How fast people left the placebo arm of an alcohol dependence trial depended on a DRD2 genotype
- A pharmacogenetic analysis of a 12-week double-blind, placebo-controlled trial of sensitizing therapy for alcohol dependence in Saint Petersburg: 150 detoxified adults, 50 each randomized to disulfiram, cyanamide or placebo; DNA was available for 116 (41, 40 and 35), genotyped at 15 loci in 9 genes.
- The main measure was the number of weeks a person stayed in the programme; leaving for any reason was counted as relapse.
- In the placebo arm, carriers of the AA genotype of rs6275 (DRD2) stayed 3.571 weeks (SE 0.72), against 7.786 (SE 1.05) for GG and 7.071 (SE 1.06) for GA; p=0.015.
- In the cyanamide arm, the CC genotype of rs1800955 (DRD4) stayed 10.154 weeks (SE 1.01), against 7.167 (SE 0.95) for CT and 9.333 (SE 1.29) for TT; p=0.052, which the authors call a tendency at the border of significance. No associations were found for disulfiram.
In this trial, "placebo response" has a narrow meaning: how long people on placebo stayed in the programme. It says nothing about symptom change. For a clinic that works with scheduled contacts, that makes it a measure of behaviour inside a service.
Weekly contact for everyone
For 12 weeks every participant came to the centre each week for remission checks, clinical and psychometric assessment, adherence control (a riboflavin marker in urine and a pill count) and sessions of a standardized course of rational psychotherapy. The 150 participants took disulfiram 500 mg a day, cyanamide 75 mg twice a day, or placebo. Leaving the programme for any reason counted as relapse.
Two genotype signals
In the placebo arm, 7 of the 35 people with DNA had the AA genotype of rs6275 in DRD2, and they stayed 3.571 weeks on average (SE 0.72), against 7.786 for GG (14 people) and 7.071 for GA (14 people); p=0.015. In the cyanamide arm, CC carriers of rs1800955 in DRD4 stayed 10.154 weeks (SE 1.01), against 7.167 for CT; p=0.052. The authors found no links for disulfiram, call all of this preliminary and ask for confirmation in larger samples.
The placebo arm is a programme
A placebo tablet in this study came with weekly attendance, adherence checks and psychotherapy. So the speed of leaving that arm shows how a person behaves inside a structured programme, and the authors themselves connect the DRD2 finding with personality and temperament.
The genotype is not a tool for the consulting room yet. What carries over is the attendance record. When a patient on a sensitizing drug begins to miss weekly visits, treat it as leaving a programme that included therapy, and answer at the level of the contact before the prescription.
A placebo arm with weekly visits and psychotherapy is a programme, and how quickly people leave it shows how they behave inside one.
The authors call the results preliminary and note that the small sample did not allow analysis of genotypes with rare minor alleles. DNA was available for 116 of the 150 participants. The cyanamide association is reported as a tendency at the border of significance (p=0.052).