The recent JAMA Psychiatry study, Emergency Department Visits Involving Hallucinogen Use and Risk of Schizophrenia Spectrum Disorder, explored a notable increase in emergency department (ED) visits related to hallucinogen use, with a focus on potential links to the onset of schizophrenia spectrum disorders.
Key Findings:
Rise in Hallucinogen-Related ED Visits:
The number of ED visits due to hallucinogens, including LSD, psilocybin, and MDMA, has significantly risen, particularly among younger populations. This aligns with changing perceptions of these substances in some parts of society.
Connection to Schizophrenia Spectrum Disorders:
Individuals who presented at EDs for hallucinogen-related issues were found to have a higher risk of later developing schizophrenia spectrum disorders. The study suggests a potential association between hallucinogen use and triggering or exacerbating underlying psychiatric vulnerabilities.
Demographic Insights:
The rise in hallucinogen use and related health complications appears to disproportionately affect young adults and men. These groups may face greater risks due to higher consumption rates and potential genetic predispositions to mental health disorders.
Clinical Implications:
Emergency physicians and mental health professionals are encouraged to screen for hallucinogen use during ED visits, particularly in individuals showing early signs of psychosis. Early identification and intervention may help mitigate long-term mental health outcomes.
This study emphasizes the importance of public health strategies addressing hallucinogen use, including education on potential risks and the establishment of protocols to identify and treat associated psychiatric conditions.
In my practice, I see many patients who have been on high doses of antipsychotics for extended periods, particularly first-generation antipsychotics, which carry a higher risk of developing tardive dyskinesia (TD). While two FDA-approved treatments for TD exist, their high cost and limited availability can make access challenging in community mental health settings. This has led me to explore alternative treatments like amantadine. Like many of you, I wanted to understand the evidence supporting its use, so let’s take a closer look at what the research says about amantadine as a treatment option for TD.
The evidence for the use of amantadine in treating tardive dyskinesia (TD) has been explored in several small randomized controlled trials (RCTs), though it remains limited compared to other treatments.
Efficacy of Amantadine: Some studies suggest that amantadine, an NMDA receptor antagonist, may offer mild to moderate improvement in TD symptoms by modulating dopaminergic pathways. For instance, an early RCT (2007) tested amantadine in schizophrenia patients with TD and reported some improvements in abnormal involuntary movements compared to placebo. However, the sample size was small, and results were modest.
Comparative Effectiveness: Few trials directly compare amantadine to other TD treatments like VMAT-2 inhibitors (e.g., valbenazine, deutetrabenazine), which are the preferred treatment options due to stronger RCT evidence. Amantadine’s effects may be less pronounced, though some patients have reported partial symptom relief, especially when TD is not severe.
Safety Profile: In RCTs, amantadine is generally well-tolerated in TD patients, with few serious side effects. However, common side effects include dizziness, insomnia, and gastrointestinal issues, which may limit its use in certain patients, particularly those with cognitive or movement comorbidities.
Overall, while RCTs support some benefit of amantadine in TD, the effect size is generally moderate. VMAT-2 inhibitors are preferred based on stronger, more consistent RCT data, although amantadine may still be considered for patients who cannot tolerate or do not respond to these primary therapies.
This post comes from another real-world case that I frequently encounter in clinical practice. Self-injurious behavior (SIB) is common in the inpatient care setting and the strategies to prevent it are mostly behavioral. Many patients and families are also looking for pharmacological options. Here are some of the more common options and recommendations for treating SIB.
Behavioral Interventions
Functional Behavior Analysis (FBA): Start with an FBA to understand why the self-injury is occurring (e.g., to gain attention, avoid demands, or self-soothe). This guides intervention planning.
Positive Reinforcement and Skill Building: Reinforce alternative, adaptive behaviors that fulfill the same needs as self-injury, such as communication skills (e.g., teaching to request attention) or self-soothing techniques.
Cognitive Behavioral Therapy (CBT): For individuals able to engage in talk therapy, CBT can address underlying thoughts and emotions driving SIB, such as distress intolerance, perfectionism, or negative self-beliefs.
Dialectical Behavior Therapy (DBT): DBT is particularly effective for reducing SIB, especially in borderline personality disorder. It combines emotional regulation, mindfulness, and distress tolerance skills.
Environmental Modifications: Minimizing triggers in the individual’s environment can help reduce occurrences. This might include changes in routines, avoiding overstimulation, or modifying demands.
Applied Behavior Analysis (ABA): Techniques from ABA, like differential reinforcement of other behaviors (DRO) or non-contingent reinforcement (NCR), can reduce self-injury by decreasing its functional value.
Pharmacological Interventions
SSRIs (Selective Serotonin Reuptake Inhibitors): Useful if self-injury is driven by anxiety, depression, or obsessive-compulsive tendencies. SSRIs can help stabilize mood and reduce anxiety, lessening the need for SIB.
Antipsychotics: Atypical antipsychotics, such as risperidone or aripiprazole, are sometimes effective, particularly in autism spectrum disorders or severe intellectual disabilities. However, weigh these benefits against side effects, especially for long-term use.
Mood Stabilizers: Medications like lithium, lamotrigine, or valproate can help regulate mood fluctuations that contribute to SIB. Lithium, in particular, has shown effectiveness in reducing aggression and impulsivity.
Naltrexone: This opioid antagonist can be effective in cases where SIB is hypothesized to release endogenous opioids, providing a calming effect.
Beta-blockers (e.g., propranolol): In cases of high impulsivity or aggression linked to SIB, beta-blockers can reduce physiological arousal, lessening the drive for self-injury.
Clonidine or Guanfacine: These medications, which target the noradrenergic system, can help reduce impulsivity and aggression in patients with ADHD or autism, indirectly lowering self-injury.
Choosing the best approach depends on the individual’s specific triggers, co-occurring conditions, and underlying motivations for SIB. Integrating both behavioral and medication interventions, while monitoring closely for effectiveness and side effects, often yields the best outcomes.
People with ADHD have been shown to use cannabis at higher rates than those without ADHD. Studies indicate that adolescents and adults with ADHD are more likely to use cannabis, and they may start using it at a younger age. This may be due to self-medication attempts, as people with ADHD often report using cannabis to help with symptoms like impulsivity, anxiety, and sleep difficulties which seems like a bad idea to me but lets look at the reasons.
2. Cannabis as a Self-Medication Attempt
Some people with ADHD use cannabis in an attempt to self-manage their symptoms. Anecdotally, users report feeling more focused, relaxed, and less anxious, though the scientific evidence on cannabis’s effectiveness for ADHD symptom management is not robust. Studies show that while some ADHD symptoms like restlessness might feel alleviated short-term, long-term outcomes often do not show sustained benefit, and impairment can increase over time.
3. Impact on ADHD Symptoms
Research on cannabis’s effect on ADHD symptoms is mixed:
Impulsivity and Attention: Cannabis can impair attention, memory, and executive functioning, which are already areas of struggle for individuals with ADHD. Heavy cannabis use is associated with poorer performance on tasks measuring these cognitive domains.
Cognitive Function: Longitudinal studies have shown that chronic cannabis use can worsen cognitive functions over time, especially if use begins in adolescence. These cognitive impacts may compound ADHD-related deficits.
Motivation and Goal-Directed Behavior: Cannabis can affect motivation and goal-directed behavior, which can exacerbate some ADHD symptoms, particularly in individuals who already struggle with organization and task completion.
4. ADHD as a Risk Factor for Cannabis Use Disorder
Studies suggest that people with ADHD may be more prone to developing cannabis use disorder (CUD) compared to the general population. Traits like impulsivity and sensation-seeking, common in ADHD, may increase vulnerability to addiction. Additionally, the reinforcing effects of cannabis (e.g., reduction in perceived anxiety) may lead to increased use and dependency in those with ADHD.
5. Genetic and Neurobiological Factors
There is some evidence suggesting that the overlap between cannabis use and ADHD may have a genetic or neurobiological basis:
Genetic Overlap: Studies have found that genes linked to ADHD, particularly those affecting dopamine function, are also implicated in substance use disorders, including cannabis use disorder.
Endocannabinoid System: ADHD and cannabis use affect dopamine and endocannabinoid systems. Some research posits that dysregulation in these systems might underlie both the propensity for ADHD and substance use, but this remains an area for further research.
6. Cannabis and Medication Interactions
For those with ADHD taking stimulant medications, cannabis use can interfere with treatment. THC, the psychoactive component of cannabis, can interact with medications like methylphenidate or amphetamine-based treatments, potentially reducing their effectiveness or exacerbating side effects like anxiety and heart palpitations.
7. Longitudinal and Population Studies
Long-term studies generally show that early and heavy cannabis use is associated with worse outcomes for individuals with ADHD. These include lower academic achievement, increased rates of unemployment, and higher incidences of mental health issues, especially when cannabis use starts in adolescence.
Summary
While some people with ADHD report short-term symptom relief with cannabis, research shows that heavy, frequent use tends to worsen cognitive deficits associated with ADHD over time. Additionally, ADHD may predispose individuals to higher rates of cannabis use and a greater risk of developing cannabis use disorder. While cannabis might seem beneficial for symptom relief in the short term, its long-term use is generally not supported as an effective management strategy for ADHD.
This post comes from a recent discussion I had with my resident about the utility of splitting clozapine doses in a recent case we had.
The evidence on splitting clozapine into multiple daily doses primarily stems from clinical observations and smaller studies rather than extensive, randomized controlled trials (RCTs). Since clozapine has a unique pharmacodynamic and pharmacokinetic profile, standardizing an RCT on dose splitting has been challenging.
Clozapine’s Half-Life and Steady-State Concentration: Clozapine has a long half-life (averaging about 12 hours), meaning steady-state concentrations can be reached without strict multiple dosing. Many patients maintain stable blood levels with once-daily dosing, especially at lower doses.
Dose Splitting and Side Effects: Some smaller studies and clinical observations suggest that splitting doses can help reduce peak plasma levels of clozapine, which can be associated with side effects like sedation, hypotension, and dizziness. In these cases, a split dosing regimen may improve tolerability, particularly in patients who experience significant sedation or orthostatic hypotension with a single daily dose.
Metabolic Side Effects and Compliance: In cases where metabolic side effects are of concern, or in patients who may not tolerate high single doses well, dividing doses could help with tolerability, potentially improving compliance and minimizing adverse effects like sedation or metabolic impact.
Seizure Risk: High plasma peaks with a single large dose may theoretically increase the risk of seizures, especially in patients on higher doses of clozapine. Dividing doses is sometimes recommended as a preventive measure to maintain a more consistent blood level, although robust RCT data supporting this specific benefit is lacking.
While RCT evidence specifically on clozapine dose-splitting remains limited, clinical judgment, patient tolerance, and monitoring of therapeutic blood levels play essential roles in tailoring dose regimens.
This post comes from my real world experience with treating many patients with treatment resistant schizophrenia. I wanted to create a consolidated post that goes over what we know about the benefits of clozapine in schizophrenia treatment as well as what we do not know. Clozapine is unique among antipsychotics due to its superior efficacy in treatment-resistant schizophrenia (TRS), but whether it is disease-modifying remains debated.
1. Superior Long-term Outcomes in TRS
Reduced Relapse Rates: Clozapine has been shown to reduce relapse rates more effectively than other antipsychotics. For instance, a large cohort study found lower rates of rehospitalization for patients on clozapine compared to those on other second-generation antipsychotics (SGAs). The lower relapse rates may suggest stabilization of disease progression.
Cognitive Benefits: Several studies report improvements or stabilization in cognitive function in patients on clozapine, which contrasts with the cognitive decline often observed in schizophrenia. The preservation or improvement in cognitive function could indicate a modification of disease trajectory.
2. Impact on Mortality and Suicidality
Reduced Mortality: Long-term use of clozapine has been associated with lower mortality rates in schizophrenia, both due to reduced suicide risk and fewer overall medical complications compared to other antipsychotics.
Suicide Prevention: Clozapine is the only antipsychotic shown to significantly reduce suicidality in schizophrenia patients, which may point to broader effects on disease severity and progression.
3. Neurobiological Effects
Neuroprotection: Preclinical and human imaging studies suggest clozapine might have neuroprotective properties. Some animal models and neuroimaging studies indicate that clozapine can increase neurogenesis, reduce oxidative stress, and potentially protect against the neurodegeneration associated with chronic schizophrenia.
Synaptic Remodeling: There is some evidence that clozapine might positively influence synaptic plasticity. Studies suggest it might normalize the synaptic dysfunction seen in schizophrenia, which could theoretically have a disease-modifying effect by restoring some aspects of brain connectivity and function.
4. Delay in Onset of TRS
Intervention Timing: There is emerging evidence suggesting that earlier introduction of clozapine (when TRS is identified) might lead to better long-term functional outcomes. This hints that clozapine could modify the disease course if used earlier in resistant cases, though direct evidence of disease modification remains scarce.
5. Chronicity and Brain Volume Loss
Potential for Reduced Brain Volume Loss: Some studies indicate that clozapine may be associated with less gray matter loss over time compared to other antipsychotics. This could imply a reduction in the neuroprogressive aspects of schizophrenia.
Limitations in Evidence
While clozapine shows many positive outcomes, definitive evidence proving it is “disease-modifying” remains elusive:
Lack of RCTs Focused on Disease Modification: Most clinical trials focus on symptomatic improvement rather than long-term neurobiological changes or functional outcomes.
Challenges in Measuring Disease Progression: Schizophrenia is a complex, heterogeneous disorder with no clear biomarkers for progression, making it difficult to measure whether clozapine alters the underlying disease process.
In summary, while there is compelling evidence that clozapine leads to better long-term outcomes and may have neuroprotective effects, proving it as a true disease-modifying treatment in schizophrenia requires more robust, long-term studies focused specifically on changes in the disease course.
The olanzapine fluoxetine combination was FDA approved in 2003 for the treatment of depressive episodes in bipolar I disorder. In 2009 it was granted approval for treatment resistant depression.
This medication consists of the atypical dopamine blocking medication olanzapine and the SSRI fluoxetine. Many people consider olanzapine to be the best antipsychotic not named clozapine (see my video on the best antipsychotic in the world). This comes from the CATIE study where olanzapine proved to be superior to other medications. It has good efficacy, once daily dosing at night, and low risk for cardiac conduction abnormalities (QTc prolongation). However, the side effects including risk for weight gain and metabolic complications have made it a second line option.
My residents often jump to this medication on the inpatient unit, but I usually tell them to use caution because of the side effects and should it not be effective, it leaves you with clozapine as the next option in terms of effectiveness.
Fluoxetine is an antidepressant that has been around a long time with a broad spectrum of indications. It’s long track record and safety profile makes it a go to antidepressant in both the adult and child adolescent populations. Its main disadvantage is drug interactions.
Dosing
People often think you can make this medication by simply combining olanzapine and fluoxetine and do not believe you need to use the brand name combination pills. I would use some caution with that approach.
When we look at the doses in the combination pill, they are ones that are difficult to make with the current available dosages. For example, olanzapine comes in 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and finally 20 mg doses.
The fixed-combination capsule (olanzapine/fluoxetine) comes in 3/25 mg, 6/25 mg, 12/25 mg, 6/50 mg, 12/50 mg. The studies leading to approval of this medication were conducted using these doses in a fixed combination. It’s not clear that dosing each individually is effective.
How to Start the Medication
For bipolar depression the olanzapine fluoxetine combination should be started at 6/25 mg dosed at bedtime. With a target dose of 6-12/25-50 mg depending on clinical response.
Labs prior to starting the medication:
You should have a baseline weight, waist circumference, blood pressure, fasting glucose and lipid profile prior to starting the medication
Cost
The combination pill is more expensive than either medication alone. According to Good Rx The 6/25 mg capsule is $140-$150 per month. This is compared to olanzapine 5 mg which costs $9.00 and fluoxetine 20 mg which costs $4.00
Side Effects
Olanzapine: Most common is somnolence (dose related), dry mouth (dose related), constipation (anticholinergic), weight gain (up to 40% incidence and 10-30 lbs. of weight gain is common), increased appetite, EPS (dose related).
Fluoxetine: Nausea, diarrhea, nervousness, abnormal dreams, weight loss, sweating, tremor, sexual side effects, rash, and headaches. Rare increased risk for bleeding when combined with NSAIDs and hyponatremia in the elderly due to SIADH.
Mechanism of action
Olanzapine: Dopamine D-2 and 5-HT2A antagonist that is metabolized by CYP1A2 and CYP2D6
Fluoxetine: serotonin reuptake inhibitor that is metabolized by CYP2D6 and is an inhibitor of CYP 2C9/2C19 and 2D6 with a half-life of 4-6 days and 9 days for the metabolite norfluoxetine
The half-life is important here because what happens when someone stops taking the medication? The olanzapine has a much shorter half-life and will be cleared from the body more rapidly leaving the person exposed to fluoxetine without a mood stabilizing element possibly inducing mania or worsening mood symptoms. This is something to be mindful of when using this combination.
Studies Showing Efficacy
The studies that resulted in FDA approval for bipolar depression in 2003 were short, 8 weeks in duration. A total of 833 patients with bipolar I depression received either olanzapine alone, olanzapine fluoxetine combination (OFC), or placebo. Patients on OFC and olanzapine alone showed a significant reduction in depressive symptoms compared to placebo as early as the end of week 1 of treatment. By the end of 4 weeks the OFC participants saw significantly more improvement than placebo or olanzapine alone. The superiority continued over the final 4 weeks of the study. By the end 24.5% of patients on placebo met remission criteria, 32.8% of the olanzapine only group achieved remission, and 48.8% of the OFC group achieved remission.
For the 2009 approval of OFC in treatment resistant depression, it was based off two eight-week double blind placebo-controlled studies using doses of 6 to 18 mg for olanzapine and 25 to 50 mg for fluoxetine. 40% of patients receiving the OFC responded to therapy Vs 30% and 26% receiving fluoxetine or olanzapine monotherapy. The starting dose was 6/25 mg and could be titrated to 18/75 mg as tolerated.
Antipsychotic Drugs and Cognitive Function: Key Findings from a Systematic Review and Meta-Analysis
Background: Cognitive impairment is a core feature of schizophrenia, often leading to significant functional disability. Antipsychotic medications are the main treatment for schizophrenia, but their impact on cognitive function remains debated.
Objective: This systematic review and network meta-analysis aimed to compare the effects of different antipsychotic drugs on cognitive function in patients with schizophrenia.
Methods: The review included randomized controlled trials (RCTs) that assessed cognitive outcomes in patients with schizophrenia treated with antipsychotics. A network meta-analysis was conducted to compare the cognitive effects across different antipsychotic drugs.
Key Findings:
Cognitive Improvement:
All antipsychotics studied showed modest cognitive benefits, though the effect sizes were small.
Second-generation antipsychotics (SGAs) generally performed better than first-generation antipsychotics (FGAs).
Among SGAs, lurasidone and amisulpride demonstrated the most pronounced cognitive improvements.
FGAs like haloperidol showed the least benefit for cognitive function.
Domains of Cognitive Improvement:
The drugs improved different cognitive domains, including working memory, processing speed, and executive functioning, though no single drug showed superiority across all domains.
Comparative Effectiveness:
In head-to-head comparisons, lurasidone and amisulpride were consistently ranked higher for cognitive improvement.
Olanzapine and risperidone also showed beneficial effects, though to a lesser extent.
Adverse Effects and Tolerability:
Cognitive improvements were often seen alongside side effects, with some drugs (e.g., olanzapine) associated with metabolic risks that may counterbalance cognitive benefits.
Limitations:
The analysis emphasized the small effect sizes, suggesting that while antipsychotics may slightly improve cognition, the changes may not be clinically meaningful in many cases.
Cognitive rehabilitation therapies may need to be paired with pharmacological treatment for more significant cognitive gains.
Conclusions: While antipsychotics can modestly improve cognitive function in schizophrenia, the benefits are relatively small, and no drug significantly outperforms others across all cognitive domains. Lurasidone and amisulpride may offer the greatest cognitive benefits, but additional interventions may be necessary to address cognitive deficits effectively.
Monoamine oxidase inhibitors (MAOIs) are a class of medications primarily used to treat depression. They work by inhibiting the activity of monoamine oxidase enzymes (MAO-A and MAO-B). These enzymes are responsible for breaking down neurotransmitters such as serotonin, norepinephrine, and dopamine in the brain. By inhibiting these enzymes, MAOIs increase the levels of these neurotransmitters, which can help improve mood and alleviate depressive symptoms.
Common Medications
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Isocarboxazid (Marplan)
Selegiline (Emsam) – Available as a transdermal patch
Side Effects
MAOIs can have significant side effects and interactions, which is why they are often not the first choice for treating depression. Some common side effects include:
Hypertensive Crisis: Consuming foods high in tyramine (such as aged cheeses, cured meats, and fermented products) can cause dangerously high blood pressure.
Orthostatic Hypotension: A sudden drop in blood pressure when standing up, leading to dizziness or fainting.
Insomnia: Difficulty falling or staying asleep.
Weight Gain: An increase in body weight over time.
Sexual Dysfunction: Decreased libido, erectile dysfunction, or difficulty achieving orgasm.
Headaches: Frequent or severe headaches.
Edema: Swelling, particularly in the lower limbs.
Fatigue: General feeling of tiredness or lack of energy.
Dry Mouth: Reduced saliva production, leading to a dry sensation in the mouth.
Precautions
Dietary Restrictions: Due to the risk of hypertensive crisis, patients on MAOIs must follow strict dietary restrictions to avoid tyramine-rich foods.
Drug Interactions: MAOIs can interact with numerous medications, including over-the-counter drugs, other antidepressants, and certain pain medications, potentially leading to severe or life-threatening conditions.
Medical Monitoring: Regular monitoring by a healthcare professional is essential to manage and mitigate potential side effects and interactions.
MAOIs can be effective for certain patients, particularly those who have not responded to other antidepressant treatments. However, their use requires careful management due to their side effect profile and interaction potential.
I constantly come across the phrase “Harvard-trained” in people’s bios. Sure, it brings instant brand recognition and credibility. But in reality, being trained at a prestigious institution—even one like Harvard—doesn’t automatically mean better skills or superior patient care.
In psychiatry, quality care is shaped by much more than where someone trained. It comes from clinical experience, empathy, lifelong learning, and the ability to genuinely connect with patients. These are the factors that truly define the impact we make.
While training is important, the real measure of a psychiatrist’s ability is in the care they provide and the outcomes they achieve. Psychiatry is such a nuanced field that no amount of prestige can substitute for hands-on experience and genuine compassion.
It’s unfortunate that where someone trained is often used as a superficial marker of competence, overshadowing the true work that goes into patient care. Personally, I’d reject a Harvard offer, because for me, it’s about one thing: providing the highest level of care possible, every single day.
