Catherine squirts the esketamine nasal spray up one nostril and then up the other under the watchful eye of medical staff.

“I suddenly feel a little drunk, not in that horrible alcohol way. I feel calm. Time slows down. The lights are brighter. The music intensifies. I can think clearly. Later my husband comes to take me home. I’m so happy. I’m chatting away coming up with ideas, plans. I can’t wipe the smile off my face.” 

For years, Catherine, 68, suffered from depression and anxiety. Oral anti-depressant medication did not relieve her symptoms. She attempted suicide multiple times. In May 2022, Catherine was accepted as a candidate for a new treatment, esketamine, administered by way of a nasal spray. “I wish I had access to it years ago, my life would be very different,” she says.

Catherine’s depression started when she was 15. “I was in a violent relationship and fell pregnant. My father was angry and with a very upset mother, they put me in a home and I lived in a room on my own.” When she gave birth, they took her baby away. He was given up for adoption. “I felt numb and broken,” she says. “Later in life when I had a miscarriage, I could not stop crying and that is when I knew I was very sick.”  

Catherine needed healing so she went in search of her lost son. They met when he was 19.  “He was so beautiful. It was pretty good, but as time went by, emotionally it wrecked me.” She struggled to leave their visits. In that tango dance of love and loss, his family disapproval casting a dark shadow, they eventually parted ways. The deep wound of her past was torn open, nevertheless

Catherine went on to qualify as an audio verbal therapist working with children with hearing loss.  

However, in 2018, the state government reduced the positions available from 20 to five.  Catherine was made redundant. “My job was me, my success, my skills.” She overdosed on pills, was admitted to the Adelaide Clinic and, when settled on medication, allowed to go  home. But the deep, dark well of sorrow crippled  her. “I had painted all my life. I couldn’t do it  anymore. I couldn’t socialise. I would just stay in  bed,” she says. 

Many others suffering mental illness also end  up in a dark place. Suicide Prevention Australia  reported that 3249 Australians died by suicide in  2022. Males are around three times more likely  to die by suicide than females. 

Enter ketamine, a drug introduced in the ’60s  as an anaesthetic, but also used illegally as a  recreational “party drug”. If snorted, the effects  of ketamine are felt quickly, bringing about a  sense of euphoria and wellbeing, though not  without troubling side effects including  hallucinations and dissociation. It’s also a drug of  dependence and easily abused. 

Ketamine has two mirror-image molecules:  R-ketamine and S-ketamine. Esketamine is the  S molecule of ketamine and is up to four times  more potent as an anaesthetic. For depression,  both esketamine and ketamine have been found  to be highly effective treatments. 

In 2014, Associate Professor Dennis Liu,  senior psychiatrist at the Northern Mental  Health Service and Clinical Associate Professor  at the University of Adelaide, was approached by  Janssen-Cilag, product sponsor, to run clinical  trials on esketamine (Spravato) for patients with  treatment-resistant depression (TRD). It’s a  novel drug, better still it appears to rewire the  brain. “When the brain is subject to stress and  depression the neurons retrieve their  communication, they retreat their fibres which  connect with other neurons, the brain slows  down,” Liu says. “When you give patients  Spravato, esketamine binds the receptor  NMDA which will activate the glutamate  pathway resulting in the release of multiple  chemicals to regrow neural genesis and neuronal  connectivity improving mood, motivation and  cognitive function.”  

Patients self-administer the Spravato nasal  spray in a clinical setting and under the strict  medical supervision of a psychiatrist, that way it  cannot be abused. It’s not a treatment for  children or pregnant women, those who are  breastfeeding nor individuals with complicated  medical histories. Patients start the treatment  twice per week for the first month reducing to  once per week in the second month and then weekly or fortnightly from month three onwards.

The patient stays for two hours under observation for side effects and blood pressure.  Liu says a “common side effect is dissociation,  an altered sense of reality, and a more severe  form is disconnection, their arms and legs are  somewhere, their mind is outside their body”.  “The side effects peak in about 45 minutes to  one hour and then the patient recovers very  quickly,” he says. Patients must be driven home  after the treatment and after a good night’s rest  are free to resume their normal activities. Liu’s first patient, David, 61, who was suicidal,  experienced feeling detached from his physical  body, but his mind was unlocked.  

“I felt like I was in a ticker-tape parade, fluttering pieces of paper everywhere, all these memories unlocked. I would grab one of these  pieces of paper and talk to my psychiatrist about  it. Over time, I was able to rationalise what had  happened, re-evaluate my life in a positive way.  

“I feel like I’m in a deep massage when I have  the treatment. I feel calm, total contentment.  This drug truly turned my life around.” 

Professor Ian Hickie, co-director health and  policy at The University of Sydney’s Brain and  Mind Centre, says “administering esketamine by  way of a nasal spray is particularly interesting because brain cells stick down into your nose, so  things that are taken intra-nasally have the capacity to directly affect the brain. Unlike  traditional antidepressants where you have to wait several weeks for a clinical response, with  the esketamine nasal spray you get the benefit  straight away, you become more hopeful, it reduces the risk.” 

However, the regulators took some convincing. In 2019, the Therapeutic Goods  Administration (TGA) recommended against  approval of the drug due to a lack of efficacy data  and later sought expert advice from the Advisory  Committee for Medicines (ACM).  

In September 2020, the ACM agreed that  Spravato had an overall negative benefit-risk  profile for the proposed indication and declared  there was “significant and unacceptable  uncertainty associated with the claims of efficacy  of esketamine in patients with TRD (treatment resistant depression)”. Janssen appealed the  decision and after ministerial-level intervention,  in March 2021, Spravato was approved and  registered under the TGA as a treatment for  TRD with the requirement for a new oral  antidepressant to commence simultaneously.  Studies published in 2020 and 2021 in the  Journal of Clinical Psychology and International  Journal of Neuropsychopharmacology found the  esketamine nasal spray resulted in a rapid  improvement in depressive symptoms.  

Liu agrees that the esketamine nasal spray is  working. “My patients are no longer suicidal.  

“They’re functioning again. They’re back working, improving relationships with family  and friends, engaging with the community.” The next step, getting esketamine Spravato  listed on the Pharmaceutical Benefits Scheme  (PBS), making it accessible and affordable to the  public, is proving to be a further challenge.  Despite three submissions to the Pharmaceutical Benefits Advisory Committee  (PBAC) (July 2021, July 2022 and July 2023),  Spravato has not been approved for PBS listing. 

In a Public Summary Document of the July  2023 meeting, the PBAC noted no new clinical  evidence was presented and remained  concerned the observed benefits were uncertain.  It’s key reason for rejecting the latest  resubmission was the economic evaluation  based on a single course of treatment limited to  a maximum of 12 months.  

The PBAC believed a high proportion of  patients would need more than one course of  treatment over a five-year period and thus it was  unlikely esketamine would be cost-effective. 

“In the mental health area, we struggle to get  new treatments,” Hickie says. “We have to  demonstrate that they are acutely effective,  there are long-term benefits, they compare  favourably with other agents in particular ways.  We don’t have anything like the clinical trial  framework that exists for cancer trials or  cardiovascular trials. The regulatory system  looks at the low cost to government of existing  treatments and asks why would we spend  thousands of dollars per month on a new  treatment such as esketamine Spravato?  

“The real comparator is the high cost of acute  health care when people are not treated for their  mental illness and end up in emergency  departments, back in hospital. The real  comparator is the impairment to people’s lives,  the cost to human life,” Hickie says. 

Spravato has given Catherine hope. “I feel  happiness and joy. I am able to paint again. I  volunteer for a charity. I’m engaging in life. I  keep saying to myself is this really happening  because of Spravato? It could only be Spravato.”. 

The clinical trials for esketamine Spravato  have ended. Treatment is only available through  limited pathways including Janssen-led access  

programs and, in some circumstances, via  funding from the Department of Veteran Affairs  and WorkCover. Full fee-paying patients in  South Australia will now pay more than $1000  per single esketamine nasal spray treatment,  putting this out of reach of many Australians. Taming the ketamine tiger to treat  

depression is becoming a key focus in other  states. In 2016-2020 University of New South  Wales Professor Colleen Loo, based at the The  Black Dog Institute in Sydney, led a randomised  controlled trial of ketamine in depression at six  mood disorder centres in Australia and one in  New Zealand involving 184 participants with  treatment-resistant depression.  

Those in the treatment group were given a  low dose of ketamine twice a week for four  weeks with the placebo group receiving  Midazolam (a psychoactive control). A study  published this year in the British Journal of  Psychiatry found a 19.6 per cent remission rate  for the treatment group, versus only 2 per cent  for the placebo group.  

“This large difference shows the ketamine  treatment was very effective, especially notable  given that, overall, the study population had  depression that was more difficult to treat than  in most other studies of ketamine,” Loo says.  

“The study was not designed to assess the  longer-term effects of continued ketamine  administration, and even for patients not being  formally classified as ‘in remission’, many still  experienced a significant reduction in  depressive symptoms.” 

The Black Dog Institute now runs a treatment program offering the low dose  generic ketamine administered via injection  under the skin, as tested in the study. This  generic drug (about $5-$20) is much less  expensive than Spravato, which is also offered at  the treatment program. As ketamine treatment  requires careful medical monitoring for two hours, regardless of whether given by injection  or through nasal spray, apart from the drug costs, there are treatment costs. Those  costs are about $300 per treatment session, and not covered by Medicare,  so again the treatment is out of reach of many. Kelly, 32, is another of Liu’s patients.  Her depression started in her early years at high  school, but she had no idea that’s what it was.  

“My parents were preoccupied with work and  being adults,” she says. “I spent a lot of time  alone. They downplayed the depression,  shrugged it off as hormones or typical teenager  mood swings. I’d be having an episode and  crying, but Mum would want an explanation. I  couldn’t give her one, she’d get angry. I just  wanted a hug, but all I felt was shame.” 

In year 10 she started self-harming with razor  blades. “I couldn’t emotionally contain how I  was feeling and so it was a release. My friends at  school did it as well, we would all compare with  each other. It got worse through adulthood,  cutting myself with razors almost weekly. I  would cut in the same place where I could cover  it up. I’ve still got scars on my wrists and legs.” 

After finishing school, Kelly enrolled at  TAFE for a media arts diploma, but near the  end, dropped out. At 21, she got a job in retail  and moved out of home. “I had a housemate who was quite open about mental health stuff,  so I thought I would try therapy. I went to a  psychologist and she referred me to a  psychiatrist who put me on Lexapro, which was horrible and after six months I went off it.” 

Kelly worked in various retail jobs, but  became so overwhelmed with panic attacks, she  would leave. She later enrolled at university to  study graphic design, but was doing poorly. 

“In 2015 I tried to kill myself by taking an  overdose of medication. I was in an inpatient  clinic for two weeks and put on a different anti depressant medication which I responded well  to for a while, though I was still self-harming  occasionally. I dropped out of university and  went back working, but around 2017 I started  suffering panic attacks again.” 

In 2019, Kelly was diagnosed with ADHD  and while medication helped, she noticed how  flat she felt and couldn’t enjoy anything. She  decided to change direction, enrolling in a  science degree and scored a part-time job with a  medical research company.  

At a conference organised by her employer,  Kelly heard a presentation on esketamine  Spravato and knew it was something she had to  try. She approached Liu, was accepted into the  early access program and commenced treatment in November 2022. 

“With the nasal spray, I feel a little drunk, but  not in a bad way,” Kelly says. “Everything in the  room looks the same, but there’s a slight delay in  how I perceive it. If I move my hand in front of  my face, a kind of blur would come behind it. I’d  start to have really organised thoughts planning  what I was going to do when I got home. I felt  really happy and positive. Before the treatment,  I couldn’t do normal stuff like organise my room  or go to the supermarket. Now I can function. I  feel normal. At work I feel a lot more confident.  

“I’m able to motivate myself and assure  myself rather than being negative.”  

Kelly has a cordial relationship with her  parents, but has never told them about her  attempted suicide and they know little  about her suffering. 

She is now in a much better place.  

“Prior to this treatment, I thought I’d be dead in my 30s, but now I’ve got  so much to live for,” she says. 

 David and Kelly are not their real names.  If you or someone you know needs help,  call Lifeline on 1311 14 or visit lifeline.org.au 

10 SAWeekend December 9-10, 2023 V3 - ADVE01Z01WE