Buspirone and Gepirone

 

Buspirone and gepirone are interesting compounds.  As shown in the above 2D structures they are structurally similar -  with the main difference being a cyclopentane ring in the azapirone structure in buspirone and two methyl groups at the same atom in gepirone. That results in the molecular formulas of both compounds to be slightly different.   

Buspirone was initially proposed as an antipsychotic medication (2) but it showed no efficacy in clinical trials.  Buspirone was FDA approved for the treatment of anxiety on September 29, 1986.  Gepirone was approved for treatment of depression on September 28, 2023. The 37-year lag time for approving gepirone has always been a mystery to me, especially given the amount of buspirone I have prescribed over the years.  Buspirone came out during an era of benzodiazepine prescribing that at times was excessive.  Alprazolam or Xanax was heavily marketing just prior to the release of buspirone and it did not take long for some experts to recommend using higher doses than the package insert to treat anxiety and panic attacks. That led to complications including excessive use and in some cases withdrawal seizures.  When buspirone was marketed, there was emphasis placed on the fact that it did not lead to excessive use, it did not affect the GABA receptor like benzodiazepines, it did not have synergism with beverage alcohol, and it did not have any withdrawal liability.  As a result, many primary care physicians tried to use it as a substitute for patients taking benzodiazepines. It was ineffective when used in that manner because of the behavioral pharmacology.  A person taking buspirone did not notice any immediate effects, unlike benzodiazepines and it did not reinforce its own use.  It also did not start to work immediately and had an onset of action more like an antidepressant. These properties had the effect of creating the perception that it was an ineffective medication and that was reinforced by some experts – who claimed that only benzodiazepines were useful for anxiety. 

Historically the enthusiasm for benzodiazepines decreased over time with antidepressants (SSRIs, SNRIs, and TCAs) being recommended for anxiety and panic rather than benzodiazepines. Some psychiatrists (like myself) used buspirone for both primary anxiety without panic and antidepressant augmentation. I found that it was an effective medication for those indications but it required a detailed discussion with the patient, especially if they had previous benzodiazepine exposure. The very favorable side effect profile – including no intoxication or withdrawal effects were an important consideration.  Generally, people exposed to that discussion did well on buspirone and were able to avoid benzodiazepines.

The activity of both compounds is thought to be mediated by 5-HT1A agonism as noted in the table below.  Using the PDSP Ki database as the source, more detailed receptor information is available for buspirone than gepirone, probably because the latter approval date.  Partial data is also given for 2 metabolites of gepirone one of which is active at the 5-HT1A receptor.

 

 

Receptor	Buspirone	Gepirone	3’-OH-gepirone	1-PP-gepirone
5-HT1A	5 - 77	38	58
5-HT1B	>10,000	>10,000
5-HT1D	>10,000
5-HT2A	138	3,630
5-HT2B	213.8
5-HT2C	489	>10,000
5-HT3	>10,000
5-HT4	>10,000
5-HT6	398
5-HT7	375
DA D4.2	78-136	58
DA D2 like	1,210
α-2	>1,042	>1,042		42

 All receptor affinities are Ki as nM from PDSP Ki database. Affinities for human receptors included where available.

 

What is the evidence these medications are effective?  The real mystery for these medications is their efficacy and favorable side effect profile compared with clinical use. In terms of side effects – I don’t think it is an overstatement to say that they have the most favorable side effect profile of any psychiatric medications. In my experience, it was rare for anyone to get a side effect.  If it happened it was most likely dizziness.  In prescribing to hundreds of people – I can recall exactly one person who got sedated. When used for antidepressant augmentation I have observed two people become hypomanic and that resolved with discontinuation of the buspirone.

I have no real information to explain the partial and delayed approvals. Most of the clinical trials for both medications occurred in the late 1980s and early 1990s. At that time there was clear evidence that both were effective for anxiety and depression and yet only buspirone was approved at the time for an anxiety indication. Psychiatrists are more typically aware of the off-label use of buspirone as an antidepressant augmenting agent from the Star*D study protocols (3).  At the time buspirone was described as one of the three best studied augmentation strategies for treatment resistant depression with lithium and thyroid hormone being the other two.

Interestingly – I am not aware of any head-to-head comparisons of azapirones to typical antidepressants for the treatment of depression. There are currently 67 studies on ClinicalTrials.gov with buspirone listed as an intervention. Most of these studies investigate the use in novel clinical situations or mechanism of action.  There is one study about anxiety and quality of life when it is used to treat depression and that currently has no publications.  Another references the Star*D study from 20 years ago.

The best single source for the efficacy of azapirones in depression, anxiety, and some novel situations is a chapter by Ninan and Muntasser(4). Their general conclusions are that buspirone is effective in treating generalized anxiety disorder (GAD), GAD with depression, and is more effective in treating the depression associated with anxiety than benzodiazepines. In studies with a crossover design and initial benzodiazepine exposure – response to buspirone was reduced but not eliminated. In a head-to-head comparison of buspirone 30 mg and venlafaxine ER (75 or 150 mg) for GAD both were superior to placebo but venlafaxine was superior to buspirone.  Buspirone has demonstrated efficacy in studies of both non-melancholic and melancholic depression.

Gepirone ER was studied in 3 RCTs for major depression and was effective in all three. One of those studies was a dose ranging study and only the higher dose was noted to be effective.  Gepirone was also studied in GAD with diazepam as a comparator.  Both medications were efficacious, but diazepam had a more rapid onset and consistent effects.  The anxiolytic effects of gepirone occurred at 6 weeks. When both medications were discontinued rebound anxiety occurred with diazepam but not gepirone.  There is some evidence from the buspirone trials that the anxiolytic effect of these medications improves over time.

The current azapirones are interesting and neglected compounds in clinical psychiatry.  They have not been vigorously studied for their primary indications of GAD and major depression.  Most of the interest in this class of medications was generated in studies that look at antidepressant augmentation. Although there is always a lack of pharmacosurveillance data in the US, my speculation is that second and third generation antipsychotics (aripiprazole, brexpiprazole) are much more likely to be prescribed as augmenting agents – despite the risk of tardive dyskinesia and metabolic effects (the azapirones have neither). In my experience with buspirone, I found it to be effective for GAD and antidepressant augmentations.  Despite the theoretical risk of serotonin syndrome – I never saw any symptoms of serotonin toxicity.  If gradually titrated - side effects were rare.  In any detailed informed consent discussion, the azapirones come across as having distinct advantages over other medication classes - primarily from the side effect perspective. With all medication there is a question of efficacy – but in relatively non-urgent situations most people prefer to try the medication with the lowest risk of adverse events – first.

 

George Dawson, MD, DFAPA

 

References:

(1) Piercey MF, Smith MW, Lum-Ragan JT. Excitation of noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with dopamine antagonist properties. Journal of Pharmacology and Experimental Therapeutics. 1994 Mar 1;268(3):1297-303.

(2) Le Foll B, Payer D, Di Ciano P, Guranda M, Nakajima S, Tong J, Mansouri E, Wilson AA, Houle S, Meyer JH, Graff-Guerrero A. Occupancy of dopamine D3 and D2 receptors by buspirone: A [11C]-(+)-PHNO PET study in humans. Neuropsychopharmacology. 2016 Jan;41(2):529-37.

Modest occupancy of D2/D3 receptors cannot R/O MOA of this plus 5-HT1A as MOA.

(3)  Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW, Rosenbaum JF, Kupfer DJ. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR∗ D) study. Psychiatric Clinics. 2003 Jun 1;26(2):457-94.

(4)  Ninan PT, Muntasser S.  Buspirone and gepirone. In: Schatzberg AF, Nemeroff CB.  The American Psychiatric Publishing Textbook of Psychopharmacology.  3^rd ed. Washington DC, American Psychiatric Publishing, 2004: 391-404.

(5)  Robinson DS, Rickels K. Buspirone.  In:  Schatzberg AF, Nemeroff CB.  The American Psychiatric Publishing Textbook of Psychopharmacology.  5th ed. Washington DC, American Psychiatric Publishing, 2017: 585-600.

“We speculate that had buspirone’s sponsor persuaded a depression rather than a GAD indication, buspirone might have well become the first 5-HT1A partial agonist developed as an antidepressant. At present, however, buspirone exists in the shadow of numerous approved antidepressant drugs with high clinical exposure and promotion”. (p. 591-592)  

A New Superfluorinated Medication

 

As a biology and chemistry major with ongoing interest – fluorinated medications have been an interest of mine for some time.  If you have taken organic chemistry – you know that fluorination significantly alters the properties of molecules due to the electronegativity of the fluorine atom.  If you are interested in the chemistry of compounds in nature – you may know none of them are fluorinated.  I pointed that out in a previous post about fluorinated molecules that are used as medications.

You can imagine my surprise when I received a solution of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane in the mail yesterday. That’s right C₁₃H₁₇F₁₃.  It’s not that people are mailing me random fluorinated compounds – this is a prescription from a dry eye specialist on the latest in dry eye care. It all started as a conversation at our last appointment.  He knows I am a nerd and I stared talking about the lack of available treatments and how it made no sense to me from a chemical perspective:

Me:  “It seems like a straightforward problem to me,  Current chemical analysis should be able to very accurately characterize the tear film including the lipid layer and just mix it up as eye drops.”

OD: “I hear you George – and we are getting close to that – in fact a new drug has just been released that is supposed to keep the tear layer from breaking up.  Are you interested in trying it?”

Of course, I was.  Dry eye disease in my case is multiple diagnoses and there seem to be no good solutions for any of them. I end up using non-preservative artificial tears 6 - 8 times per day and even then, get burning and foreign body sensations in the eye.  Worst case - my eyes start burning to the point that I can't focus and have to stop what I am doing.  Finding out that the new medication was a poly fluorinated alkane was a surprise. For the past two weeks I have been negotiating with the only pharmacy in the country that dispenses this product along with the pharmacy benefit manager. At one point a retail price of $950/3 ml was quoted and I am in the Medicare doughnut hole. For some unknown reason and appeal of the denial was granted and I got the prescription mailed to me.  I started it yesterday.

The accompanying package insert is only 2 pages in length. That is brief relative to most medications.  The results of two clinical trials are described (total of 1,217 patients). The studies were described as multicenter, randomized controlled clinical trails with a saline placebo. The trials were 57 days in duration. Toxicology has all been preclinical and mostly bioassays (Ames assay and in vitro chromosome aberration assay using human peripheral lymphocytes and in vivo bone micronucleus assays in rats). Long term toxicity studies have not been done.

I looked at what is known about the lipid layer that is provided by Meibomian glands in the eyelid.  The resulting secretion mebum is a complex mixture of lipids, waxes, and other organic molecules that provide a layer over the tear layer so that it does not evaporate and dissipate as quickly.  For all those details see the open access reference below.  One of the advantages of polyfluorination is that it greatly augments the lipid solubility of organic molecules.  That is good if you happen to want a controllable lipid layer over and aqueous layer, but it may cut both ways. There is plenty of lipid content in the human body where these compounds can enter. per- and poly-fluoroalkyl substances (PFAS) are examples of industrial chemicals that have become environmental contaminants in drinking water, food, and air.  A 2015 study looking at 2011 data suggested that 97% of American had PFAS in their blood, although there is some suggestion that these numbers have been decreased with less production and removals from products.  Technically the dry eye medication that I have reviewed here is a polyfluorinated alkyl product.  I will be following this release closely especially any after market adverse events and the literature on whether there is concern that this molecule might accumulate in lipid tissue in the body.  Ideally a product will be available that will mimic Meibomian gland secretion in terms of the lipids that are naturally there.

The potential dual nature of this medication highlights a dilemma that many people face every day.  Do you try a medication with potential downsides when the information about those downsides will take a while to accumulate?  To me that is always an informed consent discussion and it depends a lot on expectations and risk/benefit considerations.  In this case, dry eyes is a tremendous problem and there seem to be no other reasonable solutions. My answer currently is a qualified yes.  That may change as more is known about alternative medications that resemble the natural secretions or the toxicology of the current medication. I would characterize the level of severity of the problem as moderate.   There are more toxic medications out there and more severe conditions.

 

 

George Dawson, MD, DFAPA

 

 

References:

 

1:  Chen J, Panthi S. Lipidomic analysis of meibomian gland secretions from the tree shrew: Identification of candidate tear lipids critical for reducing evaporation. Chem Phys Lipids. 2019 May;220:36-48. doi: 10.1016/j.chemphyslip.2019.01.003. Epub 2019 Jan 17. PMID: 30660743; PMCID: PMC6600086.

2:  FDA page on PFAS:  https://www.fda.gov/food/environmental-contaminants-food/and-polyfluoroalkyl-substances-pfas

3:  FDA page on further PFAS study:  https://www.fda.gov/news-events/press-announcements/statement-fdas-scientific-work-understand-and-polyfluoroalkyl-substances-pfas-food-and-findings

4:  CDC page on Per- and Polyfluoroalkanes and Health:  https://www.atsdr.cdc.gov/pfas/resources/pfas-faqs.html

Library Access Problem Solved?

 

I have a couple of previous posts here about the disappointment of losing online access to medical journals.  The loss was due mainly to the arbitrary decisions of administrators and their lack of any ability to compromise. I offered several times to pay $1,000/year for online access to journals at the Biomed Library and was told that was not possible. More recently I donated $100 to become a Friends of the Library member with the benefit of online access to University of Minnesota Libraries. After the donation I learned that access to only occur through a terminal in a U of MN library. So every time I needed to read a paper – I would have to drive 40 miles (round trip) to get that level of access.

I read hundreds of papers per year – several of them more than once.  I must stay current and research topics for my blog and presentations. Reading one paper often results in needing to read many of the references – the amount of reading can snowball. Driving every day for access and probably having to print those references out in this age wastes both time and resources. It is still hard for me to believe that University library systems cannot charge for at home access that I can get for free through a county library.  I think they are trying to maintain a tradition that you can only get this as a perk if you are affiliated with our institution. That minimizes the role of the people paying the taxes to keep the institution afloat.  

Luckily I have patched together a system that seems to work fairly well to get the research papers that I need.  This is a Minnesota solution so although I would see if similar systems exist in your home state – there is no guarantee.

The centerpiece of the plan is my county library (Anoka County).  I tried this about 5 years ago and they did not have the necessary systems in place – but now they do.  The main option was affiliation with a much larger library system in Ramsey County. Once I was registered in both places – I had access to much more current digital media at the Ramsey County Library and the interlibrary loan system Minnesota Link (mnlink.org). Now if I am searching for a reference my Zotera app takes me to any full text references at either Ramsey County Library or Minnesota Link if I am logged in. If there are no full text references immediately available – I can search for them at Minnesota Link and expand that search if necessary to a national interlibrary loan system. The search returns a formatted reference that allows me to request the PDF and I typically get that the next business day. 

County library access is generally good but not 100%.  I would estimate it is in the 80-90% range for most medical and psychiatric references.  Many of the papers I have requested are from esoteric journals.  To cite one example – I had immediate access to a 1999 paper from the journal Depression and Anxiety today when doing some research for a friend. 

I continue to maintain my American Medical Association (AMA) and American Psychiatric Association (APA) memberships and the associated subscriptions.  The AMA subscriptions are a bonus because of the JAMA Network of subspeciality journals in 14 different specialties and access to the precursor journal Archives in Neurology and Psychiatry. The APA is much more restrictive than it used to be. Access as part of membership is restricted to the American Journal of Psychiatry (AJP).  That includes access to the American Journal of Insanity (AJI) - the forerunner before the AJP.  The AJI is indispensable in looking at historical trends in the field in the 19th and early 20th century. Researching  The precursor journal of Psychiatric Services used to be included in the membership but no longer. There are an additional 4 journals that could be provided but they all require an additional subscription fee.

I have standing subscriptions to Nature and Science magazine. I also invested in a Nature+ subscription for $30/month.  That allows me to access 55 journals published by that group but there are significant limitations. For example, I only have access to the past 5 years of journals and not older archives.  There are also some high-quality journals like Neuropsychopharmacology that are not included. In those cases I am hoping for an open access article or the authors sending me a copy of their paper through ResearchGate.

An additional bonus is that these libraries also allow access to a number of popular media sites that would otherwise require a paid online subscription of payment per view. That includes major newspapers and popular magazine that often include articles that I respond to on my blog.  

That is where my research access stands today.  It is a significant improvement at anytime since this became a problem 8 years ago.  The access to research journals through two county libraries and interlibrary loan was a game changer.  Although it is free to county residents it is paid for by property taxes and state income taxes and and I pay my fair share there. It also takes me back to my hometown county library where I worked during my college days. I was the audio-visual guy at that time and mailed materials out to different counties and individuals in a multi-county area. When I was not mailing, I was repairing 16 mm films for mailing.  Libraries provided critical access by both direct mailing and bookmobiles that travelled to different towns to provide access. It is good to see libraries providing modern access to necessary research materials and relieving some of the burden of publishing profit motives on the public. 

 

George Dawson, MD, DFAPA

Graphics Credit:  Click on the photo or complete information, graphics credits, and open access licensing information. This is A reading room in the State and University Library (Statsbiblioteket- now Royal Danish Library) in Aarhus, Denmark.

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.

The Recent Takedowns of Adult ADHD

 

Psychiatry seems doomed to argue endlessly about whether certain conditions exist or not and whether they can be characterized by written criteria. The latter condition is the most easily dismissed since clinical training is necessary to recognize conditions. You cannot just sit in an office, read the DSM and call yourself a psychiatrist. Whether conditions exist or not is more debatable but often slides into rhetoric that suggests inadequate training, ignorance, and/or significant conflict of influence or undue influence by the pharmaceutical industry. Consideration of the undue influence can easily be applied at the global level since Pharma has massive marketing efforts, direct to consumer advertising in the US, and at least one major political party pulling for them.

That brings me to the recent commentaries about adult ADHD (1, 2). The first reference (1) doubts that adult ADHD exists for the most part and sees the diagnosis primarily as the result of a marketing scheme by Eli Lilly for atomoxetine and ignoring affective temperaments and other states that may affect attention. Atomoxetine was invented as a norepinephrine reuptake inhibiting antidepressant and like other members of this class of drugs – it did not work for depression. Since it is not technically a stimulant it was tested for ADHD and found to be effective. It is unique relative to other ADHD medications and not surprisingly it was heavily marketed while on patent. The patent expired on May 2017. The years on the market patent protected were 2002-2017. The first references to the diagnosis of adult ADHD were noted in the 1980s. Reference 2 suggests that the diagnosis of ADHD in children in the US is around 2-3% with adult numbers half that based on the work of one author.  Contrasting numbers of a lifetime prevalence in adults as 8.1% and surveys estimating current prevalence at 4.4% are described as “absurdly high” but qualified on methodology (surveys vs interviews).  Some authors have the opinion that books published about adult ADHD like Ratey and Hollowell's  Driven to Distraction were a major source of public interest in the diagnosis and instrumental in getting it into the public vernacular. 

Before I get started – let me say that the only stake I have in this argument is making sure that the complexity of the situation is adequately described. Practically all the pro/con arguments in psychiatry are gross oversimplifications and based on what I know about the literature – I had no reason to expect that this was any different.  I am already on record on this blog describing how to diagnose and treat ADHD and not fall into the common problems of misdiagnosis, prescribing to people with substance use problems, or prescribing to people who view these medications as performance enhancers. I have successfully treated adult ADHD with both on and off label medications and can attest to the fact that it is a valid and treatable diagnosis.

Let me start out by looking at the prevalence estimates. These figures are very popular in the press to indict diagnosticians in the United States compared with some European countries and sell more papers. The problem with prevalence estimate is that the range can vary significantly due to methodological differences in the surveys. That question was looked at (3) and the title of that paper asked if ADHD was “an American condition”.  The authors reviewed 22 studies based on DSM-III criteria and 19 studies based on DSM-IV criteria.  Twenty prevalence estimates were done on the US and 30 were done in other countries.  They demonstrated that the range of prevalence across all studies was approximately the same and that ADHD was not just an American condition. Since then numerous prevalence studies have been done in other countries – more recently using DSM-5 criteria showing similar ranges.

On the issue of adult ADHD, a recent review looked at the issue adult ADHD and symptomatic adult ADHD prevalence by the 6 WHO regions (4).  Their overall goal was to determine the worldwide prevalence of adult ADHD. They looked at the issue of persistent or childhood onset ADHD and symptomatic adult ADHD with no evidence of childhood onset and estimated the prevalence of those two groups separately.  The pooled prevalence of persistent adult ADHD was 4.6% and for symptomatic ADHD it was 8.83%.  These authors also looked at prevalence by a list of demographic factors, diagnostic criteria, addition to geographic areas as well as the decreasing prevalence by age groups.   

 

Study	Target Population	Prevalence % (US vs Non-US) ranges or pooled
Faraone, et al (2002)	DSM-III ADHD DSM-III-R ADHD DSM-IV	(9.1-12.1) vs. (5.8-11.2) (7.1-12.8) vs. (3.9-10.9) (11.4-16.1) vs. (2.4-19.8)
Polanczyk, et al (2007)	Pooled prevalence estimates of ADHD by geographic location.  N= number of studies in each WHO designated location	North American (N=32)  6% Europe (N=32)  4.5% Oceana (N=6) 4.5% South American (N=9) 12% Asia (N=15) 4% Africa (N=4) 8% Middle East (N=4) 2.5%
Song, et al (2021)	Pooled estimates and ranges of Adult ADHD worldwide by WHO designated geographic areas	North America (N=3) 6.06% Europe (N=10) 7.12% Oceana (N=4) 9.67% South America (N=3) 6.06% Asia (N=1) 25.6% Africa (N=1) 9.17% Middle East (N=2) 16.58%

 

This study raises the issue of whether ADHD can be acquired rather than be a childhood onset illness. The reality is that there are many paths to acquired attentional deficit that have been treated over the course of my 35 years in the field.  The best examples are neurodegenerative diseases, strokes, and brain injuries. Neuropsychiatrists have written about treating the associated cognitive, mood, and motivational deficits with stimulants.  But a more relevant question is whether mechanisms exist that can result in people with none of these acquired brain injuries.  The answer comes from modern genetics. Polygenic risk scores (of all diseases) suggest that there are high risk individuals who show no evidence of an illness as adults. These examples of incomplete penetrance are usually explained as environmental factors, additional genetic dynamics such as aging or protective factors. I see no reason why these factors could not occur in an ADHD genotype after childhood. The other significant genetic factor is spontaneous mutation or as a recent commentator put it: “You don’t die with the genome you were born with.” Psychiatry has focused on familial studies for the past 50 years, but it is likely that significant numbers of most conditions occur as the result of spontaneous mutations rather than strictly hereditary transmission. That is borne out in clinical practice every day.

The authors (1) make the argument that ADHD is not a “scientifically valid” diagnosis. They explain “these symptoms have not been shown to be the result of a scientifically valid disease (adult ADHD) and better explained by more classic and scientifically validated psychiatric conditions, namely diseases or abnormalities of mood, anxiety, or mood temperament.”  Mood temperament is a stretch.  It is rarely commented on in adult psychiatry and then in extreme cases.  It is not contained in the DSM. Part of the reason is selection bias.  Psychiatrists are seeing people who have failed multiple other treatments and I have referred to this as being the treatment provider of last resort. 

Another factor is that ADHD is a quantitative rather than qualitative disorder – that is the cognitive symptoms are at the extreme end of normalcy and it is difficult to draw a line to demarcate illness from normal in many cases. A comparable example from medicine is hypertension.  The cutoff for what is considered hypertension has varied significantly over the decades (9, 10) and even now considers antihypertensive side effects as a qualifier for treatment.  That means that for any 2 people with the same marginally elevated blood pressure only one might get consistently treated. At one point hypertension was considered by some physicians to be a necessary compensatory mechanism that should not be treated (10). On the issue of quantitative aspects of psychiatric disorders in general – dimensional approaches are often suggested as a solution and the question is whether they work any better than the impairment criteria used in the DSM.  That is especially true in a clinical setting where a patient is presenting with a clear problem that they are asking for help with

On the issue of validity, studies have been done demonstrating reliability and validity (8) on both the DSM criteria as well as various rating scales for adult ADHD that are consistent with the diagnosis. There have also been detailed discussions of how to approach the problem clinically (11).  Those discussions include how to differentiate mood disorders from ADHD and how to approach the functional impairment criteria in the clinical interview.

That brings me to the issue of temperaments mentioned in reference 1.  Temperaments have been researched in various contexts in psychiatry over the past decades.  Most psychiatrists of my generation first heard about them on child psychiatry rotations and the work of Stella and Chess. In adults, temperaments are more descriptions of hyperthymia, cyclothymia, and dysthymia and are generally considered in the differential diagnosis of subclinical mood disorders.  The best example is hyperthymia and it has been referred to both as a temperament and a personality. Hyperthymic people are generally high energy, require less sleep, and are social, talkative, and outgoing. They may be very productive and have increased libido relative to their peers. In clinical interviews they may say that their friends think they are “bipolar” and need to be treated. But careful interviewing demonstrates that they lack the symptom severity and degree of impairment necessary for a diagnosis of bipolar disorder.  Ideally the initial interview results in that formulation and the psychiatrist can advise the person about why treatment is not necessary.

Reference 12 looks at the issue of temperaments in a retrospective controlled study of patients being treated with stimulants who were referred to a mood disorders clinic.  The authors acknowledge the selection bias in their study design. I can not think of a better design to pick up misdiagnosed patients than this one. To cite one example – of the 87 amphetamine treated referrals only 50% had a past diagnosis of ADHD. The authors acknowledge that there is no standard way to determine affective temperaments and decide to use the TEMPS-A with a cutoff of 75% of the items. If you are able to find a copy of the TEMPS-A (it is not easy) – you will find a list of 50 true-false questions like “I’m usually in an upbeat or cheery mood.” The questions are reminiscent of the Minnesota Multiphasic Personality Inventory (MMPI) except there are far fewer questions. The scoring guide suggests that the TEMPS-A can discriminate between hyperthymic, cyclothymic, dysthymic, and irritable temperaments. It is validated in the usual ways.  The relevant question is whether any diagnosis made with this checklist would deter you from treating a comorbid condition - like Adult ADHD?  It is one thing to survey a misdiagnosed group with the TEMPS-A and consider the clinical implications, but another to consider the presenting problem possible ADHD and whether it should be treated.

The arguments in reference 2 about overdiagnosis, the existence of adult ADHD, and the idea that ADHD can occur in adults without a childhood diagnosis can be challenged with the facts and references provided here.  The fact that we are in the midst of a multigenerational drug epidemic in an increasingly intoxicant permissive society does not mean that a diagnosis, treatment, or problem does not exist. It does mean that all psychiatrists from the moment they enter practice must exercise extreme caution when prescribing substances that reinforce their own use. 

The most likely cause of overdiagnosis is not because adult ADHD does not exist, not because of drug promotion (most are generic including the non-stimulant alternatives), or because MDs are careless.  There are basically two reasons.  First – the difficulty of diagnosing quantitative conditions. Second – sociocultural factors that exist in the US. Performance enhancement is built on the myth that you can tune your brain (or any organ) with supplements, nutrients, or medications to become a superior human being. The reality is you can alter your conscious state to believe that – but in the case of stimulants it is unlikely. The only real performance enhancement occurs because you can stay awake longer to read more and there is some evidence that your belief system is altered so that you believe you are smarter (14). These are just two of the reinforcing properties of stimulants that can lead to accelerated use and addiction.

That is my brief summary of the complexity of this situation. For more on my approach to adult ADHD (I only treat adults) – see this post.

 

George Dawson, MD, DFAPA

 

References:

1:  Ruffalo ML, Ghaemi N.  The making of adult ADHD: the rapid rise of a novel psychiatric diagnosis.  Psychiatric Times 2023 40(9): 1, 18-19.

https://www.psychiatrictimes.com/view/the-making-of-adult-adhd-the-rapid-rise-of-a-novel-psychiatric-diagnosis

2:  Frances A.  Containing The Adult ADHD Fad — With a Rejoinder from ChatGPT. 9/21/23. 

https://www.psychotherapy.net/blog/title/containing-the-adult-adhd-fad-with-a-rejoinder-from-chatgpt

3:  Faraone SV, Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: is it an American condition? World Psychiatry. 2003 Jun;2(2):104-13. PMID: 16946911  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525089/

4:  Song P, Zha M, Yang Q, Zhang Y, Li X, Rudan I. The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis. J Glob Health. 2021 Feb 11;11:04009. doi: 10.7189/jogh.11.04009. PMID: 33692893; PMCID: PMC7916320.

5: Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007 Jun;164(6):942-8. doi: 10.1176/ajp.2007.164.6.942. PMID: 17541055.

6:  Kim DS, Burt AA, Ranchalis JE, Wilmot B, Smith JD, Patterson KE, Coe BP, Li YK, Bamshad MJ, Nikolas M, Eichler EE. Sequencing of sporadic Attention‐Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2017 Jun;174(4):381-9.

7: McGough JJ, Barkley RA. Diagnostic controversies in adult attention deficit hyperactivity disorder. Am J Psychiatry. 2004 Nov;161(11):1948-56. doi: 10.1176/appi.ajp.161.11.1948. PMID: 15514392.

8: Kooij JJ, Buitelaar JK, van den Oord EJ, Furer JW, Rijnders CA, Hodiamont PP. Internal and external validity of attention-deficit hyperactivity disorder in a population-based sample of adults. Psychol Med. 2005 Jun;35(6):817-27. doi: 10.1017/s003329170400337x. PMID: 15997602.  

9:  Saklayen MG, Deshpande NV. Timeline of History of Hypertension Treatment. Front Cardiovasc Med. 2016 Feb 23;3:3. doi: 10.3389/fcvm.2016.00003. PMID: 26942184; PMCID: PMC4763852.

10:  Kotchen TA. Historical trends and milestones in hypertension research: a model of the process of translational research. Hypertension. 2011 Oct;58(4):522-38. doi: 10.1161/HYPERTENSIONAHA.111.177766. Epub 2011 Aug 22. PMID: 21859967.

11:  Murphy KR, Gordon M.  Assessment of adults with ADHD. In: Barkley RA. Attention-Deficit Hyperactivity Disorder, 3^rd edition.  The Guilford Press, New York, 2006: 425-450.

12:  Mauer S, Ghazarian G, Ghaemi SN. Affective Temperaments Misdiagnosed as Adult Attention Deficit Disorder: Prevalence and Treatment Effects. J Nerv Ment Dis. 2023 Jul 1;211(7):504-509. doi: 10.1097/NMD.0000000000001626. Epub 2023 Apr 11. PMID: 37040539.

13:  Akiskal HS, Mendlowicz MV, Jean-Louis G, Rapaport MH, Kelsoe JR, Gillin JC, Smith TL. TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament. J Affect Disord. 2005 Mar;85(1-2):45-52. doi: 10.1016/j.jad.2003.10.012. PMID: 15780675.

14:  Ilieva I, Boland J, Farah MJ. Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology. 2013 Jan;64:496-505. doi: 10.1016/j.neuropharm.2012.07.021. Epub 2012 Aug 1. PubMed PMID: 22884611.