3 Clinical psychopharmacology3.1 General pharmacology
3.1.5.1 Phases I to II
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Written by Resident Doctor Committee · Published
Before the first human dose
Development phases are named by their main question, and the stages overlap.
Candidate drugs come from target-based design, existing molecules, phenotypic screening or repurposing.
Preclinical studies assess target affinity, selectivity, pharmacokinetics, interactions, toxicity, and cardiac, respiratory and central nervous system safety, including hERG effects.
Species differences limit prediction: in 2006, TGN1412 caused severe cytokine release and multi-organ failure in six volunteers despite reassuring animal studies.
Phase I
Phase I describes first human tolerability, pharmacokinetics and pharmacodynamics, including half-life, accumulation, target engagement and which exposures to take forward. Small, short studies cannot exclude rare or delayed harms.
Study | What it does |
|---|---|
Single ascending dose | Reviews each cohort before raising the dose |
Sentinel dosing | Staggers the first participants so early toxicity shows |
Multiple dose | Assesses accumulation, steady state and delayed effects |
Additional studies | Examine food, formulation, age, organ impairment and interactions |
Stopping rules for individuals, cohorts and the whole study are set in advance, with dose increments, ceilings and observation periods.
Investigators review clinical, electrocardiogram, laboratory, concentration and pharmacodynamic data before each escalation.
Healthy volunteers or patients
Healthy volunteers | Patients | |
|---|---|---|
Rationale | Avoid confounding by illness and medication | Disease-specific targets, or effects unacceptable in healthy people |
Best suited to | Kinetics and brief reversible measures | Disease-related pharmacodynamics, some higher-risk agents |
Repurposed drugs still need evidence for new doses, populations and combinations.
Psychiatric trials must address capacity, suicide risk, medication withdrawal and undue influence.
Consent means understanding that research is not individualised treatment, not merely signing.
Phase II
Phase IIa usually tests proof of concept in the target population.
Phase IIb explores dose and informs Phase III design.
A negative result may reflect target failure, inadequate brain exposure, or the wrong dose, population, measure or duration.
An effective reference treatment shows whether the trial has assay sensitivity.
Underdosing and dropout from adverse effects can hide real efficacy.
Target engagement and biomarkers
Target engagement confirms biological activity and makes a negative efficacy result more informative, but does not establish clinical benefit.
On positron emission tomography, many antipsychotics benefit at 65 to 80% dopamine D2 occupancy, with more movement risk above it, though not universally.
A biomarker measures a biological process or response and may guide selection or dosing.
A validated surrogate must reliably predict clinical benefit, and few psychiatric biomarkers do.
Rating scales are distorted by rater drift, expectation, missing data, repeated testing and regression to the mean.
Reading early-phase results
Small samples give imprecise effects and dose curves.
Short follow-up misses delayed harm and withdrawal effects.
Multiple exploratory analyses and differential dropout produce chance or biased findings.
Early signals justify further study, not routine prescribing.
Ethical safeguards
UK medicinal product trials need regulatory and ethics approval under clinical trial rules.
Consent covers uncertainty, burdens, alternatives, compensation and withdrawal without losing usual care.
Payment compensates time and burden without becoming undue inducement.
Adults unable to consent are protected by specific clinical trial safeguards, separate from other research legislation.
A scientifically inadequate study cannot justify exposing participants to avoidable risk.