Analyse this (Image: Frank Mulle/Hollandse Hoogte/Eyevine)

IMAGINE you are a doctor before the advent of modern medical tests and your patient is gasping for breath. Is it asthma, a chest injury, or are they having a heart-attack? You don’t know and have no idea how best to help them.

Some would argue that’s what it’s like for doctors trying to diagnose mental health problems today. There are no blood tests or brain scans for mental illnesses so diagnoses are subjective and unreliable.

The issue came to a head one year ago this month, with the latest edition of psychiatry’s “bible”, the Diagnostic and Statistical Manual of Mental Disorders. The US National Institute for Mental Health (NIMH) said the DSM-5 had so many problems we effectively need to tear it up and start again. The way forward, it said, is a new research programme to discover the brain problems that underlie mental illnesses.


Let’s not study the ‘disorder’ but the underlying biological systems that are going wrong

That research is now taking off. The first milestone came earlier this year, when the NIMH published a list of 23 core brain functions and their associated neural circuitry, neurotransmitters and genes – and the behaviours and emotions that go with them (see “The mind’s 23 building blocks“). Within weeks, the first drug trials conceived and funded through this new programme will begin.

While just a first draft, the list arguably represents the future of neuroscience-based mental healthcare. “This is the Rosetta stone for characterising human mental function,” says Andrew Krystal at Duke University in Durham, North Carolina.

The list of brain systems will be the Rosetta stone for characterising human mental function

Criticism of psychiatry has been growing for years – existing treatments are often inadequate, and myriad advances in neuroscience and genetics have not translated into anything better. Vocal opponents are not confined to the US. Last week, the new UK Council for Evidence-based Psychiatry launched a campaign claiming that drugs such as antidepressants and antipsychotics often do more harm than good.

What’s more, many suspect that commonly used labels, such as depression and schizophrenia, merely group together people sharing some superficial symptoms, when their underlying brain disorders are quite different.

Genetic studies, for instance, suggest that schizophrenia and bipolar disorder, supposedly distinct conditions, involve mutations in many of the same genes. And diagnostic confusion between the disorders is common (see “What’s in a name“).

“We are just playing semantic games,” says Sami Timimi, a psychiatrist at the University of Lincoln, UK, who leads a campaign called No More Psychiatric Labels. “It’s as if calling it ‘bipolar disorder’ reveals some essential truth – it reveals more about the subjective preferences of the diagnoser,” he says.

Although the NIMH has now admitted the DSM-5 is the best approach we currently have, its research programme is an attempt to go back to the drawing board. “Let’s not try to study each ‘disorder’ but rather, the neural systems themselves, and study how they become dysregulated,” says Bruce Cuthbert, who heads the NIMH’s programme.

So what do the mind’s 23 building blocks consist of? The best mapped-out anatomically is the brain’s fear circuitry, thanks to years of scaring volunteers as they lie in fMRI scanners. This system is probably involved in phobias and post-traumatic stress disorder.

Another is the related circuitry that deals, not with present danger, but with vaguer fears that something bad might happen in future. “That circuit is very relevant to rumination and anxiety,” says Cuthbert.

Another five neural systems are components of the brain’s reward circuitry, which is active when we find something pleasurable – like eating or sex – and drives us to repeat the experience. These can malfunction when people are addicted to drugs or alcohol.

The reward system, says Cuthbert, is very powerful because one of the most important things that organisms need to learn is to seek out things like food and water. “Drug abuse hijacks that system so the cues create urges that are very hard to resist,” he says.

A malfunctioning reward system may also lie behind two of the commonest forms of mental illness: depression and anxiety. Some people with these conditions have a symptom called anhedonia, a failure to enjoy usually pleasurable activities. Someone who was once a keen gardener, say, would lose all interest in their hobby, says Krystal, who is leading the NIMH’s efforts to develop drugs that treat it. The first trial in humans of one such compound is about to begin.

Most of the other neural systems on the NIMH list – which include attention, perception, working memory, arousal and social communication – do not tie in neatly with specific mental disorders, at least not as we currently define them. Instead, they cut across many different disorders, for example, problems with memory are seen in anxiety, depression and schizophrenia. This lack of a one-to-one correspondence between the disorders and the brain systems lends weight to the idea that existing diagnostic labels are flawed.

Only with a better understanding of these brain circuits can we develop ways to monitor them objectively using tools such as brain scans and EEGs, where electrodes on the scalp record the brain’s electrical activity. A recent refinement of EEG is the ability to record “event-related potentials”, a measure of the brain’s response to specific stimuli. Electrodes on the face can also measure how much we twitch after an unexpected noise, for example, to probe activity in the brain’s fear circuitry. This is thought to go awry in people with anxiety disorders.

Carefully designed cognitive tests are also being used more frequently in psychiatric research – for instance, people who are addicted to drugs often do poorly at computer tasks involving decision-making.

Some of those monitoring systems could one day provide the long-sought “biomarkers” of mental illness. But at the moment they are still just research tools, not ready for use in the clinic. As a result, the NIMH has been criticised for raising doubts over the way patients are treated without offering an alternative. “The damage to the image of our profession has been significant,” Mario Maj of the University of Naples in Italy told delegates at the European Psychiatric Association meeting in March.

And even some DSM critics are sceptical of the NIMH approach, branding it too reductionist. “The idea that the conditions we have to deal with are reducible to simplistic biological categories is wish fulfilment,” says Timimi.

Cuthbert admits that the list is only a first attempt at getting to grips with the brain’s complexity, and is probably incomplete. “We only listed systems that have a well-specified function and a clear neural system that implements that function.” But it’s a much-needed start. “If we go too far too fast we’re liable to have problems,” he says. “We want to walk before we run.”

Leader: Rebirth of psychiatry will be slow and painful

What’s in a name? Not many people would be happy with a diagnosis of bipolar disorder. But for Erica Camus, a 33-year-old website moderator living in Stafford, UK, it was doubly disturbing. She had previously been told she had schizophrenia, after becoming convinced that someone had placed spy equipment in her home. “I find it absolutely baffling,” she says, of the change in her diagnosis. “It’s hard to relate to.” In fact, her experience is not uncommon – people with mental health problems can receive different diagnoses from different doctors or at different times in their lives. Indeed, critics claim that psychiatrists frequently use diagnostic labels that do not correspond to distinct disorders (see main story). Objective medical tests are also lacking. Psychiatrists tend to diagnose schizophrenia, for instance, if they think a patient has two out of five possible symptoms. Neuroscientists say we need to find the underlying brain disorders, so we can use brain scans, EEGs and cognitive tests to diagnose problems – and develop better treatments (see main story). Camus, who is currently well, is taking medication and having psychotherapy. But she has good reason to resent the labels assigned to her: she feels that revealing her schizophrenia diagnosis contributed to her losing a job four years ago. If not for that possibly inaccurate label, she says: “I would never have experienced the stigma I have.”

The mind’s 23 building blocks These are the brain systems the NIMH has identified. They are grouped into five categories: Negative systems Acute threat – also known as our fear circuitry. Active when we sense danger

– also known as our fear circuitry. Active when we sense danger Potential threat – active, not in presence of a threat, but when we know the risk of danger is higher than normal. Associated with a sense of unease or anxiety

– active, not in presence of a threat, but when we know the risk of danger is higher than normal. Associated with a sense of unease or anxiety Sustained threat – negative emotional state caused by prolonged exposure to unpleasant conditions. Can cause loss of enjoyment in usually pleasurable activities

– negative emotional state caused by prolonged exposure to unpleasant conditions. Can cause loss of enjoyment in usually pleasurable activities Loss – circuits active during permanent or sustained loss of a loved one, or emotionally significant objects or situation, such as shelter or status.

– circuits active during permanent or sustained loss of a loved one, or emotionally significant objects or situation, such as shelter or status. Frustration non-reward – reactions to lack of reward after sustained efforts. Can involve aggressive behaviour Positive systems Approach motivation – circuits that control our efforts to obtain a reward, such as sex or food

– circuits that control our efforts to obtain a reward, such as sex or food Initial responsiveness to reward – feelings of pleasure on obtaining a reward. Involves opioid and endocannabinoid receptors, those activated by morphine and cannabis

– feelings of pleasure on obtaining a reward. Involves opioid and endocannabinoid receptors, those activated by morphine and cannabis Sustained responsiveness to reward – mechanisms that terminate reward-seeking behaviour, such as satiety, the feeling that enough food has been eaten

– mechanisms that terminate reward-seeking behaviour, such as satiety, the feeling that enough food has been eaten Reward learning – processes by which we acquire information to predict rewards and learn to repeat the positive experience

– processes by which we acquire information to predict rewards and learn to repeat the positive experience Habit – repetitive behaviours that, once started, can be done unconsciously. Habits can free up cognitive resources Cognitive systems Attention – a range of processes that regulate access to awareness and higher cognitive systems

– a range of processes that regulate access to awareness and higher cognitive systems Perception – the processes that take sensory data and transform it into representations of the environment

– the processes that take sensory data and transform it into representations of the environment Working memory – the system that can hold and manipulate many items of information on a temporary basis

– the system that can hold and manipulate many items of information on a temporary basis Declarative memory – the encoding, storage and retrieval of representations of facts and events on a long-term basis

– the encoding, storage and retrieval of representations of facts and events on a long-term basis Language behaviour – systems that allow production and comprehension of words, sentences, and coherent communication

– systems that allow production and comprehension of words, sentences, and coherent communication Cognitive control – systems that modulate the operation of other cognitive and emotional circuits. Can involve inhibition of behaviour or selection of best response from competing alternatives Social systems Attachment – systems for bonding with friends and family. Involves hormones such as oxytocin and vasopressin

– systems for bonding with friends and family. Involves hormones such as oxytocin and vasopressin Social communication – processes involved in exchange of socially relevant information, such as speech and body language

– processes involved in exchange of socially relevant information, such as speech and body language Perception of self – circuits involved in understanding ownership of one’s own body or actions

– circuits involved in understanding ownership of one’s own body or actions Perception of others – processes involved in being aware of and reasoning about other animate entities, such as our “theory of mind” networks, which allow us to understand that other people can have different beliefs to our own Modulatory systems Arousal – a spectrum of sensitivity to stimuli, from coma and unconsciousness, through anaesthesia and sleep to full consciousness

– a spectrum of sensitivity to stimuli, from coma and unconsciousness, through anaesthesia and sleep to full consciousness Circadian rhythms – self-sustaining oscillations that organise the timing of biological systems

– self-sustaining oscillations that organise the timing of biological systems Sleep-wake cycle – recurring behavioural states that reflect coordinated changes in the brain. Regulated by physiological and circadian processes

This article appeared in print under the headline “Psychiatry: the reboot starts here”