Varenicline

Dingle_berry

The 'magic bullet' in the fight against tobacco addiction.. Again and again studies have proven its safety and superior efficacy. Yet it seems to remain under-utilised.
I've heard anecdotes of it causing adverse effects ranging from strange dreams to severe depression and hypertension. Though the large, blinded studies mentioned above don't support this. Lancet PPA AmJP EOP

Is the drug a victim of MMR/autism like publicity or is there a legitimate basis for caution? E.G. could there be a population of people susceptible to adverse effects due to something like mutations in their nACHR?
Or is it more likely that withdrawal of nicotine and its dopamine surges causes depression, which is worse in individuals without other sources of dopamine surges? Depression bad enough to cause physiological effects like hypertension? (which to me would explain why studies show no difference in adverse effects between cessation therapies - they all cause this depression). If so why doesn't any published literature hypothesise this?

Kurtosis

That's really interesting. Firstly, there are a few reasons why large randomised controlled trials may not provide evidence of harms/adverse events. The number of people recruited is normally a function of what is needed to demonstrate a beneficial effect of the treatment being investigated. Adverse events are generally (hopefully!) a rarer occurrence, so would require a larger sample size in order to show a significant risk of these if there is one. What can get around this is meta-analysis, which pools the results of multiple trials in one analysis to increase the sample size.
Another reason a trial may not show a risk of harm is to do with the type of people recruited. Often these aren't reflective of the type of people who would be prescribed a drug once it goes on the market, and they tend to be healthier, younger, and less complex, which mean they're also probably less likely to have an adverse event and more likely to have benefits from the treatment. So the inclusion/exclusion criteria for recruitment to a trial can affect how valid is to the external general population.

On varenicline specifically, the Lancet study you link to overcomes these issues in calculating a sample size based on neuropsychiatric symptoms and specifically recruiting some individuals with a psychiatric condition. It is worth keeping in mind the following from the inclusion/exclusion criteria:

Those with qualifying primary psychiatric disorders were not excluded for other psychiatric comorbidities, but those secondary allowable diagnoses were also prespecified and excluded destabilising psychiatric conditions such as alcohol and other drug use disorders within the previous 12 months. Participants had to be considered clinically stable for inclusion (ie, no exacerbations of their condition in the preceding 6 months; on stable treatment for at least 3 months, with no treatment change anticipated during the study), and considered by the investigator not to be at high risk of self-injury or suicidal behaviour as gauged by participants’ responses on the Suicide Behaviors Questionnaire—Revised,19 or Columbia-Suicide Severity Rating Scale (C-SSRS),20 both administered at screening, and, if necessary, professional mental health assessment.

That's not to say that this in any way invalidates the results, but does mean that we don't know if the results apply to people with certain combinations of psychiatric conditions, those with recent changes in clinical status or those at risk of self-harm/suicide.

In a meta-analysis in the BMJ, comparing varenicline to placebo there was no evidence of an increased risk of suicide, suicidal ideation, depression, irritability, aggression, or death; an increased risk of sleep disorders, insomnia, abnormal dreams, and fatigue; and a reduced risk of anxiety. However as you suggest, a more important comparison is varenicline versus other therapies as opposed to just placebo. There's a Cochrane review that does just that (though I haven't read it in detail yet).

If there isn't any published literature which makes the case for your hypothesis, that's a good reason to write a letter in reply to one of the recent articles to put this forward! The BMJ for example makes it very easy to submit a rapid response to a paper so it isn't a big undertaking.