Mental health disorders—particularly depression, schizophrenia, and Alzheimer’s disease—account for a huge proportion of the global burden of disease, but the outlook for better treatments looks bleak. I don’t think that was the message I was supposed to get from a conference entitled Making Sense of Mental Illness organised by EMBO at the European Molecular Biology Laboratory in Heidelberg, but I didn’t feel optimistic as I sped back to Frankfurt Airport on the ICE train.
(A man I met at the airport told me that his students thought that the conference had done the opposite of “Making sense of mental illness.” I replied with the quip of Jack Welch, once chief executive of General Electric, that “if you’re not confused you don’t know what’s going on.” The man responded: “That’s OK for an old timer like you but not so good if you’re young.” I nodded but later thought that for the young the big unanswered questions are surely more an opportunity than a threat.)
Drugs are one mainstay of treatment, and many of the big companies have pulled out of developing treatments for mental health problems. Despite a huge market and huge need, the risks are too high.
Hoffman La Roche is the exception, said Luca Santarelli, head of CNS research at the company. To produce a useful and profitable drug, he said, a company requires need, a biological target, the right compound, and the right studies. Despite global investment in neuroscience, the biology is lacking. Later in the meeting Stephen Rose, emeritus professor of biology at the Open University and a neuroscientist himself, argued that the neuroscience model of a disordered gene leading to a disordered molecule leading to a disordered mind was too reductionist to be useful. There are, he pointed out, up to 650 genes that have been linked to schizophrenia through biobank studies.
The strategy of Hoffman La Roche is to concentrate on serious mental health problems and to try and design drugs by understanding the biology of the diseases. One target is Alzheimer’s disease, and the company has a drug, gantenerumab, that has been shown to reduce amyloid in the brains of those with the disease. A trial is now underway to look at the effect on symptoms, but, said Santorelli, effective treatments may result only from starting treatment some 20 years before full Alzheimer’s disease emerges. Progress is being made with identifying who is likely to develop the condition.
Alzheimer’s disease is currently all but untreatable, and only 10% of patients with schizophrenia return to full functioning after treatment. About half of patients don’t respond at all. Hoffman La Roche’s strategy is not to try and reverse the whole disease but concentrate on the disabling symptoms of negativity and cognitive disorder. One of the big problems with proving the effectiveness of drugs in mental health disorders, he added, is the remarkably powerful placebo effect. Even patients with prolonged and intractable depression, for example, will improve when brought to a clinic, entered into a trial, and generally fussed over. This could, of course, be seen as good news.
With its mood to take risk Hoffman La Roche is working hard on neurodevelopmental disorders, which are dominated by autism and autism spectrum disorder. The need is huge, with US data pointing to 1 in 150 people being affected, and no treatments are available. Futhermore, there is, said Santinelli, strong emerging science on these disorders. But there are no good endpoints for clinical studies, and lots of operational difficulties—plus regulators have little experience with licensing drugs for neurodevelopmental disorders.
Santinelli didn’t discuss new drugs for depression, the condition that tops the burden of disease league table, but said in response to questions that two drugs were being tested. He’d earlier pointed out that a third of patents with severe depression showed no response to drugs. Tim Kendall, director of the UK National Collaborating Centre for Mental Health, quoted the systematic reviews that cast severe doubts on the effectiveness of antidepressants and described the studies, including his own, that show substantial bias in the studies that are published in journals. We seemed in discussion, however, to arrive at a consensus that antidepressants probably do work but are better than placebo only in patients with severe depression, mainly because placebos are less effective in such patients.
Surprisingly to me, there was much more enthusiasm for psychotherapy. Mathias Berger, director of the department of psychiatry and psychosomatics at the University Hospital in Freiburg, pointed out that there were more than 350 schools of psychotherapy, that there are probably more psychotherapists in Freiburg than in the whole of the UK, and that German sickness funds are spending 750m Euros a year on psychoanalysis, which has no evidence from randomised controlled trials. Despite this cynical beginning he enthused over “disorder related therapies,” particularly cognitive behavioural analysis system of psychotherapy (CBASP), which is based on a theory of severe depression resulting in large part from childhood trauma.
CBASP has three components: a therapeutic alliance, in which the psychotherapist is much more personally involved than is usually thought respectable by psychotherapists; an exploration of relationships with “significant others” from childhood; and training in conflict solving, something close to cognitive behavioural therapy (CBT), which does have lots of evidence from randomised trials to support it. Berger quoted evidence from randomised trials showing evidence of greater effectiveness for CBASP than drugs for patients with severe depression. I asked if there was more than one trial and one undertaken by anybody apart from the inventor of the therapy, and whether there were any results beyond 12 weeks. The answer seemed to be no to all of those questions, but the psychiatrists in Freiburg are now conducting a trial.
The development beyond “disorder related psychotherapy” is neuropsychotherapy, which combines psychotherapy with insights from neuroscience. One example was using oxytocin as a “trust enhancer” in couple psychotherapy. This all sounded very shaky to me, and any optimism I might have had was lost when a member of the audience asked about side effects of psychotherapy, and Berger answered ineffectiveness, cost, intimate relationships between the therapist and patient (commoner than we think, he said), a narcissistic therapist playing out his or her fantasies, and dependency.
Desperate problems need desperate remedies, and so we turned to deep brain stimulation. This involves drilling a burr hole in the skull, inserting electrodes, and connecting them to a battery on the chest that stimulates the brain 24 hours a day for years. But just how desperate depression can be was described by Lewis Wolpert, a distinguished evolutionary biologist who woke up one morning feeling suicidal. It was worse, he said, than “watching my wife die of cancer.” Depression does seem to me the very worst of diseases—because part of its symptoms are the impossibility of imagining yourself better. Wolpert has written a book on depression called Malignant Sadness; the Anatomy of Depression, and as the discussion proceeded it became steadily clearer that we shouldn’t think of depression as one condition but rather a collection of conditions ranging in severity from sadness to something so severe that it’s almost impossible to stop the sufferers killing themselves.
Deep brain stimulation has been used most for chronic pain and Parkinson’s disease, said Sidney Kennedy, professor of psychiatry at the University of Toronto, but about 100 people with severe intractable depression have now been treated, many of them in Toronto. In broad terms about half have responded and about 20% have gone into remission. Side effects include wound infection, seizures, headache, and pain at the site of the battery. Patients in the Toronto series have had the electrodes placed into the subgenual cingulate cortex, but there is a debate about where best to place the electrodes.
Kennedy started his talk by referring to One Flew Over the Cuckoo’s Nest and acknowledged that placing electrodes into patients’ brains to treat a mental condition makes many people feel uncomfortable—although perhaps less so than electroconvulsive therapy, which has good evidence of effectiveness but has been judged socially unacceptable. His conclusion was that deep brain stimulation should not be used more widely until it has been tested in high quality randomised trials that include sham stimulation (inserting the electrodes but not switching them on)—and such trials are underway.
My conclusion was that I hope that I never get severe depression, but if I don’t die in the next 10 years the chances are that I will succumb to some brain condition.
Competing interest: RS spoke at the meeting and had his expenses paid—an economy return flight and a night in a hotel one notch up from a student residence. And he spent so much time talking to people after his talk that he missed the free lunch.
The main presentations from the meeting can be accessed at: http://www.embo.org/science-policy/science-society/conferences/2011.html
And the hashtags for those who know what that means are #embo and #mentalillness
Richard Smith was the editor of the BMJ until 2004 and is director of the United Health Group’s chronic disease initiative.