Navigating therapeutic waters with a faulty diagnostic compass

Diagnostic uncertainty is the key theme of this month’s issue. But first, we wish to highlight a seemingly obscure issue of great public health impact.

Social and economic factors play a major role in the risk for non-communicable diseases, including mental health disorders. Consequently, social and economic policies are a critical health tool. Nowhere is this truer than in the area of prevention. It could be argued that the major successes in heart disease and cancer have been driven by public policy in areas such as smoking. It has also been argued that prevention in the mental health space will ultimately need to occur through public policy. This is because most of the pathoplastic risk factors for the common mental disorders are environmental and include factors such as smoking, poor diet, inadequate physical activity and harmful use of alcohol (Hayward et al., 2014; Jacka et al., 2013). In this context, Monasterio and Gleeson (this issue) have documented significant concerns about the policy implications of the Trans Pacific Partnership Agreement. There are provisions in this agreement that would increase the influence of investors and industry stakeholders in the policy-making process. Given that effective public health reform not infrequently needs to challenge the vested interests of the food, tobacco and alcohol lobbies, this may be a serious setback for preventive endeavours. Additionally, there are clauses in this Act that may extend monopolies on medications and hamper Government’s pharmaceutical cost containment efforts. From a public health perspective, it is critical that the Government’s ability to act in the best interests of the health of the nation are not compromised by this agreement and that health is a determining factor in the crafting of this legislation.

The introduction of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) has spotlighted the limitations of current diagnostic systems (Wilson, this issue). In the absence of a coherent pathophysiology for any major psychiatric disorder, such diagnostic systems are limited to the role of operationalised metaphors. Despite being, to paraphrase Churchill, the worst possible system, except for the alternatives, this launch has highlighted the shortcomings of all our diagnostic systems (Berk, 2013; Nemeroff et al., 2013). This issue of the Journal continues the debate. Sharma and Sommerdyk (this issue) argue that the term post-partum psychosis is applied inappropriately to a large number of diverse disorders whose only common characteristic is a temporal link with childbirth. They contend that a more appropriate nosology is the standard DSM-5 terminology of major depressive disorder, bipolar disorder and schizophrenia. They argue that the non-specific term post-partum psychosis is of insufficient specificity to facilitate appropriate diagnosis, railroads assessment and management towards the psychotic rather than co-existing mood symptoms, is unhelpful in assessing safety issues and offers little guidance in terms of appropriate management.

In attention deficit hyperactivity disorder, Levy (this issue) highlights issues with the DSM-5 classification and explores the possibility that RDoC (Research Domain Criteria), the new National Institute of Mental Health proposed classification, might add greater clarity. Similarly, Starcevic (this issue) highlights the complexities in the current classifications of anxiety disorders. There has been a shuffling of the deckchairs of the categories of anxiety disorders; for example, the removal of obsessive compulsive disorder, post-traumatic stress disorder and acute stress disorder from the category of anxiety disorders. Starcevic notes disquiet around the ongoing boundary dispute between mood and anxiety disorders, highlighting the clinical implications of this uncertainty. Hegerl (this issue) argues that issues regarding the core symptoms of depression beset current classifications of depression. In particular, concern regarding the diffusion of the ‘fatigue or loss of energy’ criterion is noted. The paper contends that fatigue encompasses quite diverse psychological and neurophysiological states, as does loss of energy. The phenotypes of sleepiness versus agitated exhaustion, and between inhibition of drive and impaired wakefulness regulation, are argued to occupy quite different phenotypic domains. They suggest that greater phenotypic refinement may assist in more strategic therapeutic targeting. Goldberg (this issue) summarises this diagnostic quagmire in a witty and erudite op-ed.

Rowe and colleagues (this issue) reviewed help-seeking behaviour in adolescents who self-harm. Surprisingly, less than half of adolescents who self-harm seek help, and when they do, they principally turn for help to friends and family, rather than health professionals. The Internet is increasingly used as a resource. The review found far more red than green lights on the help-seeking road. Few factors that enable help-seeking were identified, but many issues appear to inhibit help-seeking, including fear of being seen as attention-seeking, stigma and confidentiality issues. The authors suggest a number of paths forward, including public health campaigns, mental health literacy and increased availability of web-based resources. Albrecht and colleagues (this issue) reviewed the propensity for benzodiazepines to induce aggression. In this systematic review, they confirm the impression gleaned from the extant literature, that benzodiazepines are associated with aggression. In addition, the review suggests that people with high baseline levels of both aggression and anxiety may be more vulnerable to this adverse event. Amnesia and disinhibition secondary to benzodiazepines appear to be mediators of this effect. In the context of increasing rates of benzodiazepine prescription, this is an issue of significant public health and forensic consequences.

Given the disability associated with schizophrenia, and the inability of current therapies to meaningfully impact on disability and symptomatology, novel approaches are always of interest. In this issue, Balzan and colleagues (this issue) examined metacognitive training for people with schizophrenia. This aims to reduce cognitive biases that may kindle delusions. There are data indicating that multi-session metacognitive training is useful. However, the translational capacity of intensive psychosocial interventions is always limited. In this pilot study, the authors suggest that even a single session might be of clinical utility. While subject to the limitations of small pilot studies, it is nevertheless a worthwhile lead.

There is genetic variability in the serotonin transporter. The short (‘S’) allele has lower transcriptional efficiency for the transporter, and is linked to poorer treatment outcomes in depressed people prescribed selective serotonin re-uptake inhibitors. The impact of this polymorphism on emotional processing was studied by Outhred and colleagues (this issue) in people prescribed escitalopram or placebo. Examining the processing of emotional stimuli, they found that people with more ‘S’ alleles had poorer amygdala responses to positive stimuli and more robust responses to negative stimuli. Those people who had more long ‘L’ alleles had more robust amygdala responses to positive stimuli and fewer responses to negative stimuli. This suggests that pharmacogenetic variations influence brain responses to emotional stimuli.

As part of the PRIME study, Brodaty and colleagues (this issue) examined the factors that predict who might progress from mild cognitive impairment to threshold dementia. Around a third of people progressed from mild cognitive impairment to dementia in this study. Notwithstanding reports that depression might have predictive capacity, they failed to find that this was indeed a predictor. Rather, the trajectory of decline in cognition, poor premorbid cognitive function and advancing age were predictive of a dementia diagnosis. These predictive markers may assist clinicians to identify those at greatest risk. Following the theme of prediction of risk, Holmes (this issue) examined risk factors for mental disorders, specifically depression and anxiety, in people who have had a serious injury. They found that the strongest predictors were pain and persistent disability. In people who experience auditory hallucinations, Morris and colleagues (this issue) studied the role of psychological flexibility and non-judgemental acceptance. They failed to find that these influenced the process of hearing voices. However, they did find that psychological flexibility was related to patterns of psychological resistance to the voices and general well-being. While cognitive models seem to have more of an influence on disruption and distress caused by voices, emotional flexibility helps with adaptation to the psychotic experience.

To paraphrase Donald Rumsfeld, there are known knowns – things we know we know; there are known unknowns – things we know we do not know; and there are also unknown unknowns – things we don’t know we don’t know; with the latter category being the most difficult one. In navigating complex therapeutic waters with a faulty diagnostic compass, these papers highlighting diagnostic known unknowns provide greater clarity as to what we are uncertain about and where we need to proceed with caution.