23 Mar, 12 | by BMJ
Last year I attended a meeting in Heidelberg on treatment of mental health problems and came away with a bleak view of the lack of progress. This week in another delightful university town, St Andrews, I heard more positive messages.
Progress with traumatic brain injury?
Traumatic brain injury is currently one of medicine’s failures. In the US it causes 52 000 deaths and 1 365 000 hospital admissions each year, and there is no effective treatment, said Donald Stein, professor of emergency medicine at Emory University in Atlanta. The US also has some 250 000 people with traumatic brain injury as a result of the wars in Iraq and Afghanistan. Males account for roughly three quarters of all cases of traumatic brain injury, and it’s one of the commonest causes of death in young men.
Some 50 different treatments have been tried for traumatic brain injury, but all have failed. The reason, said Stein, is that traumatic brain injury is a systemic problem. The injury to the brain starts a cascade of biochemical events throughout the body. A treatment that affects only the brain is unlikely to be successful.
Stein has been working for years on the possible use of progestagens to treat traumatic brain injury. The idea emerged from the clinical observation that women do much better than men after traumatic brain injury, including stroke. Work in rats showed that females suffered less brain deficit than males for the same brain injury and that they suffered still less if in the high progesterone phase of their menstrual cycle.
The next step was to give progestagens to rats after brain injury, and these experiments showed that they could reduce the extent of brain injury. Importantly it was also found that benefits could be achieved even if the progestagens were given as late as 24 hours after the injury.
Stein and others then began to think that progestagens should be tried in humans. Many thought that the idea of giving female hormones to males was crazy, but progestagens in contrast to oestrogens do not give rise to secondary sex characteristics. Indeed, the very reason that progestagens may be beneficial is that they are pleiotropic hormones, affecting all the tissues in the body. Remember that traumatic brain injury is a systemic not just a brain disease. Other groups are exploring progestagens for the treatment of multiple sclerosis and motor neurone disease.
Two phase III clinical trials of using progestagens to treat traumatic brain injury have now been completed and a much bigger one is underway. The Food and Drug Administration in the US has very unusually allowed the trials to proceed without informed consent. Patients are given a three day intravenous infusion of progestagens, and mortality is 30% in the control arm and 13% in the treatment arm. A trial in China found similar results: 32% mortality in the controls, and 18% in those treated with progestagens.
I found myself wondering if this treatment might not keep alive people who’d be better off dead, but it looks as if progestagen improves outcomes for people at all levels of severity. Later in the afternoon, Nicole von Steinbüchel-Rheinwall, a professor of medical psychology and sociology from the University of Gőttingen, described the work of a global collaboration that has created an instrument specifically for measuring the quality of life in people with traumatic brain injury.
Now a much bigger double blind trial with 1200 patients is underway to test the use of progestagens in traumatic brain injury. Data on the first 450 patients will be analysed soon.
Many questions remain, concluded Stein. Will benefits be sustained? Might combinations of treatment be more effective? Might other conditions be treated with progestagens? Might it be possible to create a form of progestagen that could be given on the battlefield by non-physicians?
But perhaps the biggest problem if progestagen proves to be beneficial is how to get it widely used? It’s cheap and cannot be patented, so there is no incentive for a drug company to manufacture and market it. Stein’s work does receive support from a French company, but the business problem might prove to be even more difficult than the scientific and clinical problems.
Doing better in treating depression
Depression, it has always seemed to me, is the worst disease you can have because part of the condition is the impossibility of imagining recovery. Kay Jamison, a professor of psychiatry at Johns Hopkins and a professor of English at St Andrews, coauthored the definitive 900 page textbook on depression. She has also written a book on her own experience of bipolar illness, An Unquiet Mind. At the meeting she quoted Emil Kraepelin, who first distinguished between manic depression and schizophrenia, to illustrate the horrors of depression. He described a patient who hacked at the soft tissues in his neck with a chisel to try and kill himself and cut down to the vertebrae.
Jamison has for years been urging psychiatrists to follow oncologists and cardiologists and talk about the mortality of depression. There are at minimum a million deaths a year from suicide, and most of these happen in young people. The years of life lost are huge, and suicide is the second commonest cause of death in men under 60.
She insisted as well that there are effective treatments and was scornful of the media, including the medical press, for spreading the idea that antidepressants don’t work. She was equally annoyed with the several professors of psychiatry in the US who have been sacked for undisclosed funding from pharmaceutical companies. She thought that one reason for the spread of the idea that antidepressants may be ineffective is their increasing use in patients with mild depression. Another reason may be that people with severe depression often don’t take their drugs.
The treatment of bipolar and unipolar illness is different, and it is critical, emphasised Jamieson to get the diagnosis right. Bipolar illness is, she believes, underdiagnosed because the history of mania is often missed. Depressed people have disturbed cognition and do not remember their mania, and mania may manifest more as irritability than elevated mood.
If antidepressants are overused lithium may be underused. It is, she conceded, a toxic drug and it doesn’t work for everybody, but it is a lot more effective in preventing recurrence of depression than the anticonvulsants that she believes have been overpromoted in guidelines (where the authors may have been overinfluenced by drug companies).
The biggest problem with treating depression may be that patients don’t take their drugs. This is a common problem with all conditions, but one extra reason why patients with bipolar illness may be that patients become “addicted” to their own manic episodes. “Mania,” she said, “leaves cocaine for dust.”
One of the biggest “discoveries” in psychiatry is the rediscovery of psychotherapy—mainly cognitive behavioural therapy—not only as a treatment on its own for various conditions, but also to increase adherence to their drugs among patients with depression. Many trials have shown its effectiveness.
Jamison has a particular interest in depression in doctors. Depression is commoner in doctors than in the general population—perhaps because people who have experienced depression are attracted to “the healing professions” and perhaps because sleep deprivation is very powerful in unmasking depression. Suicide rates among doctors are high, and the standardised mortality ratio for women doctors is 170.
Some of you will get depression, Jamieson tells medical students, and that’s nothing to be ashamed of. What is shameful is if you don’t recognise it or succumb to the stigma attached to mental illness and don’t go for treatment.
Competing interest: RS chaired the meeting in St Andrews, had his expenses paid, and enjoyed a meal with the other speakers, students, and staff who had organised the meeting. He had a Highland Park whisky when nobody else did but if the restaurant had had any would have preferred an Islay whisky, which would have been more expensive.
RS was the editor of the BMJ until 2004 and is director of the United Health Group’s chronic disease initiative.