Thursday, July 13, 2023

Post SSRI Sexual Dysfunction (PSSD) - Current Status

 


Post Selective Serotonin Reuptake Inhibitor Sexual Dysfunction (PSSD) is a proposed disorder of sexual dysfunction that continues after antidepressant medication has been discontinued.  The symptoms include (2) prior treatment with an SSRI, a change in genital sensation after the SSRI has been stopped, decreased libido, anorgasmia, erectile dysfunction, and a duration of symptoms for 3 months following the cessation of the SSRI.  It is also a diagnosis of exclusion since pre-SSRI sexual dysfunction and other medications or medical conditions that could account for the symptoms need to be ruled out. It is a controversial diagnosis at this point because the true prevalence of the condition is unknown and the studies of the condition are generally low quality.

The diagnostic criteria for PSSD and PGAD are listed in the graphic above. It is not clear at this point what the diagnostic standard is for these disorders and heterogeneity is clearly an issue. For example, do a certain number or pattern of symptoms need to be present or could a single symptom be present with SSRI exposure and qualify for the diagnosis.

The controversy about PSSD reached its zenith with a recent article suggesting that antidepressants caused “chemical castration.”  When I first heard about this issue a few years ago it reminded me of the decades old problem of priapism (persistent painful erections) associated with trazodone use.  At the time (now about 27 years ago) I did a literature search on the incidence of spontaneous priapism in adult males and found that it matched the frequency suggested with trazodone use - but there were problems with determination of the true prevalence in both cases.

Prevalence estimates in the literature are approximate because they depend either on voluntary reporting (since there is no formal pharmacovigilance system in the United States) or available survey samples that typically have some obvious bias. In the 27 years since, I have warned every male patient I prescribed trazodone to and what to do about the problem. None of those patients developed priapism.  Two noticed they had AM erections that seemed unusual but did not develop priapism.  They ignored the erections, did not call me, and noticed that everything went back to normal.  In my experience, that is how most people manage side effects – even when you tell them they are potentially severe and may require medical or surgical intervention.

My experience with sexual side effects of antidepressants is similar. Since these side effects are common with antidepressants – it is one of many that I verbally advised patients about. My protocol was to provide people with the MedlinePlus handouts, advise them how to access the package insert for all of the detailed information, but then discuss the side effects they are most likely to encounter including antidepressant withdrawal, rare side effects that can be very serious like serotonin syndrome and drug induced liver disease, and a general advisory to call me with any questions about what might be a drug side effect: "If you feel ill assume it may be the medication and call me."  On the latter, I emphasize the call to me should been as soon as the problem develops and that I never expect that a person will “get used to” medication side effects.

The literature suggests that direct discussion of sexual side effects is more likely to result in patient reports if those side effects occur. In my experience it generally requires an explanation of what to look for in terms of libido and actual sexual functioning. Assessment is complicated by the high prevalence of these symptoms in depression and the fact that some people prefer the antidepressant effect over any lack of effect or deleterious effects on sexual functioning.

A logical place to start considering PSSD is to look at prevalence estimates from available studies.  A 19-year retrospective observational analysis of 12,302 men in an HMO setting (1) estimated the prevalence of PSSD to be 1 in 216 patients (0.46%) treated with SSRIs. The prevalence of PSSD was 4.3 per 100,000.  Cases were identified by exposure to SSRI and treatment of (erectile dysfunction) ED with PDE-5 inhibitors.  Other conditions were ruled out on an administrative basis based on BMI and medications that that potentially cause ED.  The authors point out that the design had limitations in that the trade-off of medical treatment as a proxy for ED diagnoses may underestimate the prevalence of ED/PSSD. 

In a second systematic review (2) – look at PSSD and Persistent Genital Arousal Disorder (PGAD).  PGAD can occur in the context of no treatment with an SSRI but it has also been reported after SSRI treatment.  The main differentiating point is that is has sensations of persistent genital arousal or genital dysesthesias. It may also be associated with uncontrolled orgasms.  Time criteria suggested is greater than 3 months.

These authors reference the European Medicines Agency (EMA) recognizing the PSSD diagnosis in 2019 (3).  Unfortunately, the EMA web site is only slightly more user friendly that the FDA website.  I have linked to the referenced document and included the relevant text at the top of this post.  I could find no more detailed information about the rationale for inclusion.  The suggested links just brought me back to the original document. References or even regulatory documents would be useful in this case to determine the EMA rationale for this position. It appears to have been based on a pharmacovigilance signal and that could be generated from registries in Europe, but at this point I cannot confirm the information.

The available literature on PSSD consists primarily of case reports, speculation about the biological plausibility of the disorder, and in the discussions calls for more studies of the true prevalence of the disorder.   19 studies were included in the review. Incidence or prevalence of PGAD could not be determined.

Physical causes of some of these symptoms are obviously important.  Herpes zoster or shingles infections cause about 100,000 cases of genital dysesthesias per year. There have been reports of Herpes simplex genital viral infections (HSV-1, HSV-2) causing similar symptoms. HSV-1 and HSV-2 cause significant neuropathic symptoms during acute recurrences, but that has been thought to resolve with each recurrence. Local and systemic neurological conditions affecting pelvic nerves and the autonomic nervous system are also potential causes.  There are many complicating factors when considering sexual dysfunction in the population as a whole, in untreated depression and in treated depression.

1:  Baseline rate/causes of sexual dysfunction:

In the largest post Kinsey study (7,8) , a national probability sample in the US looked at 7 indicators of sexual dysfunction including decreased desire for sex, arousal difficulties, inability to achieve climax, anxiety about sexual performance, climaxing or ejaculating too soon, physical pain during intercourse, and not finding sexual intercourse pleasurable. Only sexually active respondents were analyzed. 43% of women and 31% of men reported a problem.  Psychosocial and medical factors were also investigated and found to be relevant.  The authors conclude that sexual dysfunction is a significant public health problem.  The codebook for the original study was downloaded and medication history was not included.

2:  Baseline rate of sexual dysfunction due to depression:

Rates of sexual dysfunction in both sexes due to depression are similarly high. A comprehensive review of that literature by Gonçalves, et al (9) showed high rates of dysfunction in women than men.  Their data is summarized in the far right column in the table below.  These researchers also pointed out an important methodological problem with studies that depend on standard rating scales - some do not ask if the respondent considers the symptom to significantly affect their level of functioning. It is possible to do a rating scale experiment that show impairment when the respondent does not believe they are impaired.


3:
  Antidepressant sexual side effects:

Sexual side effects are a well-known side effect of modern antidepressants.  Various strategies have been suggested over the years to reduce or eliminate these side effects.  The only strategy I found effective was to change to a different antidepressant.  Prevalence rates of these side effects were initially available from package inserts and comparisons with placebo in drug trials.  The last summary information I have looking at those numbers is from the 2012 Drug Facts and Comparisons.  In a comparison of all of the available SSRIs at the time the following rates were suggested: decreased libido 1-12%, paresthesia (non-specific) 1-4%, abnormal ejaculation 6-27%, female genital disorders 2-10%, male genital disorders 4-10%, sexual dysfunction/impotence/anorgasmia 1-13%.   Comparisons across antidepressant classes is difficult because of changing categories. For example, SNRIs (venlafaxine, desvenlafaxine, duloxetine, milnacipran) generally have lower sexual dysfunction figures.  By the time duloxetine was marketed the package insert contained ratings from the Arizona Sexual Experiences Scale (ASEX) and comparisons with placebo.

 Conclusions:

 There are several problems with the current conceptualization of PSSD including:

1:  The evidence basis is largely anecdotal case reports, case series and abundant speculation based on those case reports.  There are no controlled studies so the prevalence of PSSD in populations untreated with antidepressants is unknown. Experts in the PSSD field also suggest this is due to changing diagnostic criteria (Goldstein).

2:  Both untreated depression and treated depression have significant symptom overlap with the suggested diagnosis of PSSD

3:  The incidence of sexual dysfunction in the general population without depression who have never been treated with antidepressant medication is high and varies as expected with comorbidities, age and other medical treatments. (Laumann). 

4:  There are no validated instruments or protocols to identify cases of PSSD. Multiple authors suggest determining the prevalence of the problem more accurately but that study would have to be carefully designed.

5:  Opinions in the popular press can bias prevalence studies at this point.  In the past, survey studies have proven that they can elicit any predetermined opinions and should be avoided.  How to eliminate this factor introduced by the press and anti-antidepressant advocates is not clear.  

6:  The determination of the pharmacovigilance signal by the EMA should be clarified.  It is possible that I did not find it.  In that case, I would appreciate being directed to that source. I emailed the European Medicines Agency asking for clarification on July 10 and am still waiting for a response. The process also has lessons for the United States.  I have long been an advocate for a more formal pharmacovigilance system in the US.  The next step would be a system like the Netherlands where any person could call in a suspected adverse event and there would be a connection to formal regulation as wording in package inserts.

7:  For psychiatrists in the US, I would see the current situation as comparable to the FDA warnings on suicidal behavior and suicidality on SSRIs and treat it the same way.  Even though pharmacovigilance in the US is basically post marketing surveillance, it makes sense to add PSSD/PGD to the informed consent discussion with patients as a potential risk of antidepressant treatment. It can be mentioned in the same discussion as sexual side effects from these medications. I would also describe these diagnoses as a work in progress at this point due to the limiting factors.

8:  The impact of the current level of discussion in the press and the effect it may have on patients taking antidepressants has not been determined at this point. In my practice in the past, most people make their own determinization of whether these warnings apply to them and may discuss it in the office, but it is reasonable to ask if they have any concerns while discussing side effects.

9: Ideological bias – there is clearly a faction of criticism that conflates pharmaceutical interests with psychiatry and makes it seem like there is a psychiatric agenda to overprescribe medications and cover-up side effects.  This same faction has a very limited to non-existent scientific basis and an equally robust clinical approach to psychiatric problems. More importantly they appear to not treat serious problems and at times have criticized people who find both psychiatric diagnosis and treatment helpful. An awareness of this bias is necessary when evaluating literature focused on the characterization and prevalence of PSSD. 

10:  Ratings from existing trials: The current controversy is reminiscent of the emotional blunting controversy (10) and the suggestion that antidepressants work by blunting emotions. Ron Pies and I reviewed studies that used the Montgomery–Åsberg Depression Rating Scale (MADRS) to show that decreased feeling was correlated with depression and that emotional blunting improved with treatment.  Existing rating scales for antidepressant trials have only 1 item that rates sexual functioning and that it the Hamilton Depression Rating Scale (HAMD). There is limited opportunity to do retrospective studies on existing clinical trials on that basis.

11:  The nocebo effect: The nocebo effect is essentially a negative expectation or expectancy that affects both the potential efficacy and side effect profile of a medication.  The effect is significant for all medication including antidepressants.  In antidepressant trials an analysis of the placebo exposed group showed that 63.9% reported treatment emergent adverse events, 11.2% experienced worsening depression, and 4.7% discontinued the trial due to an adverse event – all while taking placebo. In a recent review Colloca and Barsky discuss the importance of the media, press, and direct exposure to people with adverse events “all foster nocebo responses.” They give an example of how negative press coverage led to a 2,000 fold increase in adverse event reporting when a new medication covered by the national health plan came out. 

 If you have followed my various lines of reasoning so far it is probably apparent that I take any pharmacovigilance signal seriously. You must when you are a clinician who warns people about side effects that occur in the 1 in 10,000 to 1 in 50,000 range.  I consider the best prevalence estimate in this case to be less than 1 in 1,000, but all the experts clearly acknowledge problems with the diagnostic criteria and changing criteria.  In order to take the PSSD problem seriously it must be considered a multidisciplinary problem. Psychiatrists, neurologists, OBGYN specialists, urologists, psychologists, and physical therapists have all written about the problem and in many cases documented successful treatments. In some of those papers, multiple individual or combined treatments were highly successful. From a psychiatric standpoint, SSRIs have been resumed and treatment like adding bupropion or vortioxetine have seen successful – but the evidence basis is very limited. If this condition came to my attention in a patient, I was treating my preferred approach would be to discontinue the SSRI or SNRI if possible and develop a referral source where I could refer the patient for the necessary evaluation looking for neuropathic causes and documenting the level of sexual dysfunction. In my region that would probably involve referrals of men and women to a well-known Urology clinic that has sub-specialists in this area. The ultimate plan would also depend on patient preference, individual history of treated depression, and where the research in this disorder was at the time. Every individual needs a unique plan and looking at the heterogeneity of findings in this research – unique plans will be the rule and not the exception.

Currently, prevalence studies as well as studies that look at the issue of how these symptoms vary as people transition during episodes of treatment for depression and/or anxiety are required.  That will be a significant undertaking.  Observational studies based on active treatment may be a suitable substitute but safeguards need to be taken to assure adequate documentation of baseline sexual dysfunction, a clearly defined diagnosis and diagnostic thresholds, correlation with antidepressant treatment, and hopefully resolution both with or without treatment.

Lastly, if you are a person with any of the sexual problems described in this post – antidepressant related or not the best potential solution is a direct discussion with your personal physician or psychiatrist. If necessary, send them a link to this post and suggest they read the last two paragraphs. As always my posts are intended to be educational informed by clinical practice and not suggest that I know more than anyone else.

 

George Dawson, MD, DFAPA

 

 

References:

1:  Ben-Sheetrit J, Hermon Y, Birkenfeld S, Gutman Y, Csoka AB, Toren P. Estimating the risk of irreversible post-SSRI sexual dysfunction (PSSD) due to serotonergic antidepressants. Ann Gen Psychiatry. 2023 Apr 21;22(1):15. doi: 10.1186/s12991-023-00447-0. PMID: 37085865; PMCID: PMC10122283.

2:  Tarchi L, Merola GP, Baccaredda-Boy O, Arganini F, Cassioli E, Rossi E, Maggi M, Baldwin DS, Ricca V, Castellini G. Selective serotonin reuptake inhibitors, post-treatment sexual dysfunction and persistent genital arousal disorder: A systematic review. Pharmacoepidemiol Drug Saf. 2023 Jun 9. doi: 10.1002/pds.5653. Epub ahead of print. PMID: 37294623.

3:  European Medicines Agency. Pharmacovigilance Risk Assessment Committee recommendations on safety signals. 11 June 20191 EMA/PRAC/265221/2019 Pharmacovigilance Risk Assessment Committee (PRAC).  https://www.ema.europa.eu/en/documents/other/new-product-information-wording-extracts-prac-recommendations-signals-adopted-13-16-may-2019-prac_en.pdf

4:  Healy D, Bahrick A, Bak M, Barbato A, Calabrò RS, et al. Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin. Int J Risk Saf Med. 2022;33(1):65-76. doi: 10.3233/JRS-210023. PMID: 34719438; PMCID: PMC8925105.

5:  Lewer, D., O'Reilly, C., Mojtabai, R., & Evans-Lacko, S. (2015). Antidepressant use in 27 European countries: Associations with sociodemographic, cultural and economic factors. The British Journal of Psychiatry, 207(3), 221-226. doi:10.1192/bjp.bp.114.156786

6:  Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women's Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD). J Sex Med. 2021 Apr;18(4):665-697. doi: 10.1016/j.jsxm.2021.01.172. Epub 2021 Feb 19. PMID: 33612417.

7:  Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999 Feb 10;281(6):537-44. doi: 10.1001/jama.281.6.537. Erratum in: JAMA 1999 Apr 7;281(13):1174. PMID: 10022110.

8:  Laumann, Edward O., Gagnon, John H., Michael, Robert T., and Michaels, Stuart. National Health and Social Life Survey, 1992: [United States]. Inter-university Consortium for Political and Social Research [distributor], 2008-04-17. https://doi.org/10.3886/ICPSR06647.v2 

9:  Gonçalves WS, Gherman BR, Abdo CHN, Coutinho ESF, Nardi AE, Appolinario JC. Prevalence of sexual dysfunction in depressive and persistent depressive disorders: a systematic review and meta-analysis. Int J Impot Res. 2023 Jun;35(4):340-349. doi: 10.1038/s41443-022-00539-7. Epub 2022 Feb 21. PMID: 35194149

10:  Dawson G, Pies RW.  Antidepressants do not work by numbing emotions. Psychiatric Times. Sept 26, 2022:  https://www.psychiatrictimes.com/view/antidepressants-do-not-work-by-numbing-emotions

11:  LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury. [Updated 2019 May 4]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548069/

12:  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.

13:  Haanpää M, Paavonen J. Transient urinary retention and chronic neuropathic pain associated with genital herpes simplex virus infection. Acta Obstet Gynecol Scand. 2004 Oct;83(10):946-9. doi: 10.1111/j.0001-6349.2004.00500.x. PMID: 15453891.

14:  Ooi C, Zawar V. Hyperaesthesia following genital herpes: a case report. Dermatol Res Pract. 2011;2011:903595. doi: 10.1155/2011/903595. Epub 2011 Apr 18. PMID: 21747842; PMCID: PMC3130996.

15:  Whalen AM, Mateo CM, Growdon AS, Miller AF. Sacral Myeloradiculitis: An Uncommon Complication of Genital Herpes Infection. Pediatrics. 2019 Jul;144(1):e20182631. doi: 10.1542/peds.2018-2631. PMID: 31217310.

16:  Reisman Y. Sexual Consequences of Post-SSRI Syndrome. Sex Med Rev. 2017 Oct;5(4):429-433. doi: 10.1016/j.sxmr.2017.05.002. Epub 2017 Jun 20. PMID: 28642048.

 

 

Case Reports (not exhaustive – truncated at 10 – I think these references capture the largest numbers):

1:  Ekhart GC, van Puijenbroek EP. Blijvende seksuele functiestoornissen na staken van een SSRI? [Does sexual dysfunction persist upon discontinuation of selective serotonin reuptake inhibitors?]. Tijdschr Psychiatr. 2014;56(5):336-40. Dutch. PMID: 24838589.

From 2002 to 2012, 19 cases reported to Netherlands Pharmacovigilance Centre, Lareb occurring after patients has stopped the medications for 2 months to 3 years. Approximately 1 million people per year are prescribed antidepressants in the Netherlands.  See: https://www.statista.com/statistics/718241/usage-of-dispensed-antidepressants-in-the-netherlands/

2:  Patacchini A, Cosci F. A Paradigmatic Case of Postselective Serotonin Reuptake Inhibitors Sexual Dysfunction or Withdrawal After Discontinuation of Selective Serotonin Reuptake Inhibitors? J Clin Psychopharmacol. 2020 Jan/Feb;40(1):93-95. doi: 10.1097/JCP.0000000000001154. PMID: 31834096.

3:  Bolton JM, Sareen J, Reiss JP. Genital anaesthesia persisting six years after sertraline discontinuation. J Sex Marital Ther. 2006 Jul-Sep;32(4):327-30. doi: 10.1080/00926230600666410. PMID: 16709553.

Single case of a 26-year-old man.

4:  Waldinger MD, van Coevorden RS, Schweitzer DH, Georgiadis J. Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential (TRP) ion channels. Eur J Pharmacol. 2015 Apr 15;753:263-8. doi: 10.1016/j.ejphar.2014.11.031. Epub 2014 Dec 4. PMID: 25483212.

43 yr old man with loss of smell, taste, and skin sensation shortly after he started to take paroxetine for depression.  He has associated problems with sexual functioning and sensation for 2 years after the paroxetine was discontinued.  Full Text

5:  De Luca R, Bonanno M, Manuli A, Calabrò RS. Cutting the First Turf to Heal Post-SSRI Sexual Dysfunction: A Male Retrospective Cohort Study. Medicines (Basel). 2022 Sep 1;9(9):45. doi: 10.3390/medicines9090045. PMID: 36135826; PMCID: PMC9503765.

13 male patients referred for treatment.  PSSD sx onset 2-4 weeks after discontinuation of SSRI.  Retrospective, uncontrolled treatment study. Most patients were significantly improved at 12 month follow up after treatment with vortioxetine, bupropion, or mechanical stimulation on a standard scale.

6:  Reisman Y, Jannini TB, Jannini EA. Post-selective serotonin reuptake inhibitor sexual dysfunctions (PSSD): clinical experience with a multimodal approach. Journal of Men's Health. 2022 Aug 1;18(8):165.

12 male patients with a “high probability” of PSSD 9-26 months post treatment with an SSRI (one patient was treated with amitriptyline). Retrospective, uncontrolled treatment study with all patients improving at 12 months.

7:  Chinchilla Alfaro K, van Hunsel F, Ekhart C. Persistent sexual dysfunction after SSRI withdrawal: a scoping review and presentation of 86 cases from the Netherlands. Expert Opin Drug Saf. 2022 Apr;21(4):553-561. doi: 10.1080/14740338.2022.2007883. Epub 2021 Nov 27. PMID: 34791958.

86 cases reported to the Netherlands Pharmacovigilance Center of Lareb from 1992 to 2021.  Longest duration was 23 years.  Common symptoms were loss of libido, erectile dysfunction, and anorgasmia.

8:  Dannon PN, Iancu I, Cohen A, Lowengrub K, Grunhaus L, Kotler M. Three year naturalistic outcome study of panic disorder patients treated with paroxetine. BMC Psychiatry. 2004 Jun 11;4:16. doi: 10.1186/1471-244X-4-16. PMID: 15191617; PMCID: PMC441384.

143 patients with panic disorders treated with paroxetine were followed for one an acute treatment phase followed by either 12 month or 24-month paroxetine maintenance.  Relapse rates in both groups were similar. Sexual side effects were determined clinically rather than a structured interview asking about sexual desire and sexual function. Prevalence of sexual side effects was 30% in both groups and the presence of agoraphobia potentiated these side effects – consistent with some psychological theories.  Not clear about the status of sexual side effects during the discontinuation phase.

9:  Healy D, Le Noury J, Mangin D. Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases. Int J Risk Saf Med. 2018;29(3-4):125-134. doi: 10.3233/JRS-180744. PMID: 29733030; PMCID: PMC6004900.

300 cases (221 on antidepressants) solicited through a web site established by the authors. They acknowledge the design of the likely encouraged reporting. The authors calculate a causality score based on the Naranjo algorithm that is described as the “probability of an adverse drug reaction.”  This paper has a unique take on the effects of antidepressants that are not seen in any other references. It is available online and I encourage anyone who is interested to access it and read it.  One example that is incredible and seems uncomplicated by clinical experience: “The ability of serotonin reuptake inhibitors to reduce genital sensation is well known. Almost everyone who takes one will experience some degree of genital numbing, often within 30 minutes of taking the first dose.”

10.  Csoka AB, Bahrick A, Mehtonen OP. Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. J Sex Med. 2008 Jan;5(1):227-33. doi: 10.1111/j.1743-6109.2007.00630.x. Erratum in: J Sex Med. 2008 Dec;5(12):2977.. Csoka, A [corrected to Csoka, AB]. PMID: 18173768.

3 cases of persistent sexual dysfunction 3 of 1300 subjects from an Internet group that were assessed as credible were interviewed.  No medical causes for the sexual dysfunction were determined. 


Supplementary 1:

I received a reply today from the European Medicines Agency on my request for information on their regulatory decision to include language on sexual dysfunction from SSRIs.  The entire response is given below.  

 

Dear Dr Dawson,

Thank you for your request for access to documents.

We are writing to inform you that the Agency is not in a position to process your request.

Transparency is an important feature of the European Medicines Agency's operations.  As for any public authority, the Agency strives to be as open as possible about how it works and how it comes to its decisions.

However, due to the increasingly high volume of access to documents requests resulting in an excessive workload, and in order to avoid the core business tasks of the Agency and its performance being jeopardised by the administrative workload related to activities within Regulation (EC) 1049/2001 regarding public access to European Parliament, Council and Commission documents (the Regulation), the Agency has taken the decision to process only access to documents requests submitted by citizens of the European Union and natural or legal persons residing or having their registered office in a EU Member State.  This approach reflects Article 2(1) of Regulation (EC) No 1049/2001 and was agreed by the EMA Executive Board on 15 June 2018.

This is also clearly outlined on the Agency’s website at https://www.ema.europa.eu/en/about-us/how-we-work/access-documents under the heading “Who can request access to documents”.

If you have a European affiliate, please submit a new access to documents request indicating the relevant location from EMA’s online webform https://www.ema.europa.eu/en/about-us/contact/send-question-european-medicines-agency.

Thank you for your understanding.

Kind regards,

European Medicines Agency
Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
Telephone: +31 (0)88 781 6000



Supplementary 2:

The graphic below is the reference I could find on their current site that led me to request additional information:





Saturday, July 8, 2023

The Only Gun Legislation In the Past 30 years Is Nothing To Get Excited About

 


The only thing more annoying than seeing self-congratulatory legislators not solving another problem is when they discuss their rationale for their latest decision.  That was in full view on CBS This Morning Today as Tony Dokoupil interviewed four senators Chris Murphy (D), Thom Tilis (R), John Conryn (R), and Kyrsten Sinema (I).  In the interview Sen. Murphy suggests there is evidence that “the law is starting to have some impact” according to “criminologists”.

But what is the evidence?  A summary of the bill is available at this link and it is more readable that the final version on the same web site. One of the provisions was enhanced background checks for gun purchasers 18-21 years of age.  That has resulted in 230 denials. Sen. Tilis commented that 107,000 people between the ages of 18-21 applied to purchase a gun and therefore only 0.2% were denied. No comment on the negatives of putting another 100,000 guns out on the street. I tried to find data on the NICS database but it is not available for 2022.  We don't know if a 0.2% denial rate is an exception or if it is expected.  This report states the overall denial rate was 3.92%.  He goes on to say he is proud of the fact that they have passed the “biggest investment in mental health” in history and “we all agree that behavioral health had to be the foundation of everything we did.”  

Hold on Senator! Granted I am only a psychiatrist and not a behavioral health expert – but this seems like bullshit to me. The federal government and their cronies in behavioral health managed care have been rationing services while making massive profits for the past 30 years. It is as likely that your funding intervention will have as much impact as it did on the opioid epidemic.  It also happens to be a gun extremist narrative to divert attention from the primary problem of far too many guns.

Senator Sinema suggests that “every single person” who picks up a firearm and engages in mass violence is mentally disturbed.  If that were true (and it is not) – the suggested funding through the usual channels will not impact mass shooters. Mass shooters are a product of gun extremism. They see politicians every day talking about guns as the solution to many problems. Stand your ground laws that encourage both gun violence and exoneration of the gun user. They see people being shot and killed or shot at for trivial reasons.  They see indignant gun extremists claiming that “the government” wants to kick your door down and confiscate your guns – even though with the massive number of guns in this country it is physically impossible.  They see armed “militia” intimidating state legislators on their own capitol grounds. They see social media threats about the use of arms. Most importantly – they see daily mass shootings in the United States and nobody doing anything about it. Politicians seem to blame the victims, in some cases the police, or globally “wrong place-wrong time.” You do not have to be mentally ill to be confused or driven by those messages and emotion.

Most notably – there continues to be no background checks for all gun buyers and no assault weapons ban.  There was some joking about not being able to agree on a definition of an assault weapon.  That is a basic definition and it has been defined by Congress in the past but it appeared to be off the table for this crew.

Dokoupil makes a point that violence in America seems to drive legislation and maybe the tradeoff for a Second Amendment is that there will always be violence in America. He cites examples of gangsters in the 1930s and violence in the 1970s with riots and radical politics.  That is a good sound bite but it ignores the fact that there has been no gun legislation through the past 30 years of gun violence and this anemic bill was the result of a level of gun violence that should have been an embarrassment for any legislator.  He misses the obvious point that even in the Wild West (see Tombstone Ordinance of 1881), you had to check your gun when you came into town and post-World War II we had decades of common sense gun legislation that did not involve the massive carrying of firearms.  During those decades – nobody under the age of 21 could own a handgun, guns were used for hunting, and the Second Amendment was interpreted the way it was written.  During those decades the NRA was focused on gun safety and hunting rather than flooding the streets with guns. 

There was some rhetoric about how an extreme mass shooting incident led to the bipartisanship necessary to pass this mediocre bill. First off - that is an extremely high bar.  How many catastrophes does it take to move Congress?  The answer is obviously hundreds. Secondly, it is obvious that partisanship was alive and well right in the room.  None of the Senators could even touch the assault rifle issue? Assuring the rights of people refused firearm purchases was a higher priority?  Gun extremism is alive and well and as long as one party finds it necessary to fan the culture war flames - very little movement would seem possible and that is exactly what we have seen for decades.  

The gun extremism of one political party and their judges is the current problem. An atmosphere of unabated gun extremism is unlikely to have any desired effect on mass shootings, gun homicides, gun suicides, or accidental deaths. I have attached a few paragraphs on what gun extremism is below. This is my definition. I have written about potential solutions in the past – but clearly people would rather listen to the clear thinking of their elected officials instead.

 

George Dawson, MD, DFAPA


Previous Posts:

Likely and Unlikely Causes of Mass Shootings

Another Note on Gun Extremism - An Appeal to Grandparents




Elements of Gun Extremism


1:  Misinterpreting the Second Amendment:

The culture war political party and their judges ignore the text of the Amendment which is simply:

A well-regulated Militia, being necessary to the security of a free State, the right of the people to keep and bear Arms, shall not be infringed.

Gun extremists ignore the preamble that gives the rationale for the right to bear arms and instead isolate the clause about the right to keep and bear arms and generalize it to the entire population and any firearms.  The well-regulated Militia in this case is every states National Guard.  Arms in those days were muzzle loaders that could fire 2 rounds per minute if you were an expert contrasted with 45 rounds per minute from an AR-15 semiautomatic rifle. A fully automatic AR-15 can fire 700-900 rounds per minute. Courts have taken additional steps to say that gun permits can be superfluous and that anyone requesting one should be issued one – with rare exceptions.  Local legislatures have gone ahead with permitless carry and concealed carry laws.

In debating gun extremists, a common argument is that it is protection from tyranny and that is why the Amendment is there.  When I suggested that using weapons against the US government was treason, a famous gun advocate suggested “it would depend on who won.”  Clearly there is nothing about tyranny associated with the amendment.  Gun extremists favor lawlessness and insurrection.  Their judges do as well.

2:  Putting everyone at risk:

One of the famous gun extremist arguments is that more guns results in less crime.  That is clearly not the case and the number of defensive uses of firearms does not have a significant impact on crime.  In the meantime, there are more gun suicides, homicides, accidental deaths, mass shootings, and deaths from the impulsive use of an available firearm in the US than any other high income country.

3:  Increased risk with handguns and assault rifles:

Before the gun extremism culture took over – guns in the US were used for hunting and target shooting. Some people thought they were necessary for self-defense but they were clearly in the minority.  The NRA ran Hunter Safety Courses to teach safe use of hunting firearms.  Gun extremism is a result of the culture wars approach to American politics. When one party realized they did not have much to run on they decided to make a few things up.  Gun extremism was one of those results.   Gun extremism has resulted in the proliferation of handguns and assault rifles.  Both of those weapons are designed for shooting people not wildlife. Gun extremists try to minimize the role of assault rifles by claiming that they are not fully automatic like the military version but they can still release a flurry of high velocity rounds capable of penetrating many walls – as fast as you can pull the trigger.  That is not a hunting firearm.  No need for a lot of physics - just recall that the kinetic energy of a mass is a function of the square of its velocity.  Weapons with high muzzle velocity like assault rifles will have much more energy to damage the target.

4:  Increased risk with permitless carry:

 As the gun extremists became more radical there was a progression of loosening of gun regulations.  Initially to carry guns in public you had to have a permits. In many states that required an application and background check from a county Sheriff.  For a concealed carry permit, training was required. Continued radicalization has resulted in the abolition of many of those laws so that you can purchase a handgun and carry a concealed handgun without a permit or training.  You just must meet minor age criteria. It is obvious that this is the goal of gun extremists across the USA.  Permitless carry will make every community more dangerous. Just ask your local men and women of law enforcement. 

5: The idea that gun carriers are supermen or superwomen:

In other words if you meet criteria to carry a gun your were by definition responsible and did not make any mistakes leading to the loss of life or injury. Epidemiology teaches that just having a gun on the premises greatly increases the likelihood of death by accidental injury or suicide. Every year hundreds of police officers are injured by accidental discharge of their firearms and they have more extensive and ongoing firearms training than typical gun owners, especially in this era of vanishing qualifications. The obvious political goal of gun extremists is to eliminate any qualifications except for age and possibly (if a NICS check is run) a history of felony crime or domestic violence.   

6:  The new era of shoot first ask questions later:

There have been many incidents in the news of people being shot at and in some cases killed for ringing a doorbell or accidentally driving down the wrong road. In well televised road rage incident, a man fires several rounds from a semiautomatic handgun through his own windshield at a car he mistakenly thought had fired a gun at him.  Not a thought about how far those bullets travel and who else he might hit on a busy freeway. Is this the kind of country we want to live in?  This is the country we currently have courtesy of gun extremists. 

7:  All we have to do is enforce existing laws:

This is a favorite of gun extremists as they continue to roll back existing gun laws. The also use the slogan "If guns are outlawed only outlaws will have them."  That slogan is obviously flawed at two levels.  First, nobody has ever suggested outlawing guns and as I pointed out earlier - it is physically impossible at this point.  Secondly, nobody seems to consider where outlaws get guns. A large source is theft from legal gun owners. About 380,000 guns are stolen in 250,000 incidents in the USA each year.  In other words, one of the largest sources of illegal guns in the hands of outlaws is legal guns from legal gun owners.   Keeping the streets flooded with guns keeps that process going. 



Image Credit:  Thanks to Rick Ziegler.

 


Friday, June 30, 2023

Stay Indoors - But Is That Enough?

 


Any casual reader of this blog might know that I was interested in indoor air quality including airborne viruses – long before it became fashionable. That had various origins including an undergrad focus on ecology, being raised by two heavy smokers, having to manage a coal fired stoker as a kid, working in a HEPA filtered clean room as a research assistant, and routinely getting viral respiratory infections in a hospital staff setting where we were all advised that hand washing was supposed to stop the mini-epidemics. And having asthma through all of that.

The indoor air quality issue has become complicated as our outdoor environment deteriorates. As an undergrad 50 years ago, we studied air pollution scenarios that affected large cities.  That included the concept of how smog was created by photochemical reactions but a lot of the specifics were not known.  More recently the entire Midwest and Northeastern US has been blanketed by wildfire smoke from Canada. Wildfire smoke is chemically complex.  In a lot of areas there are air quality alerts on one day due to wildfire smoke and ozone the next day. Those alerts are graduated to advise people with health conditions like asthma, emphysema, and heart disease on the lower end to limit outdoor activities or stay inside.  At high levels everyone gets the same advice.

The advice to stay inside assumes that your indoor air quality is better than the outdoor air quality that you are being warned about.  But is that a valid assumption?  How do you get measurements on everything and know the critical differences?  A good place to start is the outdoor air quality. The EPA has developed a nationwide network of sensors that detects particulates and ozone in the air and calculates the air quality index.  The AirNow app is available for your smart phone.  It gives you the outdoor reading, particulates, and ozone, as well as the break points from Good (0-50) to Hazardous (301-500). It will give you conservative advice about what to do about health and activity for those break points.

The CDC has a publication on indoor air quality in airports (1) where smoking was allowed. It provides some more intuitive markers of indoor quality. They found that the PM 2.5 (<2.5 micron particles per cubic meter) were 300+ in the smoking areas and 50+ in the areas adjacent to the smoking areas.  300+ levels are considered “very unhealthy”.  Anyone who has ever been in a smoke-filled room can probably sense that the atmosphere is not very good for your health either immediately of after leaving.  In Minnesota when the AQI was greater than 300 due to wildfire smoke – you could smell the wood fired smoke.

With an accurate assessment of the outdoor air – what about your indoor air quality?  I was fortunate enough to have purchased an air cleaner for my office with a PM 2.5 measure built into the machine. It usually reads in the 1-5 range but when the wildfire smoke arrived it was suddenly reading 40+ indoors. I had to figure out why that number was so high.  I had just replaced my furnace and it has a MERV13 filter that should provide some filtering efficiency.  The question mark was how my air exchanger fit into the mix.

My house is about 15 years old and like most modern houses it is considered airtight.  The concern by builders and contractors with modern homes is that they are so airtight that it leads to indoor air pollution from a number of sources including any combustion processes in the home and volatile compounds in the air from various sources like cleaning products.  As a result, air exchangers are installed to vent the indoor air and bring in fresh outdoor air.  These air exchangers are designed to reduce heat exchange and most do not have HEPA ( High Efficiency Particulate Air [filter])  filters.  They have a relatively primitive filtration system to remove mainly insects and very large particles. They can easily bring in outdoor smoke so it is a good idea to have it shut off on days where there is very high particulate matter.

The problem with my new system is that I was not sure that the air exchanger was off.  When my new furnace was installed the air exchanger was integrated into a touch panel with 30 different options and several ventilation settings.  I talked with 5 technicians (3 from the HVAC contractor, 1 from the air exchanger manufacturer, 1 from the smart thermostat manufacturer).  They all agreed shut off the air exchanger was a good idea but they gave me widely varying advice.  I decided to experiment myself over a period of 12 hours and generated the following graph (click to enlarge).

The first section shows the AQI outdoors versus indoors running the MERV 13 filter through the furnace.  There is no difference over that time period.  The next period I shut off the furnace filter and used a free-standing Space Gaard air cleaner with a MERV 8 (MERV = Minimum Efficiency Reporting Values) filter. Notice that during this time period the wind picked up outdoors, blew off some smoke and the PM 2.5 dropped from 160 to about 90.  At that time I talked with a 6th technician and he gave me clear advice on how to shut off the air exchanger.  The last section is with the air exchanger off and all air circulating through the furnace filter MERV 13.  At that point the indoor AQ drops consistently despite a blip upwards in the outdoor PM 2.5 and continued to drop to 10.  To me that illustrates the importance of making sure the air exchanger if off when the outdoor AQ is poor and actively managing it to turn it one when the outdoor AQ is acceptable.

A related indoor AQ related to viral transmission is the carbon dioxide CO2 levels.  Lower levels correlate with less people rebreathing air in the room and that decreases the risk of infection from airborne viruses. Outdoor CO2 is roughly 400-420 ppm. My indoor measure is currently 570 without the air exchanger on.

There are currently PM 2.5 and CO2 monitors available in most home stores and large online retailers.  What we really need is a more comprehensive single device that measures and records all of the parameters. I would suggest PM 2.5, PM 10, CO2, Ozone, and Volatile Organic Compounds (VOC).  The closest I could come to that device was a gadget that required that I purchase a separate weather station and even then the bandwidth to multiple devices was limited.

Home HVAC system design could also use some innovation. Just based on my experience durability is a problem. Should an HVAC system last longer than 14 years?  Probably.  But the design itself does not seem very efficient.  I am not a certified HVAC tech by any means but it appears to me that the air exchanger introduces outdoor air into the system after the air filter so that any particulate matter in the outdoor air does not get at least one pass through the highest efficiency filter.

Outdoor air quality is a little discussed casualty of climate change. As the environment deteriorates, I expect that there will be increasing amounts of wildfire smoke and it will be chemically more complex. I currently wear an N95 mask outdoors during the alerts, but I can envision a time in the not-too-distant future where respirators that can also remove ozone and organic chemicals will also be necessary. Geography is no longer helpful in separating clean air from polluted air. Monitoring your personal indoor air quality and figuring out how to manage it will become the most critical part of home management. I have posted a few things that you can do right now and I am always interested in other ideas about how to address this problem.  Please post any of those ideas in the comments section.

 

George Dawson, MD, DFAPA

 

 

References:

1:  Centers for Disease Control and Prevention (CDC). Indoor air quality at nine large-hub airports with and without designated smoking areas--United States, October-November 2012. MMWR Morb Mortal Wkly Rep. 2012 Nov 23;61(46):948-51. PMID: 23169316.

2:  CDC Health Alert Advisory.   Wildfire Smoke Exposure Poses Threat to At-Risk Populations.  Link


Update 07/06/2023: 

One week after turning off my air exchanger - the PM 2.5 in my house is down to 6 or essentially normal.  I talked with my air conditioning tech who also services the air exchanger and he agreed with the approach.


Image Credit:

Canadian Wildfire Smoke in Minneapolis

Chad Davis from Minneapolis, United States, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons

file URL:  https://upload.wikimedia.org/wikipedia/commons/c/c0/Canadian_Wildfire_Smoke_in_Minneapolis_%2852907984452%29.jpg

page URL:

https://commons.wikimedia.org/wiki/File:Canadian_Wildfire_Smoke_in_Minneapolis_(52907984452).jpg




Tuesday, June 27, 2023

Hippocrates the Projective Test

 



There is no doubt that the ancient physician Hippocrates was an advanced thinker in terms of medicine and its conceptualization. He is widely credited with advancing nosology and diagnostics as well as professionalism. In the field of medicine, he was studied right up until the turn of the 19th century by physicians who attended medical schools in Europe.  Like all prominent figures from the past there is a question of whether invoking Hippocrates these days represents idealization or rhetoric more than his accurate historical position. 

I am referring specifically to a blog by Nassir Ghaemi, MD entitled Hippocratic Psychopharmacology.  After correcting the aphorism “First do no harm” to “As to diseases, try to help, or at least not harm.” he elaborates on a few ideas from Hippocrates and the implications for modern medicine. He interprets the preamble of Hippocrates statement to mean that diseases must be identified and if you cannot or will not take the disease concept seriously you cannot help anyone as a doctor. He emphasizes that there should be a focus on not doing any harm and that overall treatment should be conservative. He acknowledges a bias that too many medications are being used in modern times.

Hippocrates additional idea is that diseases are a natural process and they heal naturally and physicians should not get in the way of that process. He discusses self-limited, treatable, and incurable diseases suggesting only the treatable illnesses are a focus for physicians.

Hippocrates was apparently not enough so Holmes Rules and Osler’s rule are added. The explanation of Holmes Rules is inconsistent because initially it described prescribing based on benefits first and harms second, but in the elaboration the assumption is supposed to be that the medication is harmful. If that is your assumption harms would seem to be prioritized.  Here is an excerpt from the post from 1861:

“……I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind, – and all the worse for the fishes.”

In other words, if you wanted to prescribe something – there is nothing useful to prescribe and given the time frame - that is correct.  1861 was before the discovery of germ theory.  Of the estimated 750,000 Civil War (1861-1865) deaths at the time about 2/3 died of diseases that are treatable in modern times. The only effective medical treatments at the time were citrus fruits and vegetables to prevent scurvy, smallpox vaccines, and quinine for malaria. Four types of wound infections were described including tetanus, erysipelas, hospital gangrene, and pyemia or sepsis with mortality rates of 46-90%.  Since there were no antibiotics infected wounds were treated with repeated debridement or amputation with the hope that remaining healthy tissue would generate an inflammatory and healing response. 

In his writings, Hippocrates describes many forms of orthopedic treatment and general medical treatment for infections including gangrene and erysipelas. Those afflictions were not likely to heal without significant medical and surgical interventions. I suppose in keeping with the stated philosophy they could be reclassified as “untreatable.” The question might become were untreatable diseases less treatable in Hippocrates time than during the Civil War? Either way it is likely that Hippocrates watched at least as many of his patients die as Civil War surgeons did and those were very high mortality rates.

Ghaemi uses the example of antidepressants in bipolar disorder as breaking Holmes Rule “egregiously.” Unfortunately, the presentation of bipolar disorder may not be that clear cut.  As a tertiary care psychiatrist, it was common to see people experience manic episodes after years of treatment for unipolar depression with antidepressants or even as an antidepressant is tapered and discontinued. You must have seen a manic episode along the way in order make the diagnosis and stop the antidepressant.  It also helps if the patient is under the care of a psychiatrist and it is likely the vast number of antidepressants in these presentations were prescribed by other specialists or nonphysicians. I have never heard of a psychiatrist needing more evidence to stop antidepressants in bipolar disorder.  It was done routinely by my colleagues in acute care.

Osler is quoted in the discussion of Osler’s Rule:

“A man cannot become a competent surgeon without a full knowledge of human anatomy and physiology, and the physician without physiology and chemistry flounders along in an aimless fashion, never able to gain any accurate conception of disease, practicing a sort of popgun pharmacy, hitting now the malady and again the patient, he himself not knowing which.”

And what exactly was known in Osler’s time about pathophysiology and pharmacotherapy?  Probably not much more than was known at the time of the Civil War.  Paton’s reference (5) contains several additional quotes to illustrate what he describes as Osler’s nihilism including that there were no useful treatments for scarlet fever, pneumonia, and typhoid fever.  Diarrhea and dysentery were common in soldiers leading to both compromised health status and death.  A summary quote from Osler’s time suggests there were only a few useful treatments including iron for anemia, quinine for malaria, mercury and potassium iodide for syphilis and that there were no other drugs supported by experimental evidence.  It turns out that that the evidence for potassium iodide in syphilis was restricted to reducing inflammation in some late-stage lesions since it was not an anti-spirochetal agent (4).

If Osler was aware of a potentially effective drug – he may have pushed it beyond what his colleagues were using as evidenced in this quote:

'At times of crisis Sir W. Osler and others have pressed up the nitrites to huge doses, in persons upon which these drugs had been well tested. Sir William said he had never seen harm come of large doses if cautiously approached. I think he used to speak of 20-30 grains of sodium nitrite per diem. I have administered half as much in a day.' (pp 88-9).” (3)

20-30 grains of sodium nitrite is roughly equivalent to 1,329 to 1,980 mg.  In a 70 kg patient that would be 19-28.3 mg/kg.  The worrisome complication from nitrites is methemoglobinemia. In severe cases it can result in coma, cardiac arrythmias, and death. PubChem suggests that intravenous doses of 2.7 – 8 mg/kg can be problematic. A leading toxicology text suggests that when sodium nitrite is given intravenously to treat cyanide poisoning the dose is 300 mg given at a rate of 75-150 mg/minute intravenously with a repeat dose at half the amount if necessary, monitoring for symptoms of nitrite toxicity. While it is difficult extrapolating oral toxicity from IV administration there are reports of life threatening and fatal oral ingestions resulting from taking 12.5-18 g of sodium nitrite. The EPA recommends limiting exposure to 1.0 mg/kg/day. All of this toxicology information suggests the the doses that Osler was using were pushing the limit, but it also points to another deficiency in suggesting that his parsimony (or nihilism) is a touchstone for modern physicians.  That deficiency is that his outcomes were unknown. The case reports that I have found were generally limited to a case or two. I could not find any outcomes for high dose versus low dose nitrites for angina or congestive heart failure. Modern nitrate preparations such as isosorbide mono and di-nitrates are limited by tolerance to the vasodilating effect. I may be wrong but I speculate the Osler knew very little about the pharmacology of nitrites and the mechanisms of tolerance and toxicity.

A common theme for these conservative historical pharmacologists is that it is easy to be conservative when there are no known effective treatments.  When your category of treatable diseases is small – it is easy to rationalize watching the self-limited and untreatable illnesses run their course.  There was a very long period of slow progress in therapeutics between the time of Hippocrates (460-375 BCE) and Osler (1849-1914). Penicillin was not available to treat syphilis until 1943. Even though there was some basic science research in pharmacology in the mid 19th century, Paton’s review shows that potentially effective medications, in pill form and in significant numbers did not occur until about 1920.

Apart from limited therapeutic options, the doctrine of informed consent was either nonexistent or much less clear in earlier times.  Gutheil and Applebaum (6) trace the early evolution and consolidation as occurring in the 1950s and 1960s in the US.  The earliest clear application was for surgery and invasive treatments extending to medical treatments.  In psychiatry, that also extended to medication treatment and neuromodulation but at the time of this book whether it was necessary for psychotherapy or not was not clear.  To me one of the clearest reasons for informed consent is the level of uncertainty in medicine. We know probabilities at the population level but are rarely able to predict side effects and adverse reactions at the individual level.  I have written about my approach to this problem on this blog and it is basically a shared decision-making model where the patient is informed of the uncertainty of both efficacy and adverse events as clearly as possible. That information was not available to to earlier physicians. Detailed regulatory information in package inserts is a relatively recent phenomena starting in 1968 in the US with several modifications since then.  

Ghaemi winds down his critique emphasizing diagnoses over symptoms.  He uses the bipolar disorder example again and hedges suggesting that is it acceptable to treat symptoms sometimes but there are no guidelines only the rather extreme criticism that by treating diseases and developing a Hippocratic psychopharmacology we can avoid the “eclectic mish-mash which is contemporary psychiatry.”

It is apparent to me that Hippocrates and Osler have very little to offer present day psychopharmacologists. They both a had very large body of patients who could not be treated. Both had limited evidence-based pharmacopeias and both prescribed toxic compounds with no clear guidelines or suggestion of efficacy. On diseases, syndromes, and symptoms – the issues are much clearer these days but much is still written about how these concepts are confusing. That is especially true in psychiatry where decades of debate has not resulted in any more clarity.  It is not as easy to separate out insomnia, anxiety, and mood disturbance with bipolar disorder as Ghaemi makes it seem, but treating them all at once in a single point of time is probably not the best approach. In clinical practice at least some people have insomnia, anxiety disorders, and depression prior to the onset of any diagnosis of bipolar disorder. Assuming adequate time to make those historical diagnoses, there are no clear guidelines about what should be treated first and no clinical guidelines on when medications should be started and stopped.  It all comes down to the judgement and experience of the physician and patient consent and preference. Evidence based medicine advocates always argue for that approach but it it highly unlikely that there will be clinical trials for every scenario and the trials that do occur are often limited by inclusion and exclusion criteria.   Hippocrates and Osler have no better guidance.

As therapeutics has evolved, polypharmacy has become a part of the clinical environment of all specialists.  It is common to see patients taking multiple medications in order to treat their cumulative diseases, even before a psychiatric medication is prescribed. Despite all of the rhetoric – I am convinced that experts can manage polypharmacy environments if they need to and do it with both therapeutic efficacy and minimal to no side effects.  

For the record, I agree with Ghaemi’s overall message that you need good indications for medical treatments and that the fewer medications used the better. Those decisions need to incorporate, current evidence, informed consent, and frequent detailed follow up visits to reduce the risks of inadequate treatment and adverse events. That is hard work - not helped by guidance from the ancients or modern-day philosophers.

 

George Dawson, MD, DFAPA

 

References:

1:  Ghaemi N. Hippocratic Psychopharmacology.  Jun 16, 2023. https://psychiatryletter.com/hippocratic-psychopharmacology/

2:  Burns SB.  Civil War Disease and Wound Infection https://www.pbslearningmedia.org/resource/ms17.socct.cw.disinf/civil-war-disease-and-wound-infection/  Accessed on 06.20.2023

3:  Paton W. The evolution of therapeutics: Osler's therapeutic nihilism and the changing pharmacopoeia. The Osler oration, 1978. J R Coll Physicians Lond. 1979 Apr;13(2):74-83. PMID: 374726; PMCID: PMC5373168.

4:  Keen P. Potassium iodide in the treatment of syphilis. Br J Vener Dis. 1953 Sep;29(3):168-74. doi: 10.1136/sti.29.3.168. PMID: 13094013; PMCID: PMC1053890.

5:  Howland MA.  Nitrite (amyl and sodium) and sodium thiosulfate.  In:. Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR Hoffman RS (eds). Goldfrank’s Toxicologic Emergencies. McGraw-Hill Education; 2019. P. 1698-1701.

6:  Gutheil TG, Appelbaum PS.  Clinical Handbook of Psychiatry and the Law, 3rd ed. Lippincott, Williams and Wilkins; 2000; Philadelphia, PA: 154-157.

7:  Writings of Hippocrates. Translated by Francis Adams. Excercere Cerebrum Publications; 2018.

 

 

Graphics Credits:

 

William Osler aged 32: Notman photographic archives, Public domain, via Wikimedia Commons.  https://upload.wikimedia.org/wikipedia/commons/e/e9/William_Osler_1881.jpg

Hippocrates: ESM, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons. https://upload.wikimedia.org/wikipedia/commons/8/82/Facultat_de_Medicina_de_la_Universitat_de_Barcelona_-_Hip%C3%B2crates_de_Kos.jpg