AUSTRALIAN MEFLOQUINE & TAFENOQUINEVETERANSCurrent SituationNeeds of Affected Veterans and FamiliesMajor Stuart McCarthyCorrect as at 7 February 2016

Tafenoquine

Mefloquine“We owe it this generation of veterans to recognize the neurological and psychiatric effects of mefloquineneurotoxicity alongside PTSD and TBI for what they are: the third signature injury of modern war.”

Dr Remington Nevin, 2013

Scope• Background on mefloquine & tafenoquine toxicity in

Australian veterans• Mefloquine neurotoxicity and health impacts• Mefloquine as a cause of suicide• Problems Experienced by Veterans with

Mefloquine/Tafenoquine Toxicity (M/TfT)• Misinformation from Department of Defence• Needs of mefloquine & tafenoquine veterans• Support from Repatriation Medical Authority• Support from Department of Veterans’ Affairs

Background on Mefloquine & TafenoquineToxicity in Australian Veterans• Synthetic quinoline anti-malarials known for their neurotoxic properties since 1940s.• Mefloquine:

• Developed by WRAIR in the 1970s, early testing on prisoners, soldiers and subjects third world countries.• Licensed by regulators in late 1980s - early 1990s in absence of Phase III clinical trials.• Introduced into ADF in the early 1990s but has never been first-line anti-malarial:

• Prior to 2001 – several thousand prescriptions?• Timor Leste trials 2000-2002 – approx 1,300 prescriptions.• Since 2001 – additional approx 500 prescriptions.

• Concerns about long term neuropsychiatric health impacts raised by US Dept of Veterans Affairs et al since 2004.• Found to be neurotoxic in mid 2000s, able to cause lasting or permanent brain injury, at dosages equivalent to prophylaxis.

Background on Mefloquine & TafenoquineToxicity in Australian Veterans (cont)• Tafenoquine:

• Similar drug to mefloquine, from same family, similar elimination half life also allows for weekly dose.• Has never been licensed by regulators including Australian TGA.• Prescribed to approx 1,500 ADF personnel during trials in Bougainville and Timor Leste 1998-2001.• Found to be “more neurotoxic than mefloquine” in 2009.

• Scope of the problem:• Since early 1990s, approx 5,000 Australian veterans administered mefloquine or tafenoquine.• Say 10-25% = 500-1,250 veterans with neurotoxic brain injury.• Commonly misdiagnosed with PTSD, personality disorders, “psychosomatic” neurological disorders.• Confounding factor in PTSD, TBI, etc, with implications for research.• Defence and DVA refuse to undertake follow-up studies, research etc.• No acknowledgement, rehab or support for veterans and families.• Denials, fraud, corruption and cover-ups, adding to distress.

Mefloquine (Lariam®)Background:• Member of the quinoline family of antimalarial compounds (quinine, chloroquine)• Highly effective prophylaxis / therapeutic for malarial infectionMode of action:• In the malarial parasite:• Not well understood – possible effects on malaria parasite include:

• Alteration of heme ion transport• Binding / inhibition of cellular processes in the parasite gut / nervous system• Inhibition of cellular hemozoin formation• Inhibits viral replication (ssDNA binding)

• In the nervous system:• Binds to intra- and intercellular ion channels• Disrupts mitochondrial function• Alters neurotransmitter release• Causes neuronal cell death

Adverse Effects - Disorders & Incidence Reported by the Manufacturer (despite systematic under-reporting)

Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000).

Psychiatric disordersVery common Abnormal dreams, insomnia.Common Anxiety, depression.Uncommon Agitation, restlessness, mood swings, panic attacks, confusional state,

hallucinations, aggression, bipolar disorder, psychotic disorder including delusional disorder, depersonalisation and mania, paranoia, suicidal ideation.

Nervous system disordersCommon Dizziness, headache.Uncommon Balance disorder, somnolence, syncope, convulsions, memory impairment,

peripheral sensory neuropathy and peripheral motor neuropathy (including paraesthesia, tremor and ataxia), encephalopathy.

Ear and labyrinth disordersCommon Vertigo.Uncommon Vestibular disorders (long term) including tinnitus and hearing impaired.

Symptoms of mefloquine toxicity - a toxic ‘limbic encephalopathy’ (R. Nevin, 2015)

Psychiatric PhysicalVivid nightmares, hyper-realistic dreams, insomnia Vertigo

Anxiety, irritability, restlessness, anger, extreme violence towards self and others, extraordinary self-harming behaviors, loss of social / behavioral inhibition, suicidal ideation, suicide, depression

Accommodative dysfunction (convergence insufficiency)

Paranoia / persecutory delusions, psychosis PhotophobiaSeizures (grand and petit mal) Disequilibrium

Visual / auditory / olfactory hallucinations Visual / hearing loss

Confusion, memory loss, impaired cognitive processing, loss of concentration, amnesia, dissociation, de-reaslisation

Tinnitus

Problems with executive, spatial and verbal memory

‘COMMON’ – prodromal, lasting or permanent

SNVTA

NAc

Str

Cb

Nigrostriatal / peduncluopontine (GABA, 5HT)

Hip

Am

Reward / Mesolimbic (DA)

Mesocortical (GABA, ACh)

PPTg

Sc

Rn

DysregulationIncreased excitationLoss of inhibition

Striato-cortical (Glut)

Ctx

Cortex / hippocampus:MemorySpatial coordinationDreamingSeizuresPsychosismTBIPTSD

Subcortical:AngerParanoiaAnxietyDepressionPTSD

Brain stem:BalanceHearingVision

How / where mefloquine affects

the brain?

‘Complex’ PTSD with additional defining featuresJ. C. Quinn, “Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine”, Journal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.

Dose / Tissue Loading

Risk /

severit

y of ad

verse

neurop

sychia

tric ev

ents

0

100

Px Tx

Mild

Moderate

Severe

‘normal’ population

‘normal’ population

Co-morbidity(other MH issues)

Genetic variants

Co-morbidity

‘Other’ interactions

Genetic variants(CYP450, PgP, G6PD)

Genetic variants‘Other’ interactionsCo-morbidity

‘Other’ interaction(drugs / alcohol)

MaleFemale

Up to 100%

Why Are Some Affected and Not Others?

J. C. Quinn, “Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine”, Journal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.

Mefloquine as a Cause of Suicide1. Demographic factors – males aged 30-34, indigenous, rural and remote populations.2. Psychopathology & psychiatric hospitalisation – diagnosis of a mental disorder, particularly

affective disorders, substance abuse, anxiety disorders, personality disorders and psychiatric comorbidity.

3. Previous non-fatal suicidal behaviour and suicidal ideation.4. Family history of psychopathology and suicidal behaviour.5. Physical illness, chronic physical pain.6. Negative life events and low coping potential.7. Marital status of divorced, widowed or separated.8. Low socioeconomic status, unemployment.9. Neurobiological activity – hypo-activity of the serotonergic system.10. Psychological factors – hopelessness; high aggression and impulsivity, lack of reasons for

living, cognitive rigidity, low ability to solve problems, perfectionism, psychological pain.11. Social isolation and lack of social support.

“Level A” Risk Factors for Suicide (Dunt, 2009)

Problems Experienced by Veterans with Mefloquine/Tafenoquine Toxicity (M/TfT)• No formal recognition of the chronic toxicity syndrome.• Incomplete or wrong diagnosis – malingering, failure to perform in the workplace, wrongful discharge, effects on career profile, family breakdown – currently NO veteran support organisation for M/TfTsufferers• Underlying effects on brain chemistry cause paradoxical drug reactions where treatments are applied – poor prognosis.• Mis- or confounding diagnosis of PTSD, further precluding appropriate treatment.• ‘Complex’ syndrome when PTSD and / or mTBI also identified –very poor long-term prognosis without correct diagnosis and treatment: long-term hospitalisation, incapacitation or suicide.

Misinformation from Defence – Mefloquine*“Approval” by the Therapeutic Goods Administration• Claim: “Mefloquine … is … approved by the Therapeutic Goods

Administration (TGA) for malaria prevention.”• Claim: “The ADF uses a loading dose prior to deployment to achieve

protective levels more quickly. This involves taking one dose on each of three days in the week before deployment.”

• Fact: The TGA has approved mefloquine chemoprophylaxis as a once weekly dose of 250mg.

• Fact: A once weekly dose of 250mg can cause permanent brain injury.

• Fact: The ADF loading dose is three times the weekly dose approved by the TGA for malaria chemoprophylaxis.

*http://www.defence.gov.au/Health/HealthPortal/Malaria/Anti-malarial_medications/Mefloquine/default.asp

Misinformation from Defence – Mefloquine*Numbers of Personnel Affected by Mefloquine Neurotoxicity• Deceit: 137 ADF members prescribed mefloquine 2010-2015.• Fact: In 2000-2002 alone, 1,312 ADF members prescribed mefloquinein AMI clinical trials in East Timor.• Fact: In 2006 U.S. Army researchers found that Mefloquine is able to cause permanent brain injury.Permanent Brain Injury is “Rare”• Claim: “In rare cases some neurological side-effects may be long lasting or permanent.”• Fact: There are at least several hundred serving and former ADF members whose neurological and psychiatric symptoms are consistent with mefloquine neurotoxicity.• Fact: Defence refuses to undertake medical follow-up studies.*http://www.defence.gov.au/Health/HealthPortal/Malaria/Anti-malarial_medications/Mefloquine/default.asp

Misinformation from Defence – Tafenoquine*Tafenoquine is “Not Related to Mefloquine”• Claim: “Tafenoquine is not related to mefloquine and acts quite differently in the body.”• Fact: Tafenoquine and mefloquine are both synthetic quinolinedrugs.• Fact: Tafenoquine and mefloquine are both known to be neurotoxic.Tafenoquine is not Neurotoxic• Deceit: “Tafenoquine has not been shown to have any neurotoxic or neuropsychiatric side effects.”• Fact: In 2009 U.S. Army researchers found that “tafenoquine is more neurotoxic than mefloquine.”• Fact: The report of the 2000-01 AMI trial states “There was no significant difference between [mefloquine and tafenoquine] in the number or type of adverse events.”*http://www.defence.gov.au/Health/HealthPortal/Malaria/AMI_research/tafenoquine-mefloquine/default.asp

Misinformation from Defence – TafenoquineDrug Trial in East Timor, 2000-2001*Claims:“Participation in the study was offered to a battalion group deploying to Timor-Leste for a six month period. It was optional and voluntary. Efforts were made to ensure deploying personnel were fully informed of the risks and benefits of participation before they made their decision. They were given a written information sheet, a verbal briefing and were asked to sign a consent form. Those who chose to participate were also advised of the option to opt out or withdraw from the trials at any time with no detriment to their career or future health care.”“Participation in the trials was not a pre-requisite for deployment. To provide deploying personnel with appropriate protection against malaria, those who chose to not participate in the trials were prescribed anti-malarial medication in accordance with extant health policy, which included doxycycline and mefloquine.”*http://www.defence.gov.au/Health/HealthPortal/Malaria/AMI_research/tafenoquine-mefloquine/default.asp

Misinformation from Defence – TafenoquineDrug Trial in East Timor, 2000-2001*Facts:“… evidence before a Senate inquiry in Australia has called into question the ethics of clinical trials conducted by the Australian Army Malaria Institute in 2000-2002. These trials … failed to meet applicable ethical standards which describe military personnel as vulnerable subjects. The subjects did not provide properly informed consent. Hundreds were coerced into participating under threat of being excluded from the deployment and investigators provided misleading or deceptive information regarding the drug’s side effects. Foreseeable risks of lasting or permanent CNS injury were disregarded and there was no appreciable benefit given the availability of safer alternative drugs. The safety and wellbeing of the subjects were compromised by administering personnel deployed on military operations with a drug known to cause neuropsychiatric side effects, without first conducting appropriate laboratory testing. Proper medical care has not been provided for subjects afflicted by chronic CNS toxicity as a result of the trials. When the trial reports were eventually published, relevant scientific findings regarding mefloquine CNS toxicity were omitted. According to the applicable contemporary standards, the trials were unethical.”*Major Stuart McCarthy, Were the Australian Army Malaria Institute’s 2000-2002 Mefloquine Clinical Trials in Timor Leste Ethical?, 6 February 2016

Needs of Mefloquine & Tafenoquine Veterans• Recognition/acceptance/information for affected veterans.• Repatriation Medical Authority to determine mefloquine & tafenoquineCNS toxicity as a distinct disease requiring dedicated rehabilitation.• Support for outreach program/advocacy.• Treatments/interventions:

• Harm minimisation – proper diagnosis to prevent mistreatment.• Targeted wellness programs.

• Research:• Follow-up health studies for affected veterans and families.• Therapeutics, impact of M/TfT + mTBI + PTSD.• Effective wellness/support programs – quality of life, return to work.

Need for a Dedicated RMA SOPThe Repatriation Medical Authority (RMA) has determined mefloquine and other synthetic quinolines (tafenoquine is a synthetic quinoline) to be a causal and/or aggravating factors in a variety of psychiatric, neurological, vestibular, and cardiac diseases, however there is a need for correct diagnosis & management toprevent mistreatment (including suicide risk) and ensure effective rehabilitation.“Screening for mefloquine neurotoxicity … would assist investigation, correct diagnosis, and differential diagnosis, not only improving the management of other prevalent illnesses but also reducing the risk of misdiagnosis and subsequent mistreatment. For example, pharmacotherapy presents an array of possible adverse effects. Despite misconceptions to the contrary, trauma-focused psychotherapies can cause adverse effects such as depression, panic attacks, suicide ideation, and substance abuse relapse, even when found to be efficacious in correctly diagnosed patients. Minimizing extraneous exposure to these therapies reinforces the case for proactively identifying and screening mefloquine recipients to aid correct diagnosis, rather than relying on self-reporting of psychiatric symptoms. A further measure would then be developing guidelines to assist clinical care providers in identifying personnel affected by mefloquine neurotoxicity, conducting differential diagnosis with other prevalent conditions, and providing ongoing care and management.”S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence Force”, Journal of Parasitology Research, vol. 2015, Article ID 368064, 2015.

Evidence for RMA Determination & SOP“The RMA are yet to publish a determination relating to mefloquine as a cause of toxic encephalopathy, although … they have previously recognized chronic solvent encephalopathy as a diagnosable disease. This may provide a useful guide on any future determinations regarding mefloquine CNS toxicity. Notwithstanding any remaining disputes or uncertainties regarding mefloquine toxicity, use of synthetic quinolines has been independently determined by the RMA to be a causal factor in a variety of psychiatric, neurological, vestibular, and cardiac diseases. These are strikingly similar to a list of conditions that the US Department of Veterans’ Affairs had identified from case reports in a document advising of possible long-term health effects of mefloquine as early as 2004.”S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence Force”, Journal of Parasitology Research, vol. 2015, Article ID 368064, 2015.

Evidence for RMA Determination & SOP (cont)“Reporting of psychiatric disorders linked to mefloquine use includes cases of depression, anxiety, bipolar disorder, and suicide or suicidal ideation. Reporting of neurological disorders linked to mefloquine use includes cases of neuropathies, vertigo, and hearing loss or tinnitus. Case reporting has also causally linked mefloquine to tachycardia. One interesting observation about this list of disorders is that, although mefloquine is a known ototoxicant, there is as yet no direct evidence that it can injure the peripheral nervous system; therefore a number of the recognized peripheral disorders may be more plausibly attributed to the CNS toxicity syndrome previously described.”

S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence Force”, Journal of Parasitology Research, vol. 2015, Article ID 368064, 2015.

Evidence for RMA Determination & SOP (cont)“… there is now compelling evidence for the previously described chronic CNS toxicity syndrome, linked to mefloquine prophylaxis, consistent with the literature on epidemiology and neurotoxicology. There is direct evidence that mefloquine is able to accumulate in the human brain and interact with neuronal targets in the CNS, consistent with both clinical observations and plausible pathophysiological mechanisms. There is direct evidence that mefloquine … [is] able to cause lasting or permanent [neuronal] injury ... Multiple neurological syndromes occur in response to this single neurotoxic agent, including a variety of chronic, clinical disorders which have been determined as causally linked to mefloquine use by [the RMA], in accordance with epidemiological principles, against an appropriate standard of medical-scientific evidence. The syndrome has varying presentations involving a host of nonspecific symptoms. The symptoms are often mimicked by other prevalent neuropsychiatric disorders, with competent medical authorities having determined that mefloquine use is able to confound the diagnosis and management of those disorders.”S. McCarthy, “Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence Force”, Journal of Parasitology Research, vol. 2015, Article ID 368064, 2015.

This evidence exceeds the standard required by the RMA.

Department of Veterans’ Affairs• Public recognition of mefloquine and tafenoquine CNS toxicity – no

more denials.

• Awareness for affected veterans, families, medical practitioners, counsellors and case managers.

• Funding for research, including toxicology, diagnostics, veterans’ health and social studies.

• Dedicated rehabilitation programs.

• Dedicated family and social support programs.

ConclusionMefloquine and tafenoquine have almost certainly killed and seriously wounded more Australian veterans than the Taliban.

For these veterans and their families there has been no acknowledgement or support. Indeed they have been subjected to more than a decade of systematic neglect, denial, fraud, corruption and abuse, by the medical system that is supposed to support them.

This needs to be addressed urgently, including support from DVA and other veterans’ organisations.