Are there potential problems in the latest study on antipsychotic medication reduction and discontinuation?

 

A study on antipsychotic medication reduction and discontinuation came out yesterday with fanfare.  The fanfare was basically because the principal investigator is a self-proclaimed critical psychiatrist with many criticisms of psychiatric medication and the results of her trial contradicted the primary hypothesis of the study and that was:

“Our hypothesis was that antipsychotic reduction would improve social functioning with only a small increase in relapse rate.”

Relapse rate in this case was defined as rehospitalization and the authors subsequently state that they thought a 10% rate of relapse would be “acceptable.”  The irony of this situation (ideology versus real world treatment) was not lost on anyone. Several people seemed to congratulate the authors on publishing results inconsistent with their ideology although the study was so embedded in the UK research infrastructure – I doubt that not publishing it would have been an option.

As a clinical trialist myself – the research seems to present several problems and creates several questions that could suggest that it was designed to optimize the likelihood that antipsychotic medication could be reduced and possibly discontinued. Before I get into those scenarios let me briefly summarize the results.  The paper is open access and can be downloaded as well as another paper that describes the research protocol.

In the study there were two arms an antipsychotic maintenance arm (N=127) and a reduction arm (N= 126). Diagnoses were taken from clinical information and the clinical staff had treatment responsibility for the patients.  In those patients who were randomized to dose reduction, a tapering protocol was suggested to the clinical staff and if it went well at some point the option for a more rapid taper or discontinuation was offered.  The research staff monitored the protocol. Baseline and outcome measure included a number of checklists to assess side effects, sexual side effects, positive and negative symptoms, quality of life, and social outcomes at the reassessment points.  Raters were blinded but the measures are essentially self report.  The ultimate result was that the risk of adverse outcomes was worse in the reduction arm with no associated improvement in social functioning.   

He are some potential issues that I noticed based on my experience in clinical trial design and on research review boards.

1.  Recruitment – described in the following:

“Participants were recruited from 19 National Health Service Trust mental health organisations across England. Potential participants were identified initially by clinical staff or recruited through advertisements placed in clinical settings and social media; those patients who expressed an interest in participating were sent further information”.

Not enough information. What did the advertisements say? Were subjects aware of who was running this trial and what the goal of the research was? Were the patients asked why they were interested in participating in this trial?  Were they asked what they think about taking a medication? Did the subjects have any exposure to the considerable press that the critical psychiatry group and the principal investigator generate?  Descriptions in the lay press have been demonstrated to have significant effects on perceived side effects – even to the point of creating a nocebo effect (6) – is there any reason to think that a group emphasizing side effects and minimizing any therapeutic effects might have a similar impact? If that is the case – how would it affect this trial?  

2.  Inclusion/Exclusion criteria –

“Exclusion criteria included being considered by a clinician to pose a serious risk of harm to self or others were the individual to reduce their antipsychotic medication, being mandated to take antipsychotic medication under a section of the Mental Health Act, having been admitted to hospital or treated by a crisis service for a mental disorder within the last month, lacking capacity to consent, having insufficient spoken English, pregnancy, breastfeeding, and being involved in another trial of an investigational medical product; eligibility was assessed by researchers and confirmed by the Principal Investigator for the site.”

Practically all the exclusion criteria result in a population that may be more likely to discontinue antipsychotic medications with less difficulty. Consistent with this is the antipsychotic doses of both the reduction and maintenance arm of 300 mg chlorpromazine equivalents (on average).  According to the Maudsley Prescribing Guidelines (4) 300 mg chlorpromazine is considered the minimally effective dose of medication for relapsing schizophrenia. Whether this was a representative sample of the 4109 patients put forward for research by clinicians a comparison of the demographics and medication doses would have been of interest.  

Selection bias may also be evident in the Consort diagram (page 4).  After subjects consented to be contacted by the research team (N= 958) – a total of 562 declined participation. Was that because they did not want to take the chance of randomization to a medication reduction?

3.  Diagnoses – the diagnosis required was schizophrenia or non-affective psychoses with recurrent episodes. The diagnoses were taken from clinical records.  Considerable heterogeneity is introduced with the non-specific category of psychoses with an unpredictable course for which the concept of maintenance medication was not intended.  

4.  The Dose Reduction - 

The description of the dose reductions in the paper is confusing.  It starts out describing individualized reductions every 2 months based on starting doses but at some point states the patient is allowed to discontinue the medication if the dose reduction has been going well or reduce at a rate of the equivalent of 2 mg haloperidol/day.  2 mg/day of haloperidol is not a slow reduction and it is a departure from reduction every 2 months. Some of the authors here have written about antipsychotic withdrawal reactions – how is the more rapid dose reduction or optional abrupt discontinuation justified? 

4.  Safety Monitoring/Informed Consent: 

The more clinical trials I read (and I have read thousands) – the more I want to see the consent form that each patient signs. Some of the authors here continuously talk about medication side effects.  In fact – the principle investigator (PI) has stated that in her opinion that modern psychiatric medications work in a "drug centered" rather than a disease centered model by producing side effects like sedation, cognitive impairment, dysphoria, and loss of libido (5).  In that model, symptoms of mental illness are muted by side effects rather than effectively treated. The model essentially denies the possibility of effective treatment without medication side effects.  Of course, there are medication side effects but consent forms also must contain a discussion of the risks of the intervention. How are they listed when the investigators do not believe they can be directly addressed?  Were the subjects told about the risk from medication discontinuation of recurrent psychosis, suicidal thinking, and death?  That seems especially relevant in a study where the intervention arm had twice as many deaths as the maintenance arm (see Table 4).

Along those same lines – the protocol paper for the study (2) states that a Data Safety and Monitoring Board (DSMB) assessed the ongoing safety of the protocol and made recommendation to a Programme Steering Committee providing independent oversight – even to the point of stopping the protocol if there was a substantial increase in adverse events related to the intervention. Was there a threshold? In this case why was that threshold not met?  In the trials I have been involved with the PI and the physician responsible for monitoring safety (typically me) had to clearly delineate a safety plan if any of the research subjects developed medical or psychiatric complications from the intervention.  In this case that responsibility seems to have been delegated to the clinicians originally treating the patient.

In the reported causes of death of the trial participants – how is the death of a research subject in the reduction arm attributed to antipsychotic medication when they have been on a low dose, were being followed clinically in an outpatient clinic, and their dose was presumably being reduced?  One patient in each arm died of an “accidental overdose”. What medication was implicated in the accidental overdoses?

This protocol is also a case of shifting risk for the research to the clinicians.  Here the research staff designs an intervention that likely will lead to worsening clinic status and the subjects are followed in a treatment as usual manner. Were any additional safeguards in place for that eventuality?  For example – were the subjects informed that they could contact the principal investigator or research coordinator if things were not going well?

These all seem like significant safety questions to me.

5.  Social Functioning Scale (SFS) to measure the primary outcome - 

The measured results with this scale are in the top line of Table 2 at 6, 12, and 24 months.  The scale has 79 items that are assigned to assess social functioning.  Is there a problem with taking a cross sectional sample of people stabilized on medications and hypothesizing they will function better being tapered off antipsychotic medication? There is an obvious problem and that is there is no accounting for the improvement in social functioning due to the medication in the first place. In other words - what would the subjects have scored leading up to and during the episode of acute or recurrent psychosis - the reason they are taking the medication in the first place. What would the trajectory of these scores be over time? Stabilization of psychosis involves a lot more than treating hallucinations, delusions, and thought disorder symptoms.  With stabilization there is an improvement in social behavior.  The design of the trial suggests that the problem began with medications rather than a significant psychiatric disorder. 

There is a concept in clinical psychiatry and that is trying to get the patient as close as possible to their baseline level of functioning. That requires a knowledge of what they were like before the onset of illness and restoring as much functional and social capacity as possible. That also typically means minimal to no medication side effects if possible.

6.  What is supported reduction of antipsychotic medication?

Is there a protocol that I missed?  I could not find what this means anywhere in either the protocol or final paper or in the supplementaries.  If I was tapering an antipsychotic medication I would meet more frequently with the patient, inform them of what we need to watch for, have additional caregiver and family involvement, and encourage them to call me at specific signs of early problems due to the dosage reduction. In a research protocol, research staff would call and check on how the subject was doing. I would call all of that treatment as usual (TAU) when it comes to antipsychotic medication reduction. Is supported reduction more than that?  Even TAU has been implicated as a potential placebo enhancing effect. Did it have that effect on the intervention in this case?

7.  The overstated conclusion:

“Our findings provide information for people with schizophrenia and related conditions about the probable medium-term impact of reducing the dose of their antipsychotic medication, and they highlight the need for collaborative decision making based on the sharing and careful consideration of all the evidence.”

Actually, it doesn’t.  This is what clinical psychiatrists do and more specifically it is what I did for 35 years of practice. I can still recall community psychiatry seminars with Len Stein, talking about dosage reductions of antipsychotic medications and the implication of a WHO international study looking at that problem in schizophrenia.  That seminar was in 1986. Collaborative decision making seems to be the latest term for informed consent and therapeutic alliance. Informed consent means that the patient is given enough information and discussion so that they can make a decision about the direction of their care including any medications, tests, or other interventions used. The therapeutic alliance is the affiliative relationship between the patient and physician aligned to address the patient's problems and diagnoses.  It is by longstanding definition a collaboration.

What the authors did encounter but did not discuss was the tendency of people on antipsychotics to just discontinue them (several in the maintenance group did this), how much withdrawal was encountered, and why there were no group categorical differences in side effects with the taper.  According to the Glasgow Antipsychotic Side-effect Scale (GASS) guidelines all subjects remained in the moderate side effect range. And if medications work through side effects as the critical psychiatrists say why did the subjects in the dose reduction group worsen?   

Those are a few of the problems that jumped out at me as I read this paper and the associated backgrounder. As can be seen from the above discussion many of these design factors potentially optimize the intervention group in the direction of proving the authors’ hypothesis. It also limits generalizability to other clinical settings.  That makes the result of the trial even more significant.  It also raises some issues that seem more prominent in recent years as pharmaceutical conflict of interest seems to ring hollow.  Is there an ideological conflict of interest and how is it determined?  How does it affect research design, results, and the discussion of research findings?  

 

George Dawson, MD, DFAPA

 

References:

1:  Moncrieff J, Crellin N, Stansfeld J, Cooper R, Marston L, Freemantle N, Lewis G, Hunter R, Johnson S, Barnes T, Morant N, Pinfold V, Smith R, Kent L,  Darton K,  Long M, Horowitz M, Horne R, Vickerstaff V, Jha M, Priebe S.  Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial. Lancet Psychiatry September 28, 2023DOI:https://doi.org/10.1016/S2215-0366(23)00258-4.

2:  Moncrieff J, Lewis G, Freemantle N, Johnson S, Barnes TR, Morant N, Pinfold V, Hunter R, Kent LJ, Smith R, Darton K. Randomised controlled trial of gradual antipsychotic reduction and discontinuation in people with schizophrenia and related disorders: the RADAR trial (Research into Antipsychotic Discontinuation and Reduction). BMJ open. 2019 Nov 1;9(11):e030912.

3:  Danivas V, Venkatasubramanian G. Current perspectives on chlorpromazine equivalents: Comparing apples and oranges! Indian J Psychiatry. 2013 Apr;55(2):207-8. doi: 10.4103/0019-5545.111475. PMID: 23825865; PMCID: PMC3696254.

4:  Taylor D, Paton C. The Maudsley prescribing guidelines. CRC press; 2009 Oct 30.

5:  Middleton H, Moncrieff J.  Critical psychiatry: a brief overview. BJPsych Advances (2019), vol 25, 45-54.

6:  Colloca L, Barsky AJ. Placebo and Nocebo Effects. N Engl J Med. 2020 Feb 6;382(6):554-561. doi: 10.1056/NEJMra1907805. PMID: 32023375.

Photo Credit:

Many thanks to my colleague Eduardo A. Colon, MD for the photograph at the top of this blog.