Assignment #4: Paper Critique

Agomelatine in the treatment of seasonal affective disorder

Reference:

Pjrek, Edda, Dietmar Winkler, Anastasios Konstantinidis , Matthäus Willeit, Nicole Praschak-Rieder, and Siegfried Kasper. "Agomelatine in the treatment of seasonal affective disorder." Psychopharmacology. 190(2007): 575-579.

Introduction:

This was the first study which assessed the effectiveness of the new antidepressent agomelatine, or N-[2-(7-methoxy-1-napthyl)ethyl]acetamide.

This drug acts as a melatonergic (MT1 and MT2) receptor agonist and serotonin-2C receptor antagonist. Previous studies suggested that agomelatine is able to restore disrupted circadian rhythms associated with seasonal affective disorder, or SAD.

Object of study:

To investigate the effectiveness of this drug as a treatment for SAD.

Method:

• 37 acutely depressed SAD patients (29 women, 8 men),with

  moderate or severe, recurrent major depressive disorder along with the seasonal pattern specifier (DSM-IV-TR)

• Excluded patients with subsyndromal SAD (i.e. mild winter blues), bipolar illness, psychiatric comorbidity, psychotic features, acutely suicidal, patients with a suicide attempt in the last 6 months, pregnant or breast-feeding females or women without adequate contraception, patients with severe physical illness interfering with the study, etc.

• "Washout period" of 6 months prior to study for certain medications (eg. antidepressents such as lithium, BLT, exogenous melatonin) as well as certain activities (eg. shift work, transatlantic flights, other sleep-disturbing activites) which would interfere with the results.

• Agomelatine daily dosage of 25 mg in the evening for 14 weeks

• Efficacy assessments completed:

  o Structured Interview Guide for the Hamilton Depression Rating Scale (SAD version; SIGH-SAD)

  o Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I)

  o Circscreen self-rating scale for sleep and circadian rhythm disorders

  o Hypomania Scale

• All subjects provided written informed consent before their inclusion in the study, and all ethical standards were met.

Results:

• Treatment had a progressive, statistically significant decrease on assessment scores (SIGH-SAD, CGI-S, and CGI-I) from week 2 onward (p<0.001)
• Circscreen scores improved significantly (p<0.001)
• Treatment with agomelatine over 14 weeks led to higresponse rates (75.7%) and high remission rates (70.3%)
• Scores on the Hypomania Scale were consistently low during the study
• Tolerability good: few adverse side-effect of treatment recorded

1. ~ 1/3 of patients noticed mild sleepiness after the intake of the study drug during the first days of treatment
2. Only one patient reported impairment due to daytime fatigue
3. Mild sedative potential; did NOT cause major problems and did NOT lead to cessation of treatment in most hypersomniac SAD patients
   

Figure 1: declining SIGH-SAD scores over the 14 week period

Conclusions:

• Agomelatine may be a safe, effective treatment for seasonal depression

• Action onset after 2 weeks; based on significant changes in efficacy assessments
  

• Significant reduction in self-rated Circscreen score; associated with improvements of sleep disturbances and daytime fatigue

• Large percentage of patients experienced sustained remission during the 14 weeks of this study

• Virtually devoid of the side effects typical of other antidepressants, such as the selective serotonin reuptake inhibitors

Limitations/Problems with this study:

There were several design flaws in this study, which can make one wonder just how reliable the results are. A couple of these include:

• Open design of the experiment

• Lack of a control group (e.g. no placebo), hence nothing to compare the experimental results to
  

• Relatively small sample size, possibley not representative of the enitre population
  

• Four subjects were withdrawn from the study when they showed no improvement; removal of these subjects may make Agomelatine appear to be more affective than it actually is

In my oppinion, this paper does not produce very reliable results due to the poor experimental design. There was no control group, which is key for any experiment to produce reliable results. Placebos should have been given to a randomized group, while other dosage amounts should have been administered to other randomized groups. The patients themselves were not randomly selected; those who met the criteria for the study were chosen and recruited from a single outpatient clinic in Vienna. Thi small sample is likely to not be representative of the entire population of people suffering from seasonal affectiveness disorder. The elimanation of those who did not respond to the treament right away further limited the sample size and created a bias; only those who were affected by agomelatine were included in the final results, making the drug appear more affective than what it may actually be.
Larger double-blind, controlled studies must be done to determine the efficacy and tolerability of agomelatine on SAD patients.