Ariadne’s Thread and Post-Mefloquine Toxicity

This post is linked to Functional, Fashionable or Toxic.

No professional or patient body interested in the potentially toxic effects of medicines and how to defuse these could possibly ignore the Mefloquine – Lariam story. It has featured on several RxISK posts for over a decade – The Strange History of Lariam and Lariam Hell and most recently in David Rimmington’s Sanctuary Trauma and Lariam Toxicity which is central to Ariadne’s Thread below.

Andrew Marriott’s marvelous book on the history of this drug and its problems features in If You Wake at Midnight – which is available on whichever Amazon you shop at.

Dave Rimmington introduced many of us to the idea of Sanctuary Trauma – an idea that will resonate with anyone injured by a prescription drug who finds their doctor and others in healthcare hostile to the idea a treatment could cause problems.

Remington Nevin, an acknowledged leading expert on mefloquine toxicity, part of whose story is laid out in Quinism Foundation, took a lead in drafting this post.

All of the above have contributed to Ariadne’s Thread below.

Background

Acute mefloquine toxicity has recently been recognized by Britain’s NHS – somewhat later than many other health services.  This post is not about Acute Mefloquine Toxicity, It is about enduring Post-Mefloquine Toxicity and comes a week after the British Drugs Regulator – MHRA – accepted post SSRI sexual dysfunction (PSSD) as a Post Drug syndrome although they veered away from using the word Toxicity.

Regulators, pharmaceutical companies and in this case the UK Ministry of Defence have been slow to accept that drug induced toxicity can persist, despite the fact that enduring injury from Lariam toxicity, and perhaps permanent damage, were formally acknowledged by the European Medicines Agency 12 years ago.

Ten days ago new possibilities for change opened up. The MHRA recognized that SSRI and SNRI induced Toxicity – post SSRI sexual dysfunction (PSSD) – can persist for years after treatment has stopped.  This recognition is not hidden away in the labels of these drugs.  In what appears to be a first, it can now be found in the Patient Information Leaflet

Against this background, for well over a decade, Andrew. David, Trixie Foster and many others have been working to get Mefloquine Toxicity and its persistence recognized as MHRA have just done for PSSD.

Their efforts on veterans behalf ran into several snags.  One of these arose as follows.  On the institutional side, rather than have the MoD run their own health service, and because most of those harmed have been discharged from the armed forces, given mefloquine toxicity has neuropsychiatric features, it seemed to make sense to involve National Health Service (NHS) neuropsychiatry experts. This meant a referral to mental health and neurology services.

It also took time to get recognition even of acute mefloquine toxicity and to get its use, despite its efficacy, restricted. For years, rather than having their toxic state recognized, veterans risked getting inappropriate PTSD and bipolar diagnoses – see If You Wake at Midnight.

On the Veterans side, as per good practice in other areas of medicine, it seemed to make sense to ask for a Pathway for the management of mefloquine toxicity.

However, there are no Pathways (Guidelines) for the management of any drug induced toxicities – not for tardive dyskinesia linked to antipsychotics, which we have had for over 50 years, nor for the now formally recognized PSSD, which we have had for close on 40 years.

In the absence of a Pathway, there is a problem turning veterans over to mental health or neurology input as neither service has demonstrable expertise in recognizing toxic states – See Functional, Fashionable or Toxic.

When people with post-SSRI, post-finasteride, post-isotretinoin or post-mefloquine toxicities attempt to describe how they are feeling, they will often use words like fatigue, irritable, lacking in motivation, edgy, tense, weak, tired, and confused – words we all use for toxicities whether drugs or viral.  Among these words some of us might use or be nudged into using are ‘depressed’ and ‘anxious’. If mental health or neurology personnel recognize something and wish to help, the veteran attending can end up being told they are depressed or anxious and we have treatments for that.  If they deny this, the diagnosis will be insisted on. Efforts will be made to overcome their lack of insight.  But the problem is toxicity not depression or anxiety and well-meaning efforts to treat superficial symptoms risk making things worse.

The responses from experts the MoD consulted about a Pathway for managing mefloquine toxicity have correctly said that with a condition like mefloquine toxicity, any management needs to be individual – specific to the person who consults as we can differ significantly in our responses.

On one level, this is the essence of good medical care and should be a principle applied to the treatment of all conditions in all people. But given the reflexes of most treating physicians, in the case of toxicities like mefloquine toxicity, this principle needs supplementing with a Pathway that tells healthcare staff what NOT to do.

We are not introducing something new with the Ariadne’s Thread Pathway. Based on variations in surgical operations between regions, the first Guidelines told doctors what Not to Do – do not do so many tonsillectomies or strip so many varicose veins.  Some years after that Guidelines developed into company Highways driving epidemics of new conditions like Adult ADHD and Adult ASD along with polypharmacy.

Ariadne

In Greek myth, Ariadne was a Goddess, or of divine descent.  She was a half-sister of the Minotaur – a half-bull, half-human who fed on a tribute of 7 young men and 7 young women sent from Athens to Crete every 9 years. Theseus arrived in Crete with a mission to kill the Minotaur. Ariadne provided him with the sword that did the job and a thread to find his way back out of the Labyrinth.

Ariadne’s Thread:
principles for mefloquine toxicity

1. Diagnosing a toxic state should be a physician’s first contribution, not a last resort after mental and functional diagnoses have been tried.
2. Diagnosing a toxic state is the most important contribution a physician can make. It organises the history, protects the patient from misdirected treatment, and restores a measure of intelligibility to a confusing illness.
3. Drug-induced toxicities are physical states, not mental or functional disorders.
4. Drug-induced toxicities can endure for years after the triggering drug has been stopped.
5. The persistence of these states in the absence of the drug that triggered them commonly leads doctors to mistaken diagnoses like Functional Neurological Disorder (FND), bipolar disorder, PTSD or depression.
6. FND is commonly based on a range of features that do not co-occur in ordinary neurological syndromes. That range, crossing organic boundaries, is also typical of toxic states contributing to diagnostic confusion.
7. Drug-induced toxicity should be ruled out before FND is assigned. Until that step is routine, referral into an FND service is the wrong response to a veteran with a plausible toxic exposure.
8. Generic referral to a psychiatrist or a community mental health team is not an adequate response to a suspected toxic state, even when there are prominent neuropsychiatric features. If specialist advice is needed, it should come from clinicians prepared to treat the presentation as a toxic injury.
9. Symptomatic treatment with psychotropic drugs, whether for mood, sleep, or other purposes can aggravate a toxic state rather than produce the benefits these drugs can offer in non-dysregulated states.
10. We are not yet aware of any treatment licensed for, or shown in adequate trials to reverse, mefloquine toxicity. Everything tried should be noted, and the consequences recorded in the recipient’s own words.
11. A primary care doctor, a generalist, may be safer than a psychiatrist or neurologist working to a standard mental-health or FND pathway.
12. Unless there is an established antidote for a specific problem in a majority of the toxic states being treated, consider avoiding prescribing.
13. Polypharmacy must be avoided.
14. Managing a toxicity has to be predicated on the person in front of the doctor, not on a pathway built from averages that apply to no one.

Mefloquine toxicity needs clinicians who will recognize the injury and follow a thread where there is no map.  The challenge as per Hippocrates is to not make things worse.

Ministry of Defence

We sent Ariadne’s thread to the Ministry of Defence, along with other supporting points, some of which are listed below.

The Ministry responded as follows. We would disagree with none of their points and we imagine few colleagues would.

• It is challenging to manage patients with symptomatic presentations whose aetiology is unclear.
• Our patients should be treated as individuals. A good medical history including a good past drug history is essential. The process for differential diagnosis is important.
• In syndromic presentations it is important clinicians acknowledge the patients presenting symptoms and belief about aetiology and work with them to address the symptoms.
• Advocating an approach that does not recognize any potential for comorbidity is problematic.
• NHS England appreciates that mefloquine neurotoxicity does exist and requires clinical management. We look forward to published clinical guidelines from the DHSS/ NICE.

Co-morbidity.

There is no question about the need to treat significant co-morbidity. A significant infection, an emerging diabetic or other disorder, needs management.

These are different scenarios to treating symptoms of ‘depression’ or ‘anxiety’ where these may be features of enduring mefloquine toxicity rather than a de novo comorbid neuropsychiatric disorder.

1. Depression or anxiety symptoms are often alternate expressions for a host of symptoms such as malaise, asthenia, fatigue, irritability, tension, agitation, stress, etc that arise from the toxic state rather than represent a co-morbid disorder.
2. Depression or anxiety may also represent a temporary demoralization linked to a persisting disability.
3. Neither toxicity nor demoralization are likely to respond to antidepressant treatments and neither should be diagnosed as a functional neurological disorder (FND).
4. High occupational functioning does not rule out significant injury.
5. Prior military culture and sanctuary trauma may militate against reporting problems.
6. A significant (severe) de novo onset depressive disorder warrants treatment with tricyclic antidepressants or ECT. SSRIs have never been shown to treat severe mood disorders.  Less severe mood disorders will clear within 12-16 weeks on average without treatment.
7. A 2022 FDA analysis of over 70,000 patients in antidepressant licensing trials – all done in mild depressions – show only 1 in 6 on active treatment have an unequivocally good response.
8. SSRIs are among the drugs most commonly reported to regulators for disturbed sleep, nightmares, violent dreams, confusional states, balance and vision problems, which overlap with mefloquine toxicity and may compromise future differential diagnoses.
9. There is an increased rate of suicidal (including suicide) and homicidal events on active treatment in SSRI clinical trials
10. There is an increased rate of suicides along with suicidal and homicidal events in SSRI healthy volunteer studies.
11. Against this background, a prior history of an unequivocally good response to an SSRI may support their safe use.
12. The licensing trials for antipsychotics show higher rates of completed suicides, suicidality and homicidality on treatment than is found for any other drug group. Patients with schizophrenia did not present with an inherently high risk of suicide or homicide before the introduction of antipsychotics.
13. FND is a valid but relatively rare clinical disorder and this diagnosis should only be made where significant drug toxicity has been ruled out.
14. Given there are no recognized treatments for most toxic states, it may take some time before we have treatments for Persistent Mefloquine Toxicity Syndrome and in the absence of treatments, NICE and Guidance issuing bodies are unlikely to issue Guidance

A PDF of Ariadne’s Thread, including the Ministry of Defence component is in this link. You are welcome to show it to any healthcare professionals you consult.