PRESENTATIES
DEPRESSION
Essentials of a Clinical Trial in Depression (Esketamine Example)
Why Are Depression Trials Unique and Challenging?
• Major Depressive Disorder (MDD) is a complex psychiatric condition, involving abnormal
glutamate transmission in the brain.
• Diagnosis is symptom-based (no biological marker), making subjective scales essential.
• High placebo response is a major issue → strong need for placebo-controlled designs.
• Only ~1/3 of patients respond to existing antidepressants → new treatments urgently needed.
Esketamine as Adjunctive Therapy
• Esketamine = nasal spray form of ketamine (NMDA receptor antagonist).
• Designed for patients who are treatment-resistant (don’t respond to oral antidepressants).
• Advantage: Fast onset of action (within days), unlike traditional antidepressants (weeks).
• Challenge: Ketamine increases blood pressure → must exclude patients with hypertension.
• This also affects real-world applicability and marketing → limited population.
Trial Design Features
Short Duration (8 days) – Why Acceptable?
• While antidepressant trials are usually longer, this trial was:
o Placebo-controlled → crucial due to huge placebo effects in depression.
o Treatment-resistant patients → unethical to make them wait 6–8 weeks for relief.
o Primary read-out is early improvement → aligns with fast action of esketamine.
Primary Endpoint
• MADRS Total Score (Montgomery–Åsberg Depression Rating Scale)
o Measures: sadness, sleep, concentration, suicidal thoughts, etc.
o Scale: 0 (no depression) to ~60 (very severe depression).
o Goal: significant reduction in score from baseline.
,Placebo-Controlled with Active Background
• All participants continued oral antidepressants.
• Randomized to esketamine vs. placebo spray (placebo contained denatonium to match
taste/feel).
Inclusion/Exclusion Criteria
• Inclusion: Patients with high MADRS scores (confirmed diagnosis of MDD).
• Exclusion:
o Patients with high blood pressure due to ketamine’s cardiovascular effects.
o Many psychiatric patients already have CV risk factors (smoking, stress, etc.), limiting
eligibility.
Scientific & Ethical Considerations
• Studies rely on questionnaires, so defining clinically meaningful change (e.g. ≥9-point MADRS
drop) is essential upfront.
• Objective, quantifiable read-out is critical due to the subjective nature of depression.
• Ongoing debate about long-term safety and abuse potential of ketamine-based therapies.
Key Takeaways
• Depression trials require placebo control due to strong psychological/placebo effects.
• Fast-acting treatments (like esketamine) allow short trials, especially for treatment-resistant
cases.
• Patient-reported outcomes (e.g. MADRS) are the gold standard.
• Cardiovascular risk is a major barrier to generalizing findings (internal vs. external validity).
• Trials must define clinical relevance clearly and anticipate regulatory scrutiny on safety and
efficacy.
, SCHIZOFRENIE
Essentials of a Clinical Trial in Schizophrenia
Case: Xanomeline-Trospium Chloride Trial
Why Are Schizophrenia Trials Unique?
• Schizophrenia is a chronic psychiatric disorder characterized by:
o Positive symptoms (hallucinations, delusions)
o Negative symptoms (withdrawal, lack of emotion)
o Cognitive dysfunction
• Standard treatment: D2 receptor antagonists, but they often cause serious side effects (e.g.
extrapyramidal symptoms → movement disorders similar to Parkinson's).
• Poor treatment adherence due to side effects is a major issue.
New Mechanism: Xanomeline-Trospium
• Xanomeline: acts on muscarinic receptors, not dopamine → potentially fewer movement-
related side effects.
• Combined with trospium to reduce peripheral side effects.
• Represents a novel mechanism of action in schizophrenia treatment.
Trial Design and Endpoints
Primary Endpoint:
• PANSS Total Score (Positive and Negative Syndrome Scale)
o Range: 30 (no symptoms) to 210 (severe symptoms)
o Measures: positive, negative, and general psychopathology
o Assessed after 5 weeks of treatment
Secondary Endpoints:
• PANSS positive subscale
• PANSS negative subscale
• PANSS Marder negative factor score
• Clinical Global Impression
• % of patients with ≥30% reduction in PANSS total score
DEPRESSION
Essentials of a Clinical Trial in Depression (Esketamine Example)
Why Are Depression Trials Unique and Challenging?
• Major Depressive Disorder (MDD) is a complex psychiatric condition, involving abnormal
glutamate transmission in the brain.
• Diagnosis is symptom-based (no biological marker), making subjective scales essential.
• High placebo response is a major issue → strong need for placebo-controlled designs.
• Only ~1/3 of patients respond to existing antidepressants → new treatments urgently needed.
Esketamine as Adjunctive Therapy
• Esketamine = nasal spray form of ketamine (NMDA receptor antagonist).
• Designed for patients who are treatment-resistant (don’t respond to oral antidepressants).
• Advantage: Fast onset of action (within days), unlike traditional antidepressants (weeks).
• Challenge: Ketamine increases blood pressure → must exclude patients with hypertension.
• This also affects real-world applicability and marketing → limited population.
Trial Design Features
Short Duration (8 days) – Why Acceptable?
• While antidepressant trials are usually longer, this trial was:
o Placebo-controlled → crucial due to huge placebo effects in depression.
o Treatment-resistant patients → unethical to make them wait 6–8 weeks for relief.
o Primary read-out is early improvement → aligns with fast action of esketamine.
Primary Endpoint
• MADRS Total Score (Montgomery–Åsberg Depression Rating Scale)
o Measures: sadness, sleep, concentration, suicidal thoughts, etc.
o Scale: 0 (no depression) to ~60 (very severe depression).
o Goal: significant reduction in score from baseline.
,Placebo-Controlled with Active Background
• All participants continued oral antidepressants.
• Randomized to esketamine vs. placebo spray (placebo contained denatonium to match
taste/feel).
Inclusion/Exclusion Criteria
• Inclusion: Patients with high MADRS scores (confirmed diagnosis of MDD).
• Exclusion:
o Patients with high blood pressure due to ketamine’s cardiovascular effects.
o Many psychiatric patients already have CV risk factors (smoking, stress, etc.), limiting
eligibility.
Scientific & Ethical Considerations
• Studies rely on questionnaires, so defining clinically meaningful change (e.g. ≥9-point MADRS
drop) is essential upfront.
• Objective, quantifiable read-out is critical due to the subjective nature of depression.
• Ongoing debate about long-term safety and abuse potential of ketamine-based therapies.
Key Takeaways
• Depression trials require placebo control due to strong psychological/placebo effects.
• Fast-acting treatments (like esketamine) allow short trials, especially for treatment-resistant
cases.
• Patient-reported outcomes (e.g. MADRS) are the gold standard.
• Cardiovascular risk is a major barrier to generalizing findings (internal vs. external validity).
• Trials must define clinical relevance clearly and anticipate regulatory scrutiny on safety and
efficacy.
, SCHIZOFRENIE
Essentials of a Clinical Trial in Schizophrenia
Case: Xanomeline-Trospium Chloride Trial
Why Are Schizophrenia Trials Unique?
• Schizophrenia is a chronic psychiatric disorder characterized by:
o Positive symptoms (hallucinations, delusions)
o Negative symptoms (withdrawal, lack of emotion)
o Cognitive dysfunction
• Standard treatment: D2 receptor antagonists, but they often cause serious side effects (e.g.
extrapyramidal symptoms → movement disorders similar to Parkinson's).
• Poor treatment adherence due to side effects is a major issue.
New Mechanism: Xanomeline-Trospium
• Xanomeline: acts on muscarinic receptors, not dopamine → potentially fewer movement-
related side effects.
• Combined with trospium to reduce peripheral side effects.
• Represents a novel mechanism of action in schizophrenia treatment.
Trial Design and Endpoints
Primary Endpoint:
• PANSS Total Score (Positive and Negative Syndrome Scale)
o Range: 30 (no symptoms) to 210 (severe symptoms)
o Measures: positive, negative, and general psychopathology
o Assessed after 5 weeks of treatment
Secondary Endpoints:
• PANSS positive subscale
• PANSS negative subscale
• PANSS Marder negative factor score
• Clinical Global Impression
• % of patients with ≥30% reduction in PANSS total score
