve sleep in PTSD patients, though these findings are generally based on small sample sizes and short-term trials.
A recent RCT with a synthetic cannabinoid (nabilone) reported some symptom improvement in PTSD-related insomnia and nightmares. However, larger trials with longer follow-ups are necessary to clarify the efficacy and safety for PTSD.
Depression
Few RCTs show consistent evidence supporting cannabis (CBD or THC) as an effective treatment for major depressive disorder. Some trials indicate that CBD may have antidepressant-like effects, possibly due to serotonin receptor activity, but more robust and long-term studies are needed.
Concerns persist over THC’s potential to exacerbate depressive symptoms, particularly with regular or heavy use.
Schizophrenia and Psychotic Disorders
THC-dominant products have been associated with increased risk of psychosis and exacerbation of symptoms in people predisposed to psychotic disorders. This has led to caution against THC use in people with schizophrenia.
CBD has shown promise as an adjunctive treatment in some RCTs, with findings suggesting that it may have antipsychotic effects without the psychoactive effects of THC. For example, an RCT found that CBD reduced psychotic symptoms and improved cognitive function when added to standard antipsychotic treatment, though the effects were modest.
Bipolar Disorder
Evidence from RCTs on the use of cannabis in bipolar disorder is sparse and generally negative. Some trials indicate that THC may worsen manic and depressive symptoms in bipolar patients, and there is little to no support for cannabis as a treatment for bipolar depression.
Sleep Disorders
Some RCTs have evaluated cannabinoids for sleep disturbances, with CBD showing potential for improving sleep quality. However, THC may reduce REM sleep, which could impact sleep architecture negatively over time.
For PTSD-related insomnia, cannabinoids like nabilone have shown some benefit, but the effects on sleep in general populations remain uncertain.
Limitations
Sample Sizes and Duration: Many RCTs are small and short-term, limiting the generalizability and understanding of long-term effects.
Dosing and Formulations: Variability in cannabinoid content (THC vs. CBD), formulations (edibles, oils, vapes), and dosages across studies makes comparison challenging.
Side Effects: Both CBD and THC can have side effects, though THC’s psychoactive properties can lead to cognitive impairment, addiction potential, and negative impact on mood in some patients.
While CBD shows some promise in anxiety, PTSD, and psychotic disorders, RCT evidence for other mental health conditions remains inconclusive or even negative, especially with THC. Further large-scale, long-term RCTs are needed to establish the efficacy and safety profile of cannabis-based treatments in mental health.
The use of hydrocortisone and propranolol in the prevention of post-traumatic stress disorder (PTSD) has been explored in several randomized controlled trials (RCTs). We always want to know does it work or is it just another interesting idea with little evidence to support its use
Hydrocortisone:
Hydrocortisone, a corticosteroid, has been investigated for its potential to modulate the stress response and prevent the consolidation of traumatic memories, which is thought to contribute to the development of PTSD.
Mechanism: Hydrocortisone works by increasing cortisol levels, which can suppress the stress-induced overactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol may reduce memory consolidation of trauma, thus decreasing PTSD risk.
RCT Evidence:
Schelling et al. (2004) conducted a study on patients in the ICU, where hydrocortisone was used to treat septic shock. They found that patients who received hydrocortisone had a significantly lower risk of developing PTSD symptoms at follow-up compared to the placebo group. This suggested that hydrocortisone might have a protective effect in stress-related conditions.
Survivors of trauma: In a study by Zohar et al. (2011), trauma patients who received hydrocortisone in the immediate aftermath of the traumatic event had lower rates of PTSD symptoms compared to those who received placebo. The results suggested that hydrocortisone may reduce PTSD incidence when administered shortly after trauma exposure.
Critically ill patients:Schelling et al. (2001) showed that administering hydrocortisone to critically ill patients in the ICU reduced PTSD symptoms at follow-up, supporting the idea that early cortisol intervention can modulate the long-term psychological impact of traumatic experiences.
Summary: Hydrocortisone has shown promise in reducing PTSD symptoms when administered during or soon after traumatic experiences, particularly in ICU patients or survivors of trauma. Its role appears to be in modulating the stress response and memory consolidation processes.
Propranolol:
Propranolol, a beta-blocker, is primarily used to treat cardiovascular conditions but has been studied for its effects on memory reconsolidation and emotional arousal, both of which are implicated in the development of PTSD.
Mechanism: Propranolol reduces adrenergic activity by blocking beta-adrenergic receptors, potentially interfering with the emotional enhancement of traumatic memories, thus reducing their consolidation.
RCT Evidence:
Pitman et al. (2002) conducted a double-blind, placebo-controlled trial in which trauma victims (e.g., car accident survivors) were given propranolol or placebo within a few hours of the event. At follow-up, patients who received propranolol had reduced PTSD symptoms compared to those given placebo, though the results were not statistically significant.
Brunet et al. (2008) performed a study on individuals with PTSD, where propranolol was administered before memory reactivation (i.e., recalling the traumatic event). The group that received propranolol showed reduced physiological responses to trauma reminders and decreased emotional impact, suggesting that propranolol may weaken the reconsolidation of traumatic memories.
Stein et al. (2007) did not find a significant reduction in PTSD incidence when propranolol was administered following trauma. This led to mixed conclusions regarding its preventive efficacy.
Summary: The evidence for propranolol is more mixed. While some studies suggest it may reduce PTSD symptoms by weakening emotional memory consolidation, other trials have not demonstrated a significant reduction in PTSD development.
Conclusion:
Hydrocortisone has more consistent evidence supporting its role in preventing PTSD, particularly when administered soon after trauma.
Propranolol shows mixed results, with some evidence suggesting it may reduce emotional memory consolidation and PTSD symptoms, though its effectiveness in preventing PTSD development is less conclusive.
Both treatments hold potential, but more research is needed to establish their routine use in PTSD prevention.
The evidence for the use of prazosin in major depressive disorder (MDD) comes mainly from smaller studies or trials focusing on its off-label use, as prazosin is primarily an alpha-1 adrenergic antagonist used to treat hypertension and PTSD-related nightmares.
Clinical Rationale
The theoretical rationale for prazosin in MDD is based on its ability to block alpha-1 adrenergic receptors, which may help reduce the hyperactivity of the norepinephrine system—a pathway implicated in stress and depression.
Randomized Controlled Trials (RCTs)
RCT evidence for prazosin in treating MDD is limited compared to other antidepressants, but a few studies have explored its potential benefits:
Prazosin as Adjunctive Treatment for MDD (2009): A small pilot RCT assessed prazosin as an add-on therapy for MDD in patients who were already on standard antidepressants. The results showed modest improvements in depressive symptoms when prazosin was combined with SSRIs or SNRIs, particularly in patients with high anxiety or sleep disturbances.
Prazosin for PTSD and MDD Comorbidity: Some RCTs conducted in patients with PTSD (a condition often comorbid with MDD) showed improvements in both PTSD and depressive symptoms. For example, a trial published in 2015 demonstrated that prazosin led to a significant reduction in depressive symptoms in veterans with PTSD and depression. While the trial primarily focused on PTSD, the secondary outcomes regarding depression were positive.
Prazosin and Treatment-Resistant Depression (TRD): Some trials have explored prazosin’s efficacy in treatment-resistant forms of depression, hypothesizing that its ability to reduce stress-related symptoms could augment antidepressant efficacy. However, these trials have generally been small, and results have been inconsistent or not statistically significant in terms of primary depressive outcomes.
Limitations
Sample Sizes: Most studies are small and underpowered.
Population: Most studies have focused on patients with PTSD, rather than pure MDD.
Adjunctive Use: Prazosin has mostly been tested as an adjunctive treatment, not as monotherapy for depression.
While prazosin has shown some promise in improving depressive symptoms, particularly related to sleep disturbances and anxiety, larger RCTs specifically targeting MDD are needed to establish its efficacy.
It’s obvious to me, but I think the public, including many of our patients, remains unaware of a crucial truth: Psychedelics will not cure your depression, your PTSD, or your difficult life circumstances.
There’s a growing wave of enthusiasm around psychedelics as miracle cures for mental health conditions, but the hard reality is that the evidence just doesn’t back it up—at least not yet. Even if you find yourself on the hopeful side, believing we desperately need alternatives to alleviate people’s suffering, the reported benefits of these substances have not been validated by large, rigorous, randomized controlled trials. The buzz around psychedelics often overshadows the fact that they lack the necessary scientific backing to support their mainstream use in treating complex mental health issues like depression or PTSD.
Let’s not ignore the financial stakes here either: The people promoting these drugs stand to make billions of dollars. There’s a lot of money on the table, and many in the academic community are rallying behind these companies. But we should ask ourselves—are they doing so because of solid science or because of the potential financial windfall?
These drugs have been around for decades, yet one consistent truth I’ve observed in every person I’ve known who’s used them is this: You must use them repeatedly, and they almost always experience a relapse of symptoms over time. There’s no permanent fix here, just a temporary reprieve, if even that.
We can draw parallels with other treatments like ECT (electroconvulsive therapy) and ketamine. Both have shown promise in certain cases, but I’ve yet to see anyone cured by these treatments. We often perform maintenance ECT and maintenance ketamine therapy for this very reason. Just like psychedelics, they might offer temporary relief, but they don’t provide long-term solutions without ongoing interventions.
I understand this may come off as cynical, but I’ve seen too many people fall for the hype, only to be disappointed later. People far more charismatic than me will try to convince you that psychedelics will cure everything that ails you—for a hefty price tag. Don’t buy into it without questioning the science and the motives behind the push.
An advocacy group has proposed changing the name of post-traumatic stress disorder (PTSD) to post-traumatic stress injury (PTSI) for inclusion in the DSM-5 TR. However, in November 2023, the APA steering committee rejected the proposal, citing insufficient evidence to support the change. Advocates argue that the term “disorder” is both imprecise and carries stigma, which can discourage people from seeking timely care. This delay or avoidance of care can lead to serious consequences, including suicide attempts. The term “disorder” has long been controversial in psychiatry, and I’ve always favored the use of “disease” to help distinguish between true disease processes and challenges of living. I also believe that people may be more likely to seek help if they view the issue as a disease or injury. While this change may not happen soon, maintaining open dialogue about how to encourage treatment is essential.
Since the start of the COVID-19 pandemic, countless studies have explored its impact on mental health. From both the research and my clinical experience, one thing is clear: the pandemic took a toll on people’s mental well-being.
A study published in JAMA Psychiatry dug deeper into this by asking, “How does mental health differ between vaccinated and unvaccinated people who were diagnosed with COVID-19?” The results? Conditions like depression, anxiety, PTSD, addiction, and even self-harm and suicide spiked in the weeks following a COVID-19 diagnosis. Interestingly, the vaccinated group showed lower rates of these issues, while those hospitalized for COVID-19 had longer-lasting struggles with mental health.
The takeaway is clear: getting vaccinated not only protects against the virus but may also reduce the mental health impact of a COVID-19 infection. It’s crucial to continue promoting vaccination, especially among those with pre-existing mental health conditions who are at higher risk.
The FDA’s decision to reject MDMA (methylenedioxymethamphetamine) for medical use typically stems from various concerns related to safety, efficacy, and potential for abuse.
Background
MDMA is primarily known as a recreational drug, often associated with rave and party scenes. However, it has been studied for its potential therapeutic benefits, particularly in the treatment of post-traumatic stress disorder (PTSD) and other mental health conditions.
Safety Concerns
Neurotoxicity: Research has shown that MDMA can be neurotoxic, causing damage to serotonin-producing neurons in the brain. This can lead to long-term cognitive deficits, including memory problems and mood disorders.
Cardiovascular Risks: MDMA increases heart rate and blood pressure, which can pose significant risks to individuals with underlying heart conditions. The stimulant effect can lead to hyperthermia (overheating) and dehydration.
Acute Toxicity: Overdose can lead to severe hyperthermia, serotonin syndrome, and even death. The narrow therapeutic window between a therapeutic dose and a toxic dose is a significant concern.
Efficacy Concerns
Clinical Trial Results: While there have been promising results in some clinical trials, the FDA requires extensive, well-controlled studies to confirm a drug’s efficacy. If trials do not meet these rigorous standards, the FDA may not approve the drug.
Long-term Benefits: The long-term efficacy of MDMA therapy is still uncertain. While short-term benefits have been observed, there is a need for more data on the sustainability of these effects.
Potential for Abuse and Addiction
Recreational Use: MDMA is widely used recreationally, which increases the potential for misuse and addiction. The FDA must consider the risk of the drug being diverted for non-medical use.
Dependence: There is evidence that regular use of MDMA can lead to psychological dependence, and managing this risk is crucial in the context of medical approval.
Regulatory and Ethical Considerations
Ethical Concerns: The use of a psychoactive substance in a therapeutic setting raises ethical questions, particularly regarding informed consent and the management of potential adverse effects.
Regulatory Framework: The FDA has stringent requirements for approving new medications, including ensuring that benefits outweigh risks. For a drug like MDMA, where the risks are significant, the bar for approval is high.
Conclusion
The FDA panel recently rejected the use of MDMA-assisted psychotherapy for treating PTSD, marking a significant setback for advocates of this treatment approach. The advisory committee, in a vote of 9-2, concluded that the current evidence does not support the effectiveness of MDMA in treating PTSD. Additionally, they voted 10-1 against the benefits of MDMA therapy outweighing its risks.
Several key concerns led to this decision. Firstly, issues were raised about the integrity and validity of the clinical trials conducted by Lykos Therapeutics, including potential biases, functional unblinding, and allegations of misconduct. The panel also highlighted gaps in the data, particularly regarding the potential for abuse and adverse cardiovascular events associated with MDMA.
Despite the panel’s recommendation, the FDA is not obligated to follow their advice, though it often does. The outcome has disappointed many proponents of MDMA-assisted therapy, who argue that the treatment could provide much-needed relief for PTSD patients who have not benefited from existing therapies.
The entactogen MDMA overlaps with the chemical structure of methamphetamine and mescaline and has biological effects similar to epinephrine, dopamine, and serotonin.
It increases the release of monoamines through the reversal of transporter proteins and reuptake inhibition specifically serotonin and norepinephrine. Not only does it block reuptake of serotonin and norepinephrine it enhances the release as well and inhibits VMAT preventing the packaging of monoamines into vesicles making more available for release. It also modulates glucocorticoids through the HPA axis, decreases amygdala and hippocampal activity, increases oxytocin, and increase prefrontal cortex activity.
Medical Use
MDMA started out as a therapeutic agent to enhance blood clotting for surgical procedures and trauma. Turns out it does not work very well for that indication, who would have thought. It’s currently listed as a schedule I substance (defined as having no accepted medical use, high abuse potential, and lack of accepted safety).
It was later discovered to have “empathogenic effects” helping individuals who use the medication to feel more connected to their fellow human beings. After all isn’t that what we are all after? A deep connection to others and people who truly understand us. The original name for the drug was empathy, but that has changed over the years to molly and escstcy. Personally, I like names that describe what a drug does, and empathy or empath is just so much more marketable don’t you think?
Why PTSD is a Big Problem
With several recent wars in both Iraq and Afghanistan, America has a PTSD problem with many combat veterans returning home and requiring treatment. If you ever treated patients with PTSD than you know it’s difficult and the therapy can be intense. Many patients are unable to sit with the discomfort required to reconsolidate these memories. Having worked at the VA for one year I was surprised by the number of vets with non-combat related PTSD. Honestly, they the vast majority of my cases were people who had accidents while working or in training and subsequently developed PTSD.
The idea is we need methods to enhance the efficacy and speed of trauma focused psychotherapies. What better way to do that than with empathy a medication that enhances feelings of connection. The basic idea being the patient would be given MDMA and then undergo psychotherapy and by using the medication it can influence fear extinction and memory reconsolidation. There are many mechanisms at play including effects on dopamine, serotonin, BDNF, cortisol, and oxytocin.
The concept of using a psychedelic drug to enhance the effects of psychotherapy is not a new concept, and was done for years using LSD and other compounds. What is different now, is we are trying to put the scientific rigor behind the studies to prove that it works better than placebo, and to learn more about the mechanism of action.
I want to point out that the main benefit of all these psychedelic medications seems to be enhanced neuroplasticity and the ability to form new connections in critical neurocircuits much easier than would otherwise be possible.
Benefits of MDMA Assisted Psychotherapy
-Increase blood flow to the vmPFC decreasing activation of the amygdala largely responsible for the fear response
-Enhance the production of BDNF which improves the long-term potentiation and memory consolidation
-Elevate the stress hormone cortisol which interacts with glucocorticoid receptors in the hippocampus to improve memory
-Elevates the prosocial neuropeptide oxytocin which decreases activation of the amygdala and enhances connection with the therapist
-Increased levels of dopamine which can destabilize the old memories and help with reconsolidation of new ones
-Increased serotonin levels resulting in prosocial and positive affective states.
The goal of PTSD treatment is to prevent the patient from being held hostage by these memories. We want to destabilize the old memories, modify them, and reconsolidate the new memories. The trauma still occurred, but the patient no longer has the same fear reaction to the traumatic memories.
MDMA-Assisted Therapy proved to be highly effective in individuals with severe PTSD.
-In this study investigators gave patients with PTSD 120-180 mg of MDMA along with a trauma focused psychotherapy. There were significant rates of both response and remission compared to placebo.
-MDMA was well tolerated
-It was granted breakthrough status by the FDA
-This was a big deal in the news and media outlets
-It needs to be replicated to confirm the results
Potential Adverse Effects of MDMA
-Potential for abuse and diversion (probably no take homes)
-Possible hyperthermia or hyponatremia (more common in the recreational use environment than clinical)
-People often engage in prolonged physical activity in hot environments and do not consume enough water this results in dehydration and possible hyperthermia (think large dance party)
-In the opposite case the person overcompensates and overconsumes water diluting their blood and causing hyponatremia. Excess of anything can cause problems and water is no exception.
Blue Monday and Black Tuesday
-Use of MDMA can cause low mood, irritability, and fatigue. It can occur for days after recreational use.
-In the clinical setting, fatigue, anxiety, low mood, headaches, and nausea can occur in the week after treatment
