Clinical sense about antidepressants

Cristea & Naudet (2018) conducted a content analysis of citations of Leucht et al (2012) (see previous post), a paper which concluded that psychiatric drugs are no less efficacious than other drugs. They found that identified records were overwhelmingly uncritical of the original paper and suggested it was being used to support the myth that the trivial effects of mental health drugs are to be expected and therefore accepted. 

Such uncritical thinking continues when claims continue to be made that there is no doubt about the effectiveness of antidepressants. For example, Tony Kendrick (@tony_kendrick) tweets that doctors can reassure patients that antidepressants are not simply placebos. But the editorial linked to that tweet is not open-minded enough about the data (see last post). People seem to be on the look out for evidence that counters the claim that antidepressants have little or no effect (see previous post). I’m not saying that antidepressants have been proven to be placebos. But in the same way that doctors have misled patients that the chemical imbalance theory of depression has been proven, I’m afraid we have to live with the uncertainty about whether and how antidepressants “work” (see another previous post).

As I keep saying (eg. see previous post), the reality is that the difference between active and placebo treatment in short-term trials of antidepressants is small. This small difference could be an artefact because of bias in the trial methodology, particularly unblinding. Even in the clinical trials not everyone is helped by antidepressants. They don’t always give the easy and simple answer people may have been misled to expect, particularly over the longer term (see another previous post).

Changing what doctors say about antidepressants

Kendrick & Collinson (2022) discuss the Moncrieff et al (2022) umbrella review about serotonin and depression (mentioned eg. in a previous post). As they say, doctors should not tell people with depression that antidepressants correct an imbalance or deficiency of serotonin, or that they will necessarily need long term treatment. It may well be helpful if the Royal Colleges of General Practitioners and Psychiatrists endorsed this view publicly. Trust between patient and doctor is paramount and doctors have been allowing people to believe that the serotonin theory has been proven, when this is clearly not the case.

Not that I completely agree with what Kendrick and Collinson say about antidepressants. Doctors have obviously used the serotonin imbalance theory as a means of persuading people to take their medication. True, Joanna Moncrieff probably makes too much of SSRIs being emotional suppressants (see previous post) but I do not think she has used the Moncrieff et al (2022) study to justify her scepticism about the efficacy of antidepressants, which is based on independent evidence.

In fact, Kendrick & Collinson do not reference probably the best summary of such effectiveness data (see previous post), which ironically was also published in the BMJ like their editorial. As far as they are concerned antidepressants are effective and typically quote Cipriani et al (2018a) in support, without quoting Cipriani et al (2018b) which provides a more sober interpretation of their findings. Cipriani et al merely conclude that antidepressants may be effective and do not go as far as Kendrick & Collinson in necessarily dismissing more sceptical interpretations of the data (see another previous post). Kendrick & Collinson clearly do not believe the placebo amplification hypothesis as an explanation of the clinical trial data, quoting Hieronymus et al (2018), but do not give a critical enough analysis of that paper (see yet another previous post). They are also too cavalier with the recent Stone et al (2022) study (see previous post), saying that some people experience a substantial response on antidepressants. However, this may be due to those subjects breaking the blind (see note from Irving Kirsch in Radoslaw Stupak's tweet). They also overstate the implications of the ANTLER study, to which Kendrick himself contributed, about maintenance treatment and withdrawal symptoms (see previous post).

Kendrick & Collinson are clearly fearful how patients may react if they interpret the scientific evidence as meaning that antidepressants are not effective. There are risks from stopping antidepressants. Doctors do need to provide as accurate data as possible to help people make up their minds in the inevitable uncertainty about the effectiveness of antidepressants. This includes no longer misleading them about the serotonin theory.

Sensible risk management in mental health

Hawton et al (2022) discuss why reliance on risk prediction of suicide in clinical practice has failed and outline an alternative therapeutic risk assessment, formulation and management model, which uses a person-centred approach. The focus on risk prediction and documenting risk assessment has actually misdirected the effort to prevent suicide.

Time needs to be spent on gaining therapeutic alliances rather than ticking boxes. Risk assessment is not a separate process from a full psychiatric history and mental state examination and formulation. A psychiatric management plan includes planning for safety. 

An ever more rigid and bureaucratic interpretation of risk assessment has been counterproductive, even destructive. Merely knowing about risks, even if these could be calculated precisely, may not improve practice. The fear that things may go wrong in mental health services has distracted from the task of actually making things better for people. Health care is more than a case of following rules and procedures. Conditions to improve patient safety are those that facilitate staff to bridge gaps in care, not the reverse. Risk management is actually the management of uncertainty, not the creating of an illusion of certainty (see post on my personal blog). 

Individual response to antidepressants in clinical trials

Stone et al (2022) provide data on response distributions of individual participants in antidepressant trials. It confirms previous data that shows a small 1.75 point random effects difference on the Hamilton Rating scale between drug and placebo (see previous post). The best fitting model of response distributions was three normal distributions, with mean improvements from baseline to end of treatment of 16.0, 8.9, and 1.7 points. These distributions were designated Large, Non-specific, and Minimal responses, respectively. Participants who were treated with a drug were more likely to have a Large response (24.5% v 9.6%) and less likely to have a Minimal response (12.2.% v 21.5%).

It’s important to keep in mind that this is only a best fit model and not necessarily think about it too absolutely. Also, this is not new data proving that antidepressants “work”, even if only for those that have a large or minimal response. As is said in the paper, it is still not possible to exclude the possibility that the effects of antidepressants are accounted for by functional unblinding. The placebo amplification hypothesis could still be a valid explanation of the antidepressant data (see eg. previous post). Raters' expectations and patients' suggestibility could entirely explain the small effect size found.

Stone et al suggest if the placebo amplification hypothesis is true that we "might expect shifts in the means of the response distributions for active drug relative to placebo”, which were not found. However, I'm not sure if this is true as I’m unclear if any lack of shift could instead be a result of the model. To my mind, those in the large or minimal groups could actually be the ones that are more likely to unblinded, whereas the nonspecific group essentially remains blinded. 

Florian Naudet in a useful Twitter thread emphasises that we need to start from the fact that it has been known for a long time that mean antidepressant effects in clinical trials are small. The limitations, at least, of antidepressants do need to be acknowledged. If the further claim that antidepressants are no better than placebo is true (which I think it may well be), it would have extraordinary implications for clinical practice (see eg. previous post). This is why people find it very difficult to consider that antidepressants may be no better than placebo. People do not want to undermine their faith in antidepressants (see another previous post).

Radical reform of psychiatry in Italy and beyond

Excellent podcast interview with John Foot on the politics of Franco Basaglia, based on his book (see eg. previous post). Asylums have closed across the world but as John says there is a need for a new movement.

Improving the draft Mental Health bill

The draft Mental Health Bill for England and Wales currently undergoing parliamentary scrutiny (see eg. previous post), essentially amounts to an amendment of current legislation. I would have preferred (see eg. previous post) if the government had been more ambitious and looked to replace both the current Mental Health Act (MHA) and the Mental Capacity Act (MCA). 

As I've also mentioned previously (see post), the Victoria state government in Australia is enacting a new Mental Health and Wellbeing bill, now published in its second reading. I find it an impressive document. It has very clear principles, including decision making principles for treatment and intervention, laid out on the face of the Act, which is not really the case for the draft Mental Health bill, although the White paper said it would do this (see another previous post). As I've also said before, the right to a second opinion from any psychiatrist on both detention and treatment is being strengthened in Victoria, whereas the draft bill does not go far enough in this respect (see eg. previous post). 

The Joint Committee on the draft Mental Health bill has called for evidence (see webpage). It wants to hear views on how the draft Bill could be improved, and how issues identified could be resolved. It lists particular areas of interest but answers do not need to be confined to those topics. Response are required by 16 September 2022.