"We saw a range of tolerance levels and we think it's because one person's blood vessels in the nose can be so different to the next person's, and when you spray, it crosses the thin lining, gets taken into the blood and straight to the brain. Some people got huge hits." One of the five participants, Cheryl*, said she had tried a raft of treatments for depression over the past 10 years and only ketamine - given by under-the-skin injections in a different trial - had renewed her “desire to live”. About 1 million Australians suffer from depression. Credit:Shutterstock The 66-year-old retiree from Sydney was "extremely optimistic" when she joined the pilot trial but as it went on her blood pressure increased and she couldn't fully control her hands, making it difficult to correctly self-administer the nasal spray. All participants were given training in proper self-administration techniques before receiving either a course of eight ketamine treatments or an active control over a period of four weeks, under supervision at the study centre. Each treatment consisted of 10 sprays.

Following initial reactions, the dosage was adjusted for each patient to include longer time intervals between each spray. Professor Colleen Loo from Black Dog Institute. "In my opinion, all drugs have side effects and while the side effects were a concern, I felt I was in a safe environment and the staff knew what they were doing," Cheryl said. "You need to understand that I was keen to do anything to alleviate my depression and the side effects were worth the risk." Over the past 20 years, researchers have established that ketamine, when intravenously administered, can help people with "treatment-resistant depression", and are now working to make it a less invasive, "clinically useful" treatment so that patients can get well and stay well.

The clinical trial has cast some doubt on nasal sprays, but it is still a promising method, with Johnson & Johnson's pharmaceutical company Janssen conducting trials using a sibling of ketamine called esketamine, also a general anesthetic and a dissociative hallucinogen. Professor Loo said the concerning outcome of her study didn't mean Janssen's trials couldn't be successful because it was using different preparations and spray methods. “It’s clear that the intranasal method of ketamine delivery is not as simple as it first seemed,” she said. "I wish them luck because sprays are better than injections ... this is not that straightforward, all of these complexities are things we need to sort out before we can come out and say: 'Yep this is ready for mainstream clinical use'." Associate Professor Christopher Davey, head of research group Orygen's Mood Disorders program, said he was disappointed by the trial's outcome because ketamine was so promising and nasal sprays would have helped it one day become widely available.

"There's a real need for a new antidepressant treatment; the traditional medications don't start working for weeks and at least half the people won't really get a benefit from them," he said. "I think it is an exciting development in psychiatry because we are finding potentially a new pathway for effective medications; it's opened up this door of investigation." Johnson & Johnson told Fairfax Media the Black Dog Institute's ketamine study did not in any way relate to its own trials, which use esketamine. "Esketamine is an investigational compound being studied by Janssen as part of a global development program," its spokesman said. "Esketamine is not an approved medicine in Australia and remains in clinical development. Esketamine received Breakthrough Therapy Designations from the US Food and Drug Administration in November 2013.”

In any one year, around 1 million Australian adults have depression, according to beyondblue. In another study last year, Professor Loo showed the effectiveness of ketamine’s antidepressant effects in elderly patients when delivered in repeated doses, which were adjusted on an individual basis and given by subcutaneous (under the skin) injections. “Our prior research has shown that altering the dose on an individual patient basis was important. However, we wanted to see if a simpler approach using a set dose of ketamine for all people and administered by nasal spray could work just as well in this latest pilot,” she said. “More research is needed to identify the optimal level of ketamine dosage for each specific application method before nasal sprays can be considered a feasible treatment option.” Her team is now recruiting participants for the world’s largest independent trial of ketamine to treat depression, to determine the safety and effects of repeated dosing using subcutaneous injections.