Research & Clinical Insights

Expert Perspectives on ADHD, Cannabis Research & Psychopharmacology
By Dr. Ryan S. Sultan, Assistant Professor of Clinical Psychiatry
Columbia University Irving Medical Center →

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Recent Articles

Evidence-based perspectives from NIH-funded research and clinical practice

Understanding ADHD Treatment Options for Young Adults

Published: February 1, 2026 | Reading time: 10 minutes

Attention-Deficit/Hyperactivity Disorder (ADHD) in young adults presents unique diagnostic and treatment challenges that differ significantly from both childhood and later adult presentations. As someone who has spent over a decade researching and treating ADHD across the lifespan, I've observed how this transitional period—typically ages 18-25—requires specialized understanding and tailored treatment approaches.

The Young Adult ADHD Challenge

Young adulthood represents a critical developmental period marked by increased independence, academic demands, career formation, and complex social relationships. For individuals with ADHD, these years can be particularly challenging. The structured support systems of childhood and adolescence (parental oversight, school accommodations, pediatric care) often disappear just as demands for executive function, time management, and self-directed organization reach their peak.

Research from our lab at Columbia University and others has shown that approximately 4-5% of young adults meet criteria for ADHD, with many remaining undiagnosed until this life stage. The consequences of untreated ADHD in this age group extend beyond academic performance—affecting employment stability, relationship quality, substance use risk, and overall life satisfaction.

Accurate Diagnosis: The Foundation

Before discussing treatment, accurate diagnosis is paramount. ADHD in young adults often presents differently than in children. Hyperactivity typically manifests as internal restlessness rather than physical fidgeting. Inattention appears as difficulty completing college coursework, chronic procrastination, or inability to maintain focus during work tasks rather than classroom disruption.

Key diagnostic considerations include:

• Symptom history: DSM-5 criteria require evidence that symptoms were present before age 12, though they may not have caused significant impairment until later
• Current impairment: Symptoms must cause clinically significant impairment in multiple settings (academic, occupational, social)
• Differential diagnosis: Many conditions can mimic ADHD—anxiety disorders, depression, sleep disorders, substance use, and even normal developmental variability in executive function
• Comorbidity assessment: 60-70% of adults with ADHD have at least one comorbid psychiatric condition

Comprehensive evaluation should include structured diagnostic interviews, rating scales, collateral information when possible, and assessment for common comorbidities including anxiety disorders, mood disorders, substance use disorders, and learning disabilities.

Pharmacological Treatment Options

Medication remains the most evidence-based treatment for ADHD, with effect sizes typically in the 0.8-1.0 range—considered large in psychiatric research. For young adults, understanding medication options, mechanisms, and side effects is crucial for informed treatment decisions.

Stimulant Medications: First-Line Treatment

Stimulants are considered first-line pharmacotherapy based on decades of research demonstrating efficacy and safety. These medications work by increasing dopamine and norepinephrine availability in brain regions involved in attention, impulse control, and executive function—particularly the prefrontal cortex.

Methylphenidate-based medications:

• Immediate-release: Ritalin, Focalin (4-6 hour duration)
• Extended-release: Concerta, Focalin XR, Ritalin LA (8-12 hour duration)
• Mechanism: Primarily blocks dopamine reuptake
• Advantages: Shorter half-life allows flexible dosing, generally well-tolerated

Amphetamine-based medications:

• Immediate-release: Adderall, Dexedrine (4-6 hour duration)
• Extended-release: Adderall XR, Vyvanse (10-12 hour duration)
• Mechanism: Increases dopamine release and blocks reuptake
• Advantages: Often more robust effect, longer duration with extended-release formulations

Clinical trials consistently show that 70-80% of individuals with ADHD respond to stimulant medication. However, response to specific medications varies—someone who doesn't respond to methylphenidate may respond well to amphetamines, and vice versa.

Common side effects and management:

• Appetite suppression: Often improves after 2-4 weeks; timing medication after meals can help
• Insomnia: Avoid late-day dosing; consider shorter-acting formulations
• Increased heart rate/blood pressure: Monitor at each visit; typically mild and clinically insignificant
• Emotional blunting: Dose-dependent; often indicates over-medication
• Rebound effects: Irritability as medication wears off; managed with timing adjustments or supplemental doses

For young adults, extended-release formulations often provide better all-day coverage for academic and work demands, with smoother onset and offset compared to immediate-release options.

Non-Stimulant Medications: Alternative Options

Non-stimulant medications represent important alternatives for individuals who don't tolerate stimulants, have comorbid conditions where stimulants are relatively contraindicated, or have concerns about controlled substance prescriptions.

Atomoxetine (Strattera):

• Mechanism: Selective norepinephrine reuptake inhibitor
• Onset: 4-6 weeks for full effect
• Advantages: No abuse potential, once-daily dosing, helps with comorbid anxiety
• Disadvantages: Lower effect size than stimulants, requires daily dosing, GI side effects common initially
• Best for: Individuals with comorbid anxiety, substance use history, or stimulant non-responders

Bupropion (Wellbutrin):

• Mechanism: Norepinephrine-dopamine reuptake inhibitor
• Advantages: Helpful for comorbid depression, may aid smoking cessation
• Evidence: Modest efficacy for ADHD, better for comorbid conditions
• Caution: Seizure risk at higher doses, avoid in eating disorders

Alpha-2 agonists (Guanfacine, Clonidine):

• Mechanism: Enhance prefrontal cortex function through norepinephrine modulation
• Use: Often adjunctive to stimulants, helpful for hyperactivity and impulsivity
• Advantages: Can improve sleep, reduce tics
• Disadvantages: Sedation common, less robust for inattention

Psychosocial Interventions: Essential Complements

While medication addresses core neurobiological deficits in ADHD, psychosocial interventions help individuals develop compensatory strategies, address functional impairments, and manage comorbid conditions. Research consistently shows that combined treatment (medication plus psychotherapy) produces better long-term outcomes than either alone.

Cognitive Behavioral Therapy for Adult ADHD

CBT adapted for adult ADHD focuses on practical skill development rather than traditional cognitive restructuring. Evidence-based components include:

• Organization and planning skills: Breaking large tasks into manageable steps, using calendars and reminder systems effectively
• Time management: Estimating task duration accurately, building in buffer time, using timers strategically
• Distraction management: Environmental modifications, technology tools to limit digital distractions
• Procrastination reduction: Identifying procrastination triggers, using behavioral activation, implementing the "two-minute rule"
• Emotional regulation: Managing frustration, impulsivity, and emotional reactions

Studies by Dr. Mary Solanto and others have demonstrated significant functional improvements with structured CBT protocols, with effects maintained at 6-12 month follow-up.

Coaching and Support

ADHD coaching—though less researched than formal psychotherapy—provides practical, goal-oriented support focused on accountability and skill implementation. For young adults transitioning to independence, coaching can bridge the gap between understanding strategies and implementing them consistently.

Environmental Modifications

Simple environmental changes can significantly impact ADHD symptoms:

• Workspace design: Minimize visual distractions, use noise-canceling headphones, designate specific work areas
• Technology tools: Website blockers (Freedom, Cold Turkey), task management apps (Todoist, Things), time-tracking software
• Routine building: Consistent sleep/wake times, regular meal schedules, designated study/work hours
• Exercise: Regular aerobic exercise shows modest but consistent benefits for ADHD symptoms

Special Considerations for Young Adults

College Accommodations

Students with ADHD are entitled to reasonable accommodations under the Americans with Disabilities Act. Common accommodations include:

• Extended time on exams (typically 1.5x or 2x)
• Reduced-distraction testing environments
• Note-taking assistance or lecture recordings
• Flexibility with assignment deadlines
• Priority registration for optimal class scheduling

Obtaining accommodations requires documentation from a qualified provider and coordination with the campus disability services office.

Substance Use Considerations

Young adults with ADHD have 2-3 times higher rates of substance use disorders than peers without ADHD. This comorbidity requires careful assessment and integrated treatment. Key considerations:

• Stimulant diversion risk: Education about medication security, consideration of abuse-deterrent formulations (e.g., Vyvanse)
• Substance use screening: Regular monitoring, urine drug testing when clinically indicated
• Concurrent treatment: Addressing both conditions simultaneously typically yields better outcomes
• Cannabis use: Despite perceived safety, regular cannabis use can worsen ADHD symptoms and reduce medication effectiveness

My research on cannabis use disorders has highlighted the particular vulnerability of young adults with ADHD to problematic cannabis use, making screening and intervention critical.

Transition of Care

Many young adults diagnosed in childhood face challenges transitioning from pediatric to adult care. This transition period often coincides with treatment discontinuation and functional decline. Strategies to improve transitions include:

• Gradual transfer with overlap between pediatric and adult providers
• Written care summaries including diagnostic evaluation details
• Education about differences between pediatric and adult healthcare systems
• Early establishment with adult providers before anticipated changes (college, moving)

Monitoring and Follow-Up

Effective ADHD treatment requires ongoing monitoring and adjustment. Initial medication titration typically involves weekly or biweekly visits to optimize dose and formulation. Once stable, quarterly follow-ups are standard, assessing:

• Symptom control: Using validated rating scales (ASRS, CAARS)
• Functional outcomes: Academic/work performance, relationship quality, daily living skills
• Side effects: Systematic review of common and serious adverse effects
• Vital signs: Blood pressure and heart rate at each visit
• Comorbid conditions: Depression, anxiety, substance use screening
• Medication adherence: Identifying barriers and problem-solving

Emerging Treatments and Future Directions

The field continues to evolve, with several promising developments:

Digital therapeutics: My lab's NIH-funded research is developing AI-based interventions that provide personalized, real-time support for executive function skills. Early data suggest these tools can augment traditional treatments by providing support outside clinical visits.

Novel medications: Several compounds in development target different neurotransmitter systems, potentially offering new options for treatment-resistant cases.

Neurostimulation: Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) show preliminary promise, though more research is needed.

Conclusion

ADHD in young adults requires comprehensive treatment addressing both neurobiological deficits and functional impairments. Stimulant medications remain the most effective intervention, but optimal outcomes typically require multimodal treatment combining medication, psychotherapy, skills training, and environmental modifications.

The young adult years present unique challenges—but also unique opportunities. This developmental period of identity formation and skill development is an ideal time to build compensatory strategies, establish healthy habits, and develop self-understanding that will serve individuals throughout adulthood.

For young adults struggling with ADHD symptoms, professional evaluation and evidence-based treatment can be genuinely life-changing—improving not just academic or work performance, but overall quality of life, relationships, and self-esteem.

For more information about ADHD research and treatment, see my peer-reviewed publications and current research projects.

Continue Reading:
Complete ADHD Clinical Guide | ADHD FAQs | Current ADHD Research | 411-Cited JAMA Publication

Cannabis Use and Psychosis Risk: What the Research Shows

Published: February 5, 2026 | Reading time: 9 minutes

The relationship between cannabis use and psychotic disorders has become increasingly important as cannabis legalization expands across the United States and globally. As someone whose research program focuses extensively on cannabis use and mental health outcomes, I'm frequently asked about this connection by patients, families, trainees, and the media. The evidence is now substantial—and concerning.

Understanding the Connection

The link between cannabis and psychosis is not new. Clinicians have observed this association for decades, but recent large-scale epidemiological studies have quantified the relationship more precisely and identified key risk factors that modify individual vulnerability.

What do we mean by psychosis? Psychosis refers to a loss of contact with reality, characterized by hallucinations (perceiving things that aren't there—most commonly auditory), delusions (fixed false beliefs), disorganized thinking, and impaired functioning. Psychotic disorders include schizophrenia, schizoaffective disorder, and brief psychotic disorder.

The Evidence: What Studies Show

Population-Level Studies

Multiple large cohort studies and meta-analyses have established that cannabis use increases the risk of developing psychotic disorders:

Meta-analysis findings (Marconi et al., 2016, Lancet Psychiatry):

• Any cannabis use increases psychosis risk by approximately 40% (odds ratio 1.41)
• Heavy cannabis use increases risk nearly 4-fold (odds ratio 3.90)
• Daily use shows even stronger associations
• Effects remain after controlling for confounding variables including other substance use and socioeconomic factors

Danish national registry study (Hjorthøj et al., 2023, JAMA Psychiatry):

• Analyzed entire Danish population using comprehensive health registries
• Found that eliminating cannabis use disorder could potentially prevent up to 30% of schizophrenia diagnoses in young men
• Showed dose-response relationship—more intensive cannabis use associated with higher risk
• Temporal relationship confirmed—cannabis use preceded psychosis onset

Longitudinal Studies

Prospective studies following individuals over time provide stronger causal evidence than cross-sectional data. Key findings include:

Dunedin Study (Arseneault et al., 2002):

• Followed cohort from birth; cannabis use by age 15-18 predicted adult psychosis outcomes
• Effect remained significant after controlling for baseline psychotic symptoms
• Demonstrated temporal precedence—cannabis use preceded psychosis

NEMESIS Study (van Os et al., 2002):

• Dutch population study showing bidirectional relationship
• Cannabis use predicted new-onset psychosis
• Pre-existing psychotic symptoms predicted increased cannabis use (self-medication hypothesis)

High-Potency Cannabis: A Growing Concern

Cannabis potency—measured by THC (tetrahydrocannabinol) content—has increased dramatically over recent decades. In the 1990s, average THC content was 3-4%. Today's products often exceed 15-20% THC, with concentrates reaching 80-90%.

Research on potency and psychosis risk (Di Forti et al., 2019, Lancet Psychiatry):

• Daily use of high-potency cannabis (>10% THC) associated with 5-fold increased risk of psychotic disorder compared to never users
• In areas where high-potency cannabis was readily available, incidence of first-episode psychosis was significantly higher
• Clear dose-response relationship between THC potency and psychosis risk

This finding has particular relevance in legalized markets, where high-potency products dominate retail sales and concentrates (dabs, wax, shatter) with extremely high THC content are increasingly popular.

Who is Most Vulnerable? Key Risk Factors

Not everyone who uses cannabis develops psychosis. Individual vulnerability varies based on several factors:

Genetic Risk

Genetic vulnerability to psychotic disorders substantially modifies cannabis-psychosis risk. Studies show:

• Family history: Individuals with first-degree relatives with schizophrenia show much stronger cannabis-psychosis associations
• Polygenic risk scores: Higher genetic loading for schizophrenia amplifies cannabis-related risk
• Gene-environment interaction: Cannabis use may "unmask" latent genetic vulnerability

Research suggests that for individuals at high genetic risk, even moderate cannabis use can significantly increase probability of developing psychotic illness that might not have emerged otherwise.

Age of Initiation

Adolescent brain development creates a critical vulnerability window:

• Earlier onset = higher risk: Cannabis use beginning before age 15-16 shows stronger associations with psychosis than adult-onset use
• Brain development: The endocannabinoid system plays crucial roles in brain maturation, particularly in prefrontal cortex and hippocampus
• Sensitive period: Adolescence represents a time when cannabinoid disruption may have lasting impacts

My recent research published in Pediatrics (2026) examined adolescent cannabis use patterns and highlighted the particular vulnerability of this developmental stage.

Frequency and Quantity

Clear dose-response relationships emerge across studies:

• Daily use: Substantially higher risk than weekly or monthly use
• Heavy use: Amount consumed per occasion matters—higher doses increase risk
• Duration: Years of cumulative exposure relevant—longer cannabis use history associated with higher risk

Other Risk Factors

• Male sex: Men show higher rates of both heavy cannabis use and cannabis-associated psychosis
• Polysubstance use: Combined use of cannabis with other substances (alcohol, stimulants) may increase risk
• Childhood trauma: Early adversity may increase vulnerability through stress-sensitization mechanisms
• Urbanicity: Living in urban environments associated with higher baseline psychosis risk, potentially interacting with cannabis effects

Mechanisms: How Does Cannabis Increase Psychosis Risk?

While epidemiological evidence for the cannabis-psychosis link is strong, understanding biological mechanisms remains an active area of research.

Endocannabinoid System Disruption

THC acts as a partial agonist at CB1 cannabinoid receptors, which are highly concentrated in brain regions involved in cognition, emotion regulation, and sensory processing. Chronic THC exposure may disrupt the endogenous cannabinoid system's regulatory functions.

Dopamine Dysregulation

The "dopamine hypothesis" of psychosis proposes that excessive dopamine activity contributes to psychotic symptoms. Cannabis use affects dopamine neurotransmission:

• Acutely, THC increases dopamine release in striatum
• Chronic use may lead to dopaminergic sensitization
• Interactions between cannabinoid and dopamine systems may lower threshold for psychosis

Neurodevelopmental Impact

Adolescent cannabis exposure during critical neurodevelopmental windows may alter brain maturation:

• Reduced gray matter volume in prefrontal cortex and hippocampus in heavy adolescent users
• Altered white matter integrity
• Disrupted synaptic pruning processes
• Changes in GABA-ergic interneurons that may increase circuit-level instability

Clinical Presentations

Cannabis-Induced Psychotic Disorder

DSM-5 recognizes "cannabis-induced psychotic disorder"—psychotic symptoms that emerge during or shortly after cannabis intoxication or withdrawal. Features include:

• Onset temporally related to cannabis use
• Symptoms typically resolve within days to weeks of abstinence
• May include hallucinations, delusions, paranoia
• Can be quite severe acutely, sometimes requiring hospitalization

Critical question: Does cannabis-induced psychosis resolve completely, or does it represent a harbinger of persistent psychotic illness?

Progression to Schizophrenia

Studies following individuals with cannabis-induced psychosis show:

• Approximately 40-50% go on to develop schizophrenia or other persistent psychotic disorder
• Cannabis-induced psychosis may represent an early manifestation of vulnerability rather than a distinct, self-limited condition
• Continued cannabis use after initial episode dramatically increases risk of persistent illness

Clinical Implications

Prevention and Risk Reduction

Given clear evidence of harm, public health messages should emphasize:

For adolescents and young adults:

• Delay initiation—later onset associated with lower risk
• Avoid high-potency products
• Minimize frequency—daily use particularly risky
• Understand individual risk factors (family history most important)

For individuals with family history of psychosis:

• Strong recommendation to avoid cannabis entirely
• Clear education about amplified personal risk
• Monitoring for early warning signs if use occurs

Early Intervention

For individuals developing psychotic symptoms in context of cannabis use:

• Immediate cessation: Discontinuing cannabis is first-line intervention
• Close monitoring: Assess whether symptoms resolve with abstinence
• Early treatment: If symptoms persist beyond 2-4 weeks, psychiatric evaluation and potential antipsychotic treatment
• Relapse prevention: Strong emphasis on sustained abstinence to prevent recurrence

Treatment of Comorbid Cannabis Use and Psychosis

Many individuals with established psychotic disorders continue using cannabis despite documented negative effects. Treatment approaches include:

• Motivational interviewing: Non-confrontational exploration of use patterns and consequences
• Cognitive behavioral therapy: Identifying triggers, developing coping strategies
• Contingency management: Providing incentives for abstinence (well-evidenced approach)
• Integrated treatment: Addressing both psychosis and substance use concurrently

My lab's work developing digital therapeutics for cannabis use disorder aims to improve access to evidence-based interventions for this challenging population.

The Legalization Context

Cannabis legalization has occurred rapidly, often outpacing research on public health consequences. Key considerations:

• Increased availability and potency: Legal markets predominantly sell high-potency products
• Declining risk perception: Adolescents increasingly view cannabis as harmless
• Marketing concerns: Industry marketing may not adequately communicate mental health risks
• Public health messaging: Need for education campaigns targeting high-risk groups

My research examining cannabis policy impacts on mental health outcomes aims to inform evidence-based regulatory approaches.

Controversies and Ongoing Questions

Despite substantial evidence, several questions remain:

Causation vs. correlation: While evidence strongly supports cannabis as causal risk factor, definitive proof through randomized trials is ethically impossible. However, Bradford Hill criteria for causation are largely met—consistent association, dose-response, temporal precedence, biological plausibility.

CBD and psychosis: Cannabidiol (CBD), non-intoxicating cannabis component, may have antipsychotic properties. Some research suggests CBD might mitigate THC's psychotogenic effects, though evidence remains preliminary.

Medical cannabis: For conditions like chronic pain or epilepsy, risk-benefit calculations differ. However, even medical use warrants monitoring in vulnerable individuals.

Conclusion

The evidence linking cannabis use—particularly frequent use of high-potency products during adolescence—to increased psychosis risk is now substantial and continues to strengthen. While most cannabis users will not develop psychotic disorders, the population-level impact is significant given widespread use.

For clinical practice, key takeaways include:

• Screen all adolescents and young adults for cannabis use
• Provide targeted education to high-risk individuals (family history of psychosis)
• Intervene early when psychotic symptoms emerge in context of cannabis use
• Emphasize sustained abstinence for individuals with established psychotic disorders
• Advocate for public health policies that limit youth access and require potency labeling

As cannabis policies continue evolving, research monitoring mental health outcomes—particularly in vulnerable populations—remains critical.

For more information, see my research on cannabis and mental health and FAQ answers about cannabis risks.

Continue Reading:
Complete Cannabis & Mental Health Guide | Psychosis Risk Section | Cannabis FAQs | Pediatrics 2026 Publication

The Evolution of Clozapine REMS: What Changed and Why

Published: February 10, 2026 | Reading time: 8 minutes

Clozapine represents one of psychiatry's most important yet underutilized medications. Despite being the only medication proven effective for treatment-resistant schizophrenia and the only antipsychotic demonstrated to reduce suicide risk, clozapine has historically been prescribed to fewer than 5% of individuals who could benefit from it. The primary barrier? An onerous monitoring system called REMS (Risk Evaluation and Mitigation Strategy) designed to prevent a rare but serious side effect.

My research contributed to FDA policy changes in 2017 that reduced monitoring burdens while maintaining safety. This article explains the science behind these changes and what they mean for patient care.

Why Clozapine Matters

Clozapine is uniquely effective. For individuals with treatment-resistant schizophrenia—defined as inadequate response to adequate trials of at least two different antipsychotic medications—clozapine offers response rates of 40-60%, compared to 20-30% for other antipsychotics. No other medication comes close to this efficacy.

Additionally, clozapine is the only antipsychotic proven to reduce suicidal behavior. The landmark International Suicide Prevention Trial (InterSePT) demonstrated a 25% reduction in suicide attempts and a significant reduction in suicide deaths compared to olanzapine—a critically important finding given that approximately 5-6% of individuals with schizophrenia die by suicide.

Despite this remarkable efficacy, clozapine remains dramatically underprescribed globally. Understanding and addressing barriers to clozapine use has major implications for improving outcomes in schizophrenia.

Agranulocytosis: The Risk That Changed Everything

Clozapine's restricted use stems from one serious adverse effect: agranulocytosis, a potentially life-threatening condition characterized by dangerously low white blood cell counts that leave individuals vulnerable to severe infections.

Historical context: When clozapine was first introduced in the 1970s in Europe, several deaths from agranulocytosis-related infections occurred before the risk was fully recognized. This led to clozapine's withdrawal from most markets. After subsequent studies demonstrated that regular blood monitoring could detect dropping white blood cell counts before they reached dangerous levels, clozapine was reintroduced with mandatory monitoring protocols.

The risk in numbers:

• Agranulocytosis occurs in approximately 0.8-1.0% of patients
• Risk highest in first 6 months of treatment, particularly first 18 weeks
• With monitoring, mortality from agranulocytosis is extremely rare (< 0.01%)
• Risk declines substantially after 6 months of treatment

The Original REMS: Well-Intentioned but Burdensome

When clozapine was approved in the United States in 1989, a centralized registry system was implemented requiring:

• Weekly blood tests for the first 6 months
• Biweekly blood tests for months 6-12
• Monthly blood tests thereafter
• Pharmacy verification of acceptable blood counts before dispensing medication
• Multiple separate registries (one for each brand/generic), making switches between products complicated

Additionally, the system used race-based absolute neutrophil count (ANC) thresholds that created barriers for Black patients, who on average have lower baseline neutrophil counts (benign ethnic neutropenia) without increased risk of infection.

The Problem: Barriers to Access

While monitoring is medically necessary, the original REMS system created substantial obstacles:

For patients:

• Weekly clinic visits for blood draws (transportation, time off work/school, copays)
• Fear of needles discouraging treatment initiation
• Treatment interruptions when blood tests delayed
• Difficulty transferring care between providers or locations

For prescribers:

• Complex administrative burden managing registries
• Hesitancy to prescribe due to perceived liability and hassle
• Training requirements and certification processes
• Difficulty coordinating between multiple healthcare systems

For pharmacies:

• Registry verification required before each dispense
• Multiple registry systems (different for each manufacturer)
• Technical difficulties accessing registries

The Evidence for Change

By the 2010s, decades of real-world clozapine use had accumulated substantial safety data suggesting the original REMS was more restrictive than necessary. Key findings included:

International Comparison Studies

Countries with less frequent monitoring (e.g., monthly rather than weekly) showed no increased rates of agranulocytosis-related mortality, suggesting that weekly monitoring wasn't necessary for safety.

Temporal Risk Patterns

Data clearly showed that agranulocytosis risk drops dramatically after the first 6-12 months of treatment, yet monitoring requirements remained unchanged regardless of treatment duration.

Race and Neutrophil Counts

Research demonstrated that individuals of African descent have lower average ANC values without increased infection risk. Using race-agnostic thresholds inappropriately flagged Black patients as high-risk, creating racial disparities in access.

Our research team at Columbia and colleagues compiled evidence showing that the REMS system, while protecting against agranulocytosis, was inadvertently limiting access to a lifesaving medication—particularly for minority patients and those in rural areas with limited access to frequent blood draws.

The 2015-2017 FDA Revisions

Based on accumulated evidence and advocacy from the clinical and research community, the FDA implemented significant REMS revisions in September 2015, with further updates in 2017:

Key Changes:

1. Single Shared Registry

• All clozapine products (brand and generic) use one unified registry
• Dramatically simplified switching between products
• Reduced administrative burden
• Improved care coordination across providers

2. Race-Neutral Monitoring Thresholds

• Eliminated race-based ANC cutoffs
• Implemented individualized baseline approach
• Removed discriminatory barriers for Black patients
• Better reflects scientific understanding of benign ethnic neutropenia

3. Risk-Stratified Monitoring

• Initial 6 months: Weekly monitoring (unchanged—highest risk period)
• Months 6-12: Biweekly monitoring (unchanged)
• After 12 months with stable counts: Monthly monitoring (less frequent than before)
• Option to reduce to every 6 weeks after 12 continuous months (new option)

4. Streamlined Prescriber Requirements

• Simplified certification process
• Reduced paperwork
• Improved online portal functionality

Impact of REMS Changes

Research examining pre- and post-REMS revision periods has shown:

Improved access:

• Modest increase in clozapine prescribing rates
• Reduced racial disparities in clozapine use
• Improved treatment continuity (fewer interruptions)
• Greater willingness among prescribers to initiate clozapine

Maintained safety:

• No increase in agranulocytosis-related serious adverse events
• No increase in infection-related hospitalizations
• Early detection of declining counts remains effective

While these changes represented significant progress, clozapine remains underutilized. Barriers persist, including:

• Prescriber hesitancy and lack of familiarity
• Patient reluctance due to monitoring requirements (even reduced)
• Other side effects (metabolic effects, hypersalivation, seizure risk)
• Systemic factors (insurance barriers, pharmacy limitations)

Clinical Implications: Who Should Get Clozapine?

Given its unique efficacy, clozapine should be considered for:

Primary indications:

• Treatment-resistant schizophrenia: Inadequate response to adequate trials (4-6 weeks at therapeutic dose) of at least 2 different antipsychotics
• Suicidality in schizophrenia/schizoaffective disorder: History of suicide attempts or current suicidal ideation
• Severe psychotic symptoms with high risk: Persistent severe symptoms despite other treatments

Secondary considerations:

• Severe medication side effects with other antipsychotics (especially movement disorders)
• Violent or aggressive behavior not responding to other treatments
• Treatment-resistant bipolar disorder (off-label but evidence-supported)

Starting and Managing Clozapine

Initiation:

• Baseline labs: CBC with ANC, metabolic panel, lipid panel, EKG
• Slow titration (typically 12.5-25mg initially, increasing by 25-50mg every 1-3 days)
• Target dose typically 300-450mg/day (range 150-900mg)
• Therapeutic level monitoring available (aim for 350-600 ng/mL)

Monitoring requirements:

• Weekly ANC for first 6 months
• Biweekly months 6-12
• Monthly thereafter (or potentially every 6 weeks after 12 months)
• Metabolic monitoring (weight, glucose, lipids) per standard antipsychotic protocols

Common side effects:

• Sedation (often improves over time, managed with dosing strategies)
• Hypersalivation (particularly at night; can manage with atropine or glycopyrrolate)
• Weight gain and metabolic effects (monitor and address proactively)
• Tachycardia (typically benign but monitor)
• Constipation (can be severe; aggressive bowel regimen recommended)
• Seizure risk (dose-dependent; < 5% at therapeutic doses)

Future Directions

Ongoing work aims to further optimize clozapine access while maintaining safety:

Point-of-care testing: Fingerstick devices allowing immediate ANC results at clinic visits, eliminating lab delays and improving convenience.

Biomarkers: Research into genetic or other biomarkers that could identify individuals at highest agranulocytosis risk, potentially allowing personalized monitoring frequencies.

Patient education: Better resources helping individuals understand clozapine's risk-benefit profile and make informed decisions.

Provider training: Educational initiatives to increase prescriber comfort and competence with clozapine.

Conclusion

The evolution of clozapine REMS represents an important example of evidence-based policy revision. By analyzing decades of safety data, researchers and clinicians demonstrated that monitoring requirements could be reduced without compromising safety—removing barriers to a lifesaving medication.

However, work remains. Despite improvements, clozapine continues to be underprescribed relative to the population who could benefit. For individuals with treatment-resistant schizophrenia—who often experience persistent symptoms, functional impairment, and suicide risk—clozapine represents a genuinely transformative option.

As a field, we must continue efforts to optimize the balance between appropriate safety monitoring and treatment access. Every individual with treatment-resistant schizophrenia deserves the opportunity to benefit from the most effective medication available.

For more information about clozapine and treatment-resistant schizophrenia, see my published research and FAQ responses.

Continue Reading:
Original Clozapine Research (JCP 2017) | Treatment FAQs | Current Research Projects

About the Author

Dr. Ryan S. Sultan is a double board-certified psychiatrist (Adult & Child/Adolescent) and Assistant Professor of Clinical Psychiatry at Columbia University Irving Medical Center. His research program focuses on ADHD, cannabis use disorders, and psychopharmacoepidemiology, with funding from the National Institute on Drug Abuse (NIDA). Dr. Sultan directs the Sultan Lab for Mental Health Informatics and maintains a clinical practice at Integrative Psych NYC, offering comprehensive integrative psychiatric care.

For professional inquiries, see contact information.

Related Content:
Frequently Asked Questions | Research Publications | Current Research Projects | NIH Funding | Media Appearances

Clinical Education:
Tantrums & Emotional Dysregulation | Catatonia in Adolescents | Medication Nomenclature | Telepsychiatry Integration