The unfulfilled promise of the antidepressant medications

We need more effective treatments for depression, because current treatments avert less than half of the considerable burden caused by the illness.1 Antidepressants are the most commonly used medications, taken by 10% of adult Australians each day, and at a rate that has more than doubled since 2000 to be among the highest in the world.2 Two broad forces have been argued to have driven this trend — in Australia, as in other economically developed countries. First was the broadening of the diagnostic concept of depression with publication of the Diagnostic and statistical manual of mental disorders, third edition (DSM-III) in 1980. Previously, depressive illness was considered to have two subtypes — a “neurotic” illness that responded to psychological therapies and a rarer melancholic depression that had a biological cause and responded to medications. But starting with the DSM-III, the distinction was dropped and the categories were collapsed into the broader “major depressive disorder”. This was followed shortly afterwards by the release of the first selective serotonin reuptake inhibitors (SSRIs) — the short-lived zimelidine in 1982, and then fluoxetine in 1986 — and the ensuing cultural phenomenon that encouraged us to think of depression as resulting from a chemical imbalance that could be corrected with medication. Evidence for depression being caused by a serotonin deficiency is inconclusive and contested.3

The use of antidepressants has continued to rise despite accumulating evidence that they are not as effective as was previously thought. Recent meta-analyses show a modest overall effect size of about 0.3 (although it is larger in severe depression compared with mild depression).4 The overall effect size, while modest, is similar to that of other treatments in medicine: of similar magnitude, for example, to corticosteroids for chronic obstructive pulmonary disease.5 Earlier studies had reported much larger effect sizes for the medications, in part driven by the influences of the pharmaceutical industry on selective publishing of positive results, and the substitution of outcome measures to report ambiguous findings as positive.6 Revelations of these publication strategies have done significant damage to the reputation of the medications and to the pharmaceutical companies who make and market them.7

Antidepressant use in children and adolescents has increased over the past two decades in the same way as it has for the population in general,8 and similarly, meta-analyses of their use in this group have shown smaller effect sizes than had previously been reported.9 Reanalysis of previously published trial data has shown how it was manipulated to inflate the effectiveness of the medications — by substituting pre-specified outcome measures with those more favourable to the trial medications.10 However, just as significantly, meta-analytic approaches have confirmed what had previously been suspected clinically: that antidepressants can induce an increase in suicidal thoughts and behaviours (although not completed suicides) in some young patients.9 A recent study reported that antidepressants can also cause an increase in aggressive behaviour in children and adolescents.11 Both problems are likely to be mediated by the capacity of antidepressants to cause increased agitation in some young people. Although these problems are not common (the number needed to treat for antidepressants in youth depression is 10, while the number needed to harm, in terms of increased suicidal thoughts and behaviours, is 1129), they should be considered when assessing the potential benefits and risks of using these medications in young patients.

The increasing power of placebos

Much effort has gone into delineating the reasons for the apparent falling effectiveness of antidepressants. There are likely to be multiple reasons, including the unearthing of unpublished negative trial results for inclusion in meta-analyses, thereby diluting the positive outcomes from published studies,6 and the inclusion of more “real world” patients (those with comorbid conditions and clinical complexity) in effectiveness trials. Perhaps the culprit given most attention, however, is the increasing rate of response to placebo, which is particularly high in young people. The proportion of patients responding to placebo has increased steadily over the past two decades, leading to a narrowing of the gap between response to medication and placebo.12 The placebo response is a complicated phenomenon. In part, it is driven by a positive expectation bias, but it also illustrates the statistical concept of regression to the mean, whereby patients with depressive symptoms at baseline tend to recover over time irrespective of treatment.

Why should these properties of the placebo be becoming more powerful? It is not clear. One hypothesis is that since the broadening of the diagnostic criteria for depression in the DSM-III, patients with less severe symptoms have been enrolled in treatment trials, and such patients are more susceptible to the placebo response. While there is some evidence for this,4 an analysis of severity cut-offs for study entry showed that where these were higher (ie, when depression had to be more severe for patients to be included), the placebo response rate was even greater.13 An alternative explanation is that patients in more recent trials have had a greater expectation that they will get better with medication: the placebo response rate is greatest in trials when the chance of receiving placebo is low (ie, in multi-arm trials), and lowest in two-arm trials when the chance is high, lending weight to this theory.14 The factors behind the increasing rate of response to placebo, and consequent decreasing effectiveness of medications, are evidently complicated.

Modest effect sizes are not confined to antidepressants

Despite these concerns, antidepressant medications are effective, even if only modestly so. Other treatments for depression are also effective, although the most studied of these — the psychotherapies — also have evidence of declining effectiveness in more recently published trials.15 Two particular psychotherapies have the most favourable evidence: cognitive behavioural therapy (CBT) and interpersonal psychotherapy (IPT). Both are structured, time-limited therapies that directly address the core features of depression. While both psychotherapies are effective, meta-analyses have shown that early studies reported inflated effect sizes.16,17 The reasons for this are clearer for psychotherapies than for medications. Many psychotherapy trials, especially those conducted earlier, adopted low-quality methods that were biased towards overestimating the interventions’ effects. Many therapy trials enrolled non-clinical participants (previously undiagnosed patients who scored above a threshold on a rating instrument), used non-active control conditions (eg, patients on a waiting list), analysed only participants who had completed treatment (rather than using the more rigorous intention-to-treat principle), or did not use blinded assessors.16,17 The effect size of high-quality psychotherapy trials (d = 0.2) is, consequently, less than a third of the effect size for low-quality trials (d = 0.7), and similar in magnitude to the effect size for antidepressants.17

There has been a recent focus on exercise and diet as potential interventions. While it is clear that exercise and healthy eating are associated with good mental health, it is less clear that they are effective interventions for depression.18,19 One reason for this is that adherence to exercise and diet plans is often insufficient to produce improvement,19 and even when they are adhered to, the effect sizes for such non-specific interventions are unlikely to be large. While there is yet insufficient evidence to suggest that exercise and dietary interventions can be effective as stand-alone treatments, they are still worth pursuing as adjunctive treatments — and the evidence suggests that clinicians do not recommend them often enough.20

Combined treatments

The modest effect sizes for depression treatments — and there are no well-studied treatments for depression that have large effect sizes — suggest that combining treatments might provide the best outcomes for patients. The combination of psychotherapy and medication is more effective than either alone. In adults, the effect of combined treatment compared with placebo is about twice that of medication only compared with placebo.21 Combined treatment also seems to be more effective in children and adolescents,22 although there have been fewer studies in these groups. The effects of psychotherapy and medication appear to operate independently of each other,21 providing a good rationale for their combination.

Despite the evidence of superior effectiveness for combined treatments, recent reports suggest that psychotherapy is being offered less rather than more often, at least in the United States. In the decade from 1998 to 2007, the percentage of adult patients with depression who were treated with psychotherapy declined from 54% to 43%.23 A similar decline was noted in children and adolescents, although more recent evidence suggests that this has been reversed with the increasing concerns about the safety of medications.8 In Australia, while we have clear evidence that the rate of antidepressant use is increasing, we lack comparable data for the use of psychotherapy. There are some promising signs that it is becoming easier to access psychotherapy. The federal government’s Better Access to Mental Health Care scheme was introduced in 2006, and allows general practitioners to refer depressed patients to qualified therapists for up ten sessions of Medicare-funded treatment. It has led to significant uptake and is helping to reverse the trend,24 albeit with demographic distortions in the groups who access the scheme. The uptake of psychotherapy is disproportionately higher in wealthier suburbs, and lowest in outer suburban and regional communities where rates of depression are highest.24 And although the gender gap is narrowing, use of psychotherapy is still disproportionately higher among women.25 While there is evidence that access to therapy is improving, we are yet to see whether this is translating into a reduction in the prevalence of depression.

An unfortunate nexus has developed between the diagnosis of depression of any severity and the reflexive prescription of medications as monotherapy, for which the medical profession must accept some responsibility. There is a long tradition of medical psychotherapy — important psychotherapies were developed by medical practitioners such as Sigmund Freud, Aaron Beck (CBT), and Gerald Klerman (IPT) — that seems to be in decline. Fewer doctors now have the expertise to deliver psychotherapy, the teaching of which has been de-emphasised in psychiatry training,26 and psychotherapy is now largely the domain of psychologists, social workers, and other health professionals. This appears to have had the effect of encouraging psychiatrists and other doctors to consider medication, which is their area of expertise, rather than psychotherapy as the first-line treatment for depression.

Future directions

The pharmaceutical industry has scaled back investment in developing new drugs for mental illnesses, mainly because of so many development failures,27 and it is unlikely that we will see new medications with substantially greater effectiveness in the coming years. The psychotherapies too have their limitations, and while they can be made more available, it is unlikely that new forms of psychotherapy will be developed that will have substantially greater effectiveness than existing therapies.

Some psychiatrists and researchers argue that reinstating melancholia as an illness, separate from neurotic depression, provides a solution to refining treatments.28 They argue that melancholic depression shows a distinct and selective response to antidepressant medications. Differentiating the illness subtypes, however, was never as clear in practice as some now argue. Australian psychiatrist, Sir Aubrey Lewis, pointed out in 1934 that the separation between the two was arbitrary — “a setting up of types or ideal forms, a concession to the requirements of convenient thinking in categories”29 — with most patients showing aspects of both. The belief that melancholia responds much better to medications has also not been reliably confirmed. A recent large study could find no difference in medication response between those with and without melancholic symptoms.30

Major depressive disorder is undoubtedly a heterogeneous disorder, and clearer distinctions between subtypes would make it easier to target treatments, but there is little at present to guide us as to how best to make such divisions. There is, however, a significant research effort aimed at characterising treatment biomarkers — genetic, brain imaging and neuropsychological parameters that might predict a patient’s response to particular treatments. With no likelihood that significantly better treatments for depression will emerge in the near future, better targeting of existing treatments towards patients who are most likely to respond to them is probably our best hope for improving treatment outcomes.

Treatment recommendations

While recent evidence might have tempered the initial enthusiasm for antidepressants, these agents still have a role in treating depression. Some patients show particularly strong responses to the medications31 (although we are not reliably able to predict who they will be), and there is good evidence that antidepressants are effective in preventing relapse of depression.32 The task for medical practitioners now is to place antidepressant medications in an overall treatment framework.

All patients should be offered psychotherapy where it is available, and medication should be considered if

the depression is of at least moderate severity;
psychotherapy is refused; or
psychotherapy has not been effective.

When medications are prescribed, they should be used in a way that maximises their chance of effectiveness. The dose should be increased if there has been no improvement after 4 to 6 weeks. The medication should be changed if there has been no improvement after a subsequent 6 weeks. Usually, the medication should be changed to another within the same class in the first instance (eg, from an SSRI to an alternative SSRI), and to an antidepressant of an alternative class (eg, from an SSRI to a serotonin-noradrenaline reuptake inhibitor, such as venlafaxine) if a second change is required. If this strategy is ineffective, more expert guidance is indicated: this might include considering augmentation strategies, such as lithium, or the use of neurostimulation (electroconvulsive therapy and transcranial magnetic stimulation).33 At all stages, therapy with ineffective medications should be ceased and unnecessary polypharmacy avoided. Alongside these treatment strategies, we should continue to recommend and encourage good eating and exercise, both of which are likely to help engender a healthy mind and a healthy body.

Flying under the radar: first hospitalisation with anorexia nervosa at age 54

“Is it better to walk 10 hours or cut myself … I found it reinforcing to feel a ‘lightness’ … I was surviving like a beast.. I would easily fall into a deep depression if I got better”, recounted a 54-year-old woman with a 40-year history of eating disorder, admitted to hospital for the first time with complications of her illness.

Anorexia nervosa is an often recalcitrant condition, remarkably immutable to change, due to the effect of behaviour reinforcement.1 There is also a growing literature about women with this disease presenting later in life. Body image dissatisfaction is an enduring issue for many women, with one study finding that 3.8% of women aged 60–70 years meet the criteria for having an eating disorder.2

The Diagnostic and statistical manual of mental disorders, fifth edition, has broadened the criteria for anorexia nervosa to allow for persistent behaviours that resist weight gain even in the absence of distorted body image. With this criterion, a recent study found that the prevalence of anorexia nervosa in the Australian population was about 0.46%.3 Earlier research had shown that more people with anorexia nervosa were surviving in the community than were being cared for in primary care or mental health facilities.4

At the time our middle-aged patient was referred to the consultation liaison psychiatry service, she had a body mass index (BMI) of 13.8 and was in life-threatening condition with acute kidney injury, significant anaemia, electrolyte disturbance, and delirium. Her history revealed 12 months of worsening symptoms after her mother died of cancer. This was on the background of chronic gastrointestinal disturbance, which her mother had had as well, and which was intimately linked with her disordered eating. In the acute stage, her course was complicated by severely delayed gastric emptying, necessitating a brief period of total parenteral nutrition to avoid bowel perforation.

This patient provided a convincing history of anorexia nervosa, restrictive type (in the extreme range of severity), marked by excessive walking. She did not seem to realise that the level of caloric restriction she had placed on herself was abnormal, but she did acknowledge that something was wrong because she could no longer “keep on walking” — she usually walked up to 50 kilometres each day. Her illness limited her ability to work and socialise. Her treatment was supported by a treatment order under the Mental Health Act 2000 (Qld) because of an initial brief episode of psychosis, and then maintained until after a period of stable nutritional rehabilitation.

While this patient did not conceptualise her condition as an eating disorder, she displayed impressive psychological mindedness and receptivity to considering the contribution of chronic pain, grief, and illness identity in perpetuating ill health and dysphoria. Despite her severe illness and some challenges related to eating-disordered behaviour, she had a generally cooperative attitude which further facilitated brief insight-focused supportive psychological therapy. Her BMI increased to within the normal range over several months as her care was continued under psychiatric inpatient, and then outpatient, services.

Managing mature patients with considerable life experience who have survived despite disordered eating provides unique perspectives on the balance between autonomy and control. Management of such patients requires greater flexibility.

A campaign to improve the mental health of medical students

Australian medical students responded swiftly and effectively to the increased burden of mental illness in the medical profession, which was highlighted by the 2013 beyondblue National Mental Health Survey.1 In 2012, medical student representatives from Australia’s 20 medical schools passed a health and wellbeing policy,2 then in 2013, voted student mental health as a top advocacy priority for the Australian Medical Students’ Association (AMSA), choosing to advocate for the mental health of all tertiary students through development of the AMSA Mental Health campaign.

The four key aims of the campaign were to: (i) decrease stigma and increase awareness and mental health literacy among students; (ii) promote preventive measures to improve coping strategies and resilience; (iii) enable and empower students to look out for their peers and take positive action; and (iv) facilitate improved access to and uptake of mental health services.

Our advocacy strategy targeted the general public through broadcast and print media, the medical community through medical literature and conferences, and students through social media and on-campus events.

University campuses are geographical foci for at-risk young people and are therefore ideal sites for implementing effective preventative and early intervention strategies.

A “National Vice-Chancellor Tour” involved meetings of AMSA representatives with Vice-Chancellors (or their nominated representatives) from 12 of the 20 Australian universities housing a medical school. The purpose of these meetings was to explore the experiences and attitudes of the universities towards mental health. University mental health strategies varied greatly in their scope, complexity, student consultation, evidence base, and investment.

Blue Week, a grassroots component of the campaign, aimed to destigmatise and catalyse conversations about mental illness by engaging students on university campuses and in hospitals with blue-themed events and activities. In 2014, Blue Week ran at 17 medical schools, and over 5000 students participated. Activities varied, and included comedy, yoga, meditation classes, massages, guest speakers, and blue-themed parties. Although events were held throughout the year, a national online Blue Week was held during Mental Health Week (6–12 October). During this week we shared and distributed infographics, such as the poster shown in the Box, and over 200 people shared personal experiences and advice on social media. The online Blue Week reached over 90 000 people and engaged over 11 000 in at least one of its components.

AMSA also produced the second edition of the medical student wellbeing guide, Keeping your grass greener;3 coordinated the AMSA Mentor Network; ran Academy of the Mind, an online short course available to medical students internationally; and ran numerous student mental health workshops nationally and at conferences internationally.

The AMSA Mental Health website (mentalhealth.amsa.org.au/) and social media are ongoing focal points for students to access existing resources and information, blog articles,4 relevant news, and a comprehensive database of mental health services.

Although evaluation is difficult due to limited resources, the AMSA Mental Health campaign has engaged thousands of students and medical professionals in Australia and around the world. The campaign continues to grow and evolve, building momentum in the interests of student mental health.

Box –
An infographic distributed to participants during Mental Health Week

Better Access and equitable access to clinical psychology services: what do we need to know?

Critical data on the delivery, outcomes and out-of-pocket expenses of services are lacking

The Australian Better Access to Psychiatrists, Psychologists and General Practitioners through the Medicare Benefits Schedule (Better Access) initiative aims to improve access to evidence-based mental health care in the community.1 Providing rebates for private services appears to be improving treatment uptake,2 yet the equity of Better Access has been questioned, with a recent study showing that specialised Better Access mental health services were disproportionately concentrated in affluent areas.3 This effect was particularly visible for clinical psychology services, with more than 2.5 times the volume of these services provided in the most, versus least, affluent areas. Within Better Access, clinical psychology services are intended for “the treatment of patients with complex and/or chronic mental health disorders, quite often with comorbid drug and alcohol problems”.4 As these patients are also more likely to experience financial distress and live in socio-economically disadvantaged areas,5 there is a pressing need to identify why clinical psychology services may be particularly vulnerable to inequitable service distribution.

Cost as a factor in inequitable access to clinical psychology services

Potential causes proposed for this inequitable service distribution include higher-paid professionals choosing to live in more affluent areas and work closer to home, or patients’ out-of-pocket expenses for these services being prohibitive.3 The differential impact of out-of-pocket expenses on access to specialist health services is widely recognised.6 Such expenses include those associated with attending treatment sessions, with incidental costs (eg, lost income, childcare, travel) averaging $57 per treatment session for face-to-face psychological interventions.7

Copayments, often used as a cost-sharing mechanism to distribute health care burden and encourage more judicious use of health services,8 are another common cost. Within Better Access, copayments are the responsibility of patients and cannot be covered by private health insurance rebates or other schemes, although they may be reduced through Medicare safety net arrangements after a specific threshold of expenses has been reached.9 Although copayments may place a financial burden on patients, they are often essential for supplementing non-remunerated tasks, including administration, professional development and supervision, to ensure sustainable private practice.10,11

Why comorbidity may be more important than copayments

However, there is evidence to suggest that copayments for clinical psychology services cannot fully account for inequitable service provision. Roughly 35% of Better Access clinical psychology services are bulk-billed (no copayment), with this rate similar to that for consultant psychiatry services (36%) and lower than that for services provided by other allied health professionals (43%).12 However, average copayment amounts are lower for clinical psychology services ($32) than for other allied health professionals ($37) or consultant psychiatry services ($82).12 So, while Better Access services are associated with higher out-of-pocket expenses overall — compared with schemes such as Access to Allied Psychological Services (ATAPS), where one in 20 sessions incurs a copayment averaging $13.5913 — these costs are not unique to clinical psychology services. Instead, epidemiological and treatment outcome studies suggest that comorbidity is a more likely contributor to inequitable Better Access clinical psychology service distribution.

Currently, there is no routine data collection on the number of treatment sessions provided by health professionals once Better Access allowances (ten individual and ten group sessions per calendar year) have been exhausted. Yet, several factors suggest that, if clinical psychology services are being used for more complex and comorbid presentations as intended, these services will extend beyond ten individual sessions. Comorbidity between mental disorders can signal more severe and treatment-resistant presentations and is often the norm, rather than the exception, in those with mental illness.14 Current best-practice guidelines for managing comorbid mental and substance use disorders include providing empirically supported treatments for each disorder, either sequentially or concurrently.15 Clinical practice guidelines synthesising high-quality clinical and health economic research literature, such as the guidelines developed by the United Kingdom’s National Institute for Health and Care Excellence,16 highlight that these empirically supported treatments are likely to extend beyond ten individual sessions, even for single disorders treated in isolation (Box). Although there is some debate about whether comparable treatment outcomes can be achieved in fewer sessions,17 it is unlikely that combinations of empirically supported treatments for multiple disorders (even in reduced formats) can be contained to ten individual sessions.

The financial impact of mismatched policy and practice

It is important to consider the financial impact of this mismatch between Better Access allowances and empirically supported treatment guidelines. Any sessions beyond Better Access allowances are not supported by alternative initiatives, such as ATAPS, or the Medicare safety net. Private health insurance rebates may also be less available to this population, as increased mental disorder has been linked to both limited financial resources5 and reduced private health insurance coverage.18 Currently, there is little guidance about how to adapt therapy for people with complex presentations who cannot afford treatment beyond ten individual sessions. The Australian Psychological Society recommends adjusting usual intervention techniques to “ensure an outcome is achieved” within available sessions,19 but it is unclear how this is to be achieved or what impact these modifications will have on the effectiveness of treatment.20 There is also little guidance about how to use combinations of Better Access individual and group sessions to best support people with comorbid disorders.

After exhausting Better Access allowances, people who cannot afford ongoing care may be referred to other services, such as consultant psychiatrists (up to 50 individual consultations subsidised by Medicare per year1) or community mental health services. Yet, limited availability of these services may result in long waiting periods, reflecting the “missing middle” of the mental health system.21 It is also unclear whether referral to consultant psychiatrists or community mental health teams for delivery of psychological interventions reflects the most cost-effective or efficient use of scarce health resources. Extending Better Access clinical psychology allowances from ten to 16 sessions, as has been proposed,21 may help bring health policy more in line with empirical evidence.

However, the reduced provision of Better Access clinical psychology services in less affluent areas may not necessarily reflect poor treatment coverage in these areas. Better Access is only one component of federal mental health investment, representing 9.5% ($907.9 million) of federal government spending on mental health in 2012–13.21 It is complemented by a range of programs (eg, ATAPS) targeting hard-to-reach and disadvantaged populations. Lower Better Access coverage in some areas may not be inequitable if general practitioners are instead referring a comparable proportion of people to alternative schemes. This highlights how complex networks of funding arrangements make it hard to assess the overall equity of services.

Implications for mental health policy

Exploring discrepancies between clinical practice guidelines and reimbursement structures highlights the importance of empirical evidence in the design of health care financing. Although finite resources are a constraint in any health care system, without thoughtful consideration of empirically supported treatments, short-term cost-saving measures may have longer-term financial consequences. For example, capping Better Access sessions may contain costs in the short term but may also result in ineffective treatment, increasing rates of drop-out, relapse or reluctance to engage in treatment.22 This may then result in increased costs such as welfare payments, lost productivity and increased use of other health care services. The most recent estimate of the costs of mental disorders in Australia reaches up to $40 billion each year,21 highlighting the importance of identifying cost-effective methods for reducing this burden.

Rather than capping the number of sessions, more creative approaches to achieving efficiencies in the mental health system, while also potentially enhancing the quality of clinical care, could be explored. An example of this could include replacing the review of GP Mental Health Treatment Plans after six sessions with innovative technologies for tracking clinical trajectories. Recent estimates show that patients seek an average of 4.8 Better Access sessions,23 but it is unclear whether these brief treatment courses reflect successful treatment outcomes or treatment drop-out. This means the six-session review may occur too late to identify people at risk of poor outcomes. Anecdotally, requiring a review after six sessions can also have the unintended effect of setting unrealistic expectations about progress that demotivate patients or create treatment delays that negatively affect momentum of change. An alternative may be replacing the six-session review with the use of standardised assessment measures to monitor trajectories of symptom change, identify at-risk patients, provide clinically useful information to practitioners and generate real-time service use data.24

The importance of measurement for management

There is a critical lack of data on the delivery of mental health services under Better Access,21,25 including limited data on how practitioners adapt therapies to fit session constraints, the impact of these modifications, relapse rates, average out-of-pocket costs (not just copayments), the influence of the Medicare safety net on copayments and how various populations may be differentially affected by all these factors. A full understanding of the effectiveness and equity of Better Access requires information about the number of sessions completed once Better Access allowances have been exhausted, the utility of separating Medicare Benefits Schedule items for individual and group psychological therapy and how people transition through services over time.

With the most recent Australian population survey of mental disorders and service use conducted almost a decade ago,26 it is essential to develop a plan to ensure the collection of timely and meaningful data to inform current mental health reforms. It is also essential to take a multidisciplinary approach to mental health policy, to ensure policies facilitate the delivery of best-practice care to those who need it most.

Box –
Number of sessions for psychological interventions recommended by NICE clinical guidelines for mental disorders16

CBT = cognitive behavioural therapy. NICE = National Institute for Health and Care Excellence. * These figures do not include initial assessment sessions, which are typically required to confirm and refine diagnosis.4 † Signifies the current cut-off of Better Access sessions. ‡ Some sessions longer than 60 minutes recommended. § Recommended in conjunction with pharmacotherapy for moderate to severe presentations.

Biological models of mental illness: implications for therapy development

Systems approaches are needed to recognise the complexity of the biological bases of psychiatric disease

The bases of mental disorders can best be understood as a complex interplay between biological, psychological, social and lifestyle factors: a classic bio-psycho-social-lifestyle model. There are undoubtedly some disorders where a biological model alone is more appropriate — this applies particularly to the psychotic disorders — but even in such cases it must be acknowledged that these illnesses are strongly influenced by psychosocial and lifestyle factors. What makes a biological understanding of mental illnesses necessary, however, is that it opens the way for the development of rational treatments. This has been the quest since antiquity, with treatments predicated on the putative underlying biological causes: purging and bleeding patients to correct imbalances in the humours to treat melancholia, which was attributed to an excess of black bile, or removing sources of focal infection, such as the teeth, tonsils and even the colon, that were once regarded as causing mental disorders. While these models perhaps now seem far-fetched, they were not entirely implausible when one considers contemporary neuro-endocrine and neuro-inflammatory models of mental illness.

Biological explanations of mental disorders gained momentum in the early 1950s through a series of fortuitous discoveries in psychopharmacology coupled with “reverse engineering”. Firstly, chlorpromazine, initially synthesised as an antihistamine, unexpectedly alleviated hallucinations and other symptoms of schizophrenia. Similarly, it was noticed that iproniazid, originally used to treat tuberculosis, made some lucky patients inappropriately happy; imipramine (considered to be another antihistamine) and structurally similar to chlorpromazine, was also found to have antidepressant activity.

As chemical neuroanatomy advanced from the late 1950s, models of mental illness were developed. For example, the dopamine hypothesis of schizophrenia was based, in part, on the discovery that chlorpromazine inhibited dopaminergic transmission, leading to further drugs being developed that blocked dopamine D₂ receptors. It was subsequently found that imipramine and monoamine oxidase inhibitors with antidepressant properties also modified catecholaminergic transmission, and depression was consequently seen as the result of reduced catecholamine levels in the brain. This concept was refined by incorporating serotonin (5-HT) and the complex regulation of multiple monoamine receptor types into the model, and the development of agents that specifically targeted serotonin transmission, the selective serotonin re-uptake inhibitors (SSRIs). This focus on the monoamines and other neurotransmitters led to new me-too medications, the key elements of which remained blocking D₂ receptors in schizophrenia and stimulating serotonin and noradrenaline receptors in depressive and anxiety disorders. The robust antipsychotic properties of clozapine, despite its being only a weak D₂ receptor antagonist, spurred exploration of other neurotransmitters implicated in schizophrenia, including roles for 5-HT_2A and 5-HT_2C receptors, leading to the development of further second generation antipsychotics.

The winding road to new therapies

While these neurotransmitter hypotheses are of great heuristic value, they do not sufficiently explain mental disorders, nor does targeting these transmitter systems completely ameliorate their symptoms. Further, more recent findings have implicated several other pathways.

So how do we develop the next generation of therapies for people with psychiatric disorders? The traditional route was to identify a singular molecular focus, which could then be targeted. While this approach has intrinsic scientific rigour, is tightly hypothesis-driven, and has mechanistic appeal, it has not been a fruitful approach for developing truly novel therapies. It is also problematic for mental disorders, for which there is no clearly identified final common functional pathway, and where the patterns of biomarker abnormalities in seemingly different conditions overlap to a significant degree. This problem is partially the product of existing phenomenologically based diagnostic systems, such as the Diagnostic and statistical manual of mental disorders (DSM), which cannot accurately define phenotypes that are based on phenomenology rather than biological sub-categories. To overcome the problem, the National Institute of Mental Health (United States) has adopted a shift in emphasis in its Research Domain Criteria (RDoC) from diagnosis to symptom domains.1 These symptom domains — negative valence, positive valence, cognitive function, arousal, and social process systems — are mapped against the underlying genes, molecules, neural circuits and neurophysiology that putatively underpin them. While this new approach is a welcome injection of novel thinking, it matches clinical needs poorly, and we are yet to see positive outcomes from its application. There are nevertheless hopes that it will help elucidate brain processes and models of mental illness that can be used to identify therapeutic targets.

One can also adopt systems-based philosophies that are more broadly directed at networks involved in the pathophysiology of mental illness.2 This approach is gaining traction with the identification of a number of non-monoaminergic systems and processes that have been implicated in the pathogenesis of several psychiatric disorders, including inflammation, dysregulated oxidative signalling, neurogenesis, apoptosis and mitochondrial dysfunction. These functionally interacting cellular pathways combine in contributing to the dysregulation of systems and networks in the genesis of many non-communicable disorders, which are rarely the outcome of an abnormality in a single element. The gut microbiome has recently been identified as a critical system in its own right, with profound impacts on immune regulation and other systems. As it can be influenced by diet, it is correspondingly being seen as a plastic target in the development of novel therapies.3

A number of studies have examined such systems, and this approach remains one of the more promising avenues for therapeutic development. It must be noted that many of the known drivers of psychopathology, as varied as stress, poor diet, smoking, physical inactivity, sleep disturbance and vitamin D insufficiency, have common effects upon inflammation and oxidative stress, for example. While such drivers of psychopathology are deemed to be lifestyle factors, they exert their effects through their impact on recognised biological systems. By the same token, seemingly psychological risk factors, such as early trauma, can lead to biological changes through epigenetic effects on the reactivity of the hypothalamic–pituitary–adrenal axis and the activity of the immune system.

Putting it all together

An integrative model incorporating lifestyle and risk variants, operative neurobiological pathways, and the impact of those pathways on brain structure and function is thus beginning to emerge. The systems biology approach emphasises the fact that these are not siloed systems and that they interact intimately in complex and sometimes unpredictable ways. To capture the underlying pathophysiology of such multisystem dysfunction, novel molecular techniques, including the “omics” platforms, are needed, buttressed by big data analytic techniques. Researchers have leveraged these systems approaches to productively target inflammation, and a number of leads are being followed up, including the therapeutic benefits of agents such as celecoxib, aspirin, statins, minocycline, and antibodies to immune factors (such as tumor necrosis factor [TNF-α]).4 Given the ubiquity of oxidative stress in neuropsychiatric disorders, the first generation of investigations of therapies that modulate redox biology have been promising.5 In addition, the first studies targeting mitochondrial dysfunction are underway. Disruptions of the circadian system are also found in mental disorders, and novel treatments for re-synchronising these systems (bright light, melatonin receptor agonists) offer new approaches to therapy.6

A key element underpinning biological models of mental illness is the genetic component. High hopes of identifying a single gene for specific psychiatric disorders have evaporated with the advent of molecular genetics. In the disorders with the greatest heritability, numerous single nucleotide polymorphisms (SNPs) have been identified, each of which alone has only a very weak effect. More than 100 SNPs associated with schizophrenia have been identified by genome-wide association studies. A genetic relationship with the major histocompatibility complex locus has been described, and complement component 4 (C4) alleles that affect the expression of C4A and C4B proteins have recently been associated with schizophrenia;7 functionally, these findings may offer an explanation for the loss of cortical grey matter in people with schizophrenia. They also concur with much earlier biomarker findings that implicated abnormal C4 expression in the pathophysiology of depression.8 This illustrates that bottom-up biomarker and top-down genetic approaches can complement each other in clarifying the pathogenesis of psychiatric disorders. Additionally, in silico approaches have been used in hypothesis generation for detecting potential therapeutic agents.9

However, it needs to be stressed that almost all current therapies arose by exploiting serendipitous clinical findings, and it makes sense not to abandon this avenue of drug discovery.10 It remains crucial that clinical acuity and research platforms such as epidemiology continue to be utilised, to facilitate the detection of unexpected associations between treatment and clinical disease burden. A clear understanding of biological models of psychiatric dysfunction and how they interact and complement each other, using the full array of neuroscientific approaches available, remains essential for developing more effective therapies for disabling mental disorders. But this needs to be an iterative and bi-directional process, with back translation of clinical findings to reverse engineer neurobiology, historically a fruitful avenue for uncovering the underlying pathophysiology of these disorders.

Breaking down the silos of treatment for post-traumatic stress disorder: integrating mind and body

Scalable interventions for PTSD that target mental health and comorbid cardiometabolic health are urgently required

There is increasing awareness of post-traumatic stress disorder (PTSD) among the general community, particularly in relation to the high incidence of the condition and its impact on high-risk populations, such as defence force veterans and emergency service first-responders. PTSD is a highly prevalent and costly condition associated with high rates of comorbid mental disorders, including anxiety and depression, and substance use.

There is growing interest in second-line or adjunctive treatments for PTSD. For example, a recently published randomised controlled trial established the efficacy of mindfulness-based stress reduction (an intervention that teaches individuals to attend to the present moment in a non-judgemental, accepting way) for treating PTSD among veterans.1 Participants were randomly assigned to receive either 8 weeks of mindfulness-based stress reduction therapy, delivered during weekly 2.5 hour group sessions, or an active control condition consisting of group sessions focusing on life problems. The majority of patients were also receiving pharmacotherapy (51/58 in the mindfulness group and 49/58 in the control group). Participants in the adjunctive mindfulness group were significantly more likely to experience clinically meaningful improvements in PTSD symptoms at 2-month follow-up (48.9% v 28.1%). Research among other trauma-affected populations suggests that improvements associated with mindfulness interventions can be maintained for up to 2.5 years following treatment.2

The scalability of the mindfulness intervention (ie, the ability to demonstrate efficacy under controlled and real-world conditions, and the capacity to reach a greater proportion of the eligible population3), combined with low levels of participant dropout and a robust effect size,1 represent a positive step towards establishing mindfulness interventions as an adjunctive treatment for PTSD. This is particularly pertinent where first-line interventions such as trauma-focused cognitive behaviour therapy may not be available.

There is growing evidence that PTSD, along with other mental disorders, is strongly associated with somatic, lifestyle-related comorbidities including obesity, diabetes and cardiovascular disease, with 39% and 49% of patients with PTSD meeting criteria for metabolic syndrome and abdominal obesity respectively.4 In people with psychotic disorders, this overwhelming burden of poor physical health across their lifespan, and its link with premature mortality, has been described as a scandal,5 with numerous calls to arms from clinicians and researchers, and the development of effective prevention-focused interventions. Such initiatives are starting to challenge the view that weight gain and poor cardiometabolic health are inevitable comorbidities for people with mental illness.

The high rate of preventable cardiometabolic disease in PTSD warrants consideration when developing and testing adjunctive or second-line treatments such as mindfulness. In the general population, physical activity is the cornerstone of treatment and prevention of cardiovascular disease, yet people with PTSD are known to be less physically active than the general population, highlighting the need for interventions to address this key modifiable risk factor. A recent systematic review and meta-analysis identified four randomised controlled trials investigating the effect of varying modalities of physical activity interventions for people with PTSD, including structured exercise and yoga.6 Physical activity was found to be more effective than control conditions at reducing PTSD symptoms, while also reducing depressive symptoms. The physical activity interventions ranged from 6 to 12 weeks involving 1–2 supervised sessions per week, including resistance training, yoga-based exercises, aerobic exercise, or a combination of all three modalities. Based on previous research in other mental disorders, the optimal exercise program (frequency, intensity, duration and modality) is contingent on individual factors including previous exercise history, severity of psychiatric symptomatology, somatic comorbidities and motivation. Australian physical activity guidelines7 provide clinicians with a structured framework for increasing habitual levels of physical activity in daily living.

The moderate to high effect sizes reported in trials of physical activity-based interventions in comparison to usual care alone are comparable to those achieved with mindfulness.6 In addition to reducing symptoms of PTSD and depression, structured resistance training and walking have been found to reduce cardiometabolic risk through significant reductions in waist circumference and self-reported sedentary behaviour, which are established independent risk factors for all-cause mortality.8 Further, exercise, particularly resistance-based (strengthening) exercise, can be seen as a mindful activity9 in which the basic principles of mindfulness (attending to the present moment in a non-judgemental and accepting manner) can be utilised. In addition, mindfulness and exercise are both known to be highly acceptable, and may the reduce perceived barriers and stigma that some patients experience when accessing mental health treatment, given that both are considered mainstream and health-benefiting behaviours.

The challenge for future research lies in designing and implementing combined interventions on a large scale, incorporating both best-practice mindfulness and exercise components in addition to usual care. Allied health clinicians with expertise in exercise programming (such as exercise physiologists10 and physiotherapists11) may assist in the design and delivery of best-practice physical activity interventions. Robust economic evaluations also need to accompany such research to establish their cost-effectiveness. Such an approach is likely to contribute to breaking down the silos of PTSD treatment, in order to integrate interventions that address the body and the mind. The physical consequences of PTSD can no longer be ignored and it is time to implement effective multidisciplinary treatments.

To screen for depression or not?

Screening may be appropriate to reconsider once we can ensure adequate response to any identified potential cases

Depression presents a significant public health challenge for both the community and the medical profession. In Australia, depression and anxiety affect a substantial proportion of the population (4.8% of men and 10% of women) and is responsible for 8% of the total loss in disability-adjusted life years.1 It is the top-ranking cause of non-fatal disease in the Australian community for women,2 and is also associated with an increased risk of ischaemic heart disease and suicide, both causes of early death.

Depressive disorders present diagnostic challenges, not least because in some cases depression is the first presentation of bipolar disorder. Further, treatment may be complicated and limited owing to the symptomatic heterogeneity of depression; complex comorbidities with anxiety, substance abuse, physical health problems or other factors; and the ongoing stigma that hinders many individuals from openly discussing their mood problems. As a result, rates of detection, diagnosis based on clinical presentation, and sufficient intervention remain inadequate. Indeed, a recent meta-analysis from the United Kingdom suggests that the diagnosis was only correct in 47% of cases presenting in primary care.3 This does not account for those cases that fail to present in the first place, supporting calls to consider widespread screening for depression, especially in primary care settings where the majority of depressive disorders are treated. But is screening for depression in primary care a useful and viable option?

In January 2016, the United States Preventive Services Task Force published its latest recommendation statement in relation to screening for depression in adults.4 The statement recommended that sufficiently reliable self-report tools are now available to make screening for depression feasible and reliable in primary care. The task force further opined that screening leads to accurate diagnosis and treatment in this setting. Clearly, the latter component is critical to render screening valuable, and the authors drew heavily on the developing evidence around models of collaborative care and depression care management.5,6 The task force recommended use of the Patient Health Questionnaire-9 (PHQ-9), but as noted in an accompanying editorial,7 the statement acknowledged that the positive predictive value of the PHQ-9 is only 50%, and that it cannot be considered a replacement for appropriate clinical assessment. In other words, screening is important but it cannot be relied upon.

The idea of screening-led prevention and early intervention is inherently attractive. Within Australia, efforts thus far have focused on high-risk groups such as pregnant or perinatal women and Aboriginal and Torres Strait Islander populations.8,9 However, a pragmatic perspective that acknowledges the limitations of current mental health service delivery for broader treatment of depression would also have to recognise that international evidence for broad primary care population screening is mixed.

After several years of research and development, the Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders were released in late 2015.10 The guidelines conceptualise both depression and bipolar disorder along a spectrum with considerable overlap, and discuss in detail the diagnosis and management of both conditions. The guidelines do not specifically recommend screening in primary care or other settings. This is because self-assessment via the internet and other self-report screening measures is likely to raise concerns but not necessarily identify those who need help or ensure that they seek proper advice. Once suspicion of depression has been raised by a clinician, the use of a standardised psychiatric measure is preferable but the question remains as to whether general practitioners should initially use their clinical judgement or a screening tool to identify depressive illness. To this end, they can be equipped with measures that corroborate key symptoms but reliance should never rest solely on self-report measures.

Historically, depression has been underdiagnosed, and the stigma of its incidence remains a challenge to encouraging patients to access treatment. We can anticipate increased capacity for the treatment of depression in the new world of integrated mental health service delivery promised in the Australian government’s response to the National Mental Health Commission review of mental health programs and services. The stepped care model has the potential to provide optimal support for people with a major depressive disorder. Once these initiatives are established and further data have been gathered as to their suitability and appeal, perhaps then it will be time to revisit the recommendations regarding screening. However, at this point in time there does not appear to be sufficient evidence of pragmatic value to warrant the burden that implementation and continuous screening for depression in primary care would impose.

A concise and authoritative guide to schizophrenia

Fast facts: schizophrenia. 4th ed. Shôn W Lewis and Robert W Buchanan. Health Press, 2015 (119 pp, $15.00 rrp). ISBN 9781908541604.

Schizophrenia is one of the worst diseases afflicting humankind, affecting one in a hundred people. Lewis and Buchanan, from Manchester and Baltimore respectively, have produced a conspectus of exceptional quality on this, the most severe of mental illnesses. Although I have treated and studied schizophrenia since the advent of chlorpromazine, I have rarely encountered such a compact storehouse of easily assimilated information on this diverse syndrome. Most of the contents will be understood by today’s doctors. But there are many parts that will also help carers and families, an unusual asset.

In some 100 pages, we are told of the syndrome’s history from antiquity to the introduction of the present name by Bleuler. Alas, the word “schizophrenia” now brings fear and pervasive stigma, apart from being etymologically absurd. Some of us hope it will be replaced one day, just as happened with Alzheimer disease and Down syndrome. In Australia’s present population, we can expect more than 4000 new cases a year, mostly in young people. Incidence will be higher in our large cities and migrant populations. Although about 15% will never recover, few of us know that up to 20% of new cases will recover fully and never have a relapse — if they stay away from dopaminergic drugs such as cannabis. In the massive international effort to identify susceptibility genes and copy number variants, some replicated findings are emerging. Engagingly, a little is now known about specific gene–environment interactions. Schizophrenia is now seen as a disorder of brain development, starting in utero.

For day-to-day clinical practice and teaching, I was delighted to find a coloured diagram of the brain showing those cortical and white matter areas where delusions and hallucinations are now known to have their origin. Madness resides in the brain.

A concise exposition is given of drug treatment according to the stage of the disorder, but also a most welcome emphasis on psychological and social treatments, both conspicuously underused in most services. To the authors’ further credit, the book is drawn to an end with an account of early intervention and prevention. This book is an eximious asset.

Psychostimulants ‘over prescribed for ADHD’

Practitioners need to be more careful when assessing and diagnosing attention deficit hyperactivity disorder (ADHD), experts say.

In an editorial published in the Medical Journal of Australia, Dr Adrian Dunlop, from the University of Newcastle, and Professor Louise Newman, from the Centre for Women’s Mental Health at the Royal Women’s Hospital in Melbourne wrote that the implication of overdiagnosis is that disorders of children are being ‘medicalised’.

“There are risks for children that the use of stimulant medication is a simplistic attempt to find solutions to more complex problems underlying behavioural and emotional difficulties,” they wrote.

They said there has been a rise in ADHD diagnoses since the 1970s, which is in part due to an increasing understanding and awareness of risk factors.

When diagnosing, other conditions such as trauma-related neurodevelopmental difficulties, autistic spectrum disorder, and fetal alcohol spectrum disorders need to be excluded.

“It is therefore important that diagnosis includes a clear differential approach and that it is not made in a perfunctory fashion,” they wrote.

There are no national guidelines, however the Royal Australian and New Zealand College of Psychiatrists supports the Canadian or United Kingdom guidelines for ADHD treatment.

Related: ADHD critique divides specialists

Those guidelines both highlight the need for comprehensive assessment for ADHD.

There is also an approach supported by specialist medical colleges that suggests the ‘universal precautions’ concept could be applied, which routinely assesses all patients for risk of diversion, misuse or overdose both before and on an ongoing basis while prescribing psychoactive drugs.

“While careful assessment and universal precautions will not stop all non-medical use of prescription stimulants, including poisonings, they remain practical and feasible approaches to limit misuse,” the authors concluded.

“Ice” (crystal methamphetamine): concerns and responses

There is no cause to feel impotent, despite disturbing media reports about methamphetamine

Methamphetamine has been around for some time. Although it is now available in a crystal form that is more potent and more readily smoked than earlier forms, no-one should feel impotent in the face of widespread alarmist commentary about this drug.

The recent National Ice Taskforce Report1 describes a pattern of increasing use of methamphetamine over the past decade. Compounding the effect of the shift in use from the older amphetamine sulphate to methamphetamine (in powder or crystal form) is the increase in purity of illicit methamphetamine: the purity-adjusted price (the dose obtained for a given price) is now similar for both methamphetamine forms,2 so that users obtain much larger doses. This probably underlies the evidence of more regular and greater levels of dependent use among people who use the drug, and also some of the increases in observed harms.3

The medical profession is pivotal in responding to these changes, and needs to provide clear, evidence-based responses and care for those affected; it is not “someone else’s problem”.

People who use methamphetamine come into contact with the general health care system for a number of reasons, ranging from problems directly related to use (eg, insomnia, acute mental health problems) to complications of use (eg, injuries, infections and cardiovascular problems), some of which may be detected while providing other care (eg, during antenatal care). Some users present when seeking treatment from general practitioners, including some requesting benzodiazepines or other sedatives, but methamphetamine use may not be disclosed or the GP may not have asked about it; sometimes it is other members of the family who seek help.

People who use methamphetamine are generally younger (under 40 years of age); more men than women use these drugs, and users commonly experience mental health and other substance use problems.4 Use is more prevalent among some groups more frequently exposed to health risks, especially Aboriginal and Torres Strait Islander people, and the gay, lesbian, transgender and transsexual communities. Recent use is more common in rural and remote communities. Most people who have used methamphetamine have done so only occasionally; however, the best available data suggest that there are now more regular and dependent users of the drug than at any other time in the past decade.5

What would be an appropriate response? There is a pressing need for a flexible and coordinated treatment system that can respond in a timely manner to people who use amphetamines. We need to develop the skills, confidence and capacity to do so. Drug and alcohol specialists, nurses, psychologists and other allied health practitioners all play key roles in partnership with primary and acute care services, including emergency departments and mental health services. Strategies to engage the broader medical workforce are urgently needed. GPs cite a range of reasons for feeling unskilled or unsupported in managing people with substance misuse problems, so that many are reluctant to do so.6 This situation must be changed if we are to improve our frontline responses to problems linked with methamphetamine use.

Optimal alcohol and drug-specific treatments incorporate multidisciplinary care that also attends to co-occurring substance use (eg, tobacco), as well as to physical, mental health and social problems. Psycho-social treatment approaches include specific drug counselling and support, withdrawal services, day programs and residential treatment for those who require more intensive support. Assertive follow-up and proactive relapse prevention programs are crucial, as the relapse rate among dependent methamphetamine users is high.

More research is needed to develop methods for better attracting methamphetamine users to treatment, to provide brief interventions for those with less severe problems, and to improve treatments for those who need intensive assistance. In addition to ongoing research overseas, a recently announced NHMRC grant to fund research that explores an alternative pharmacotherapeutic approach (application 1109466) and another that will examine the particular needs of Aboriginal communities (application 1100696) are promising starts.7

The alcohol and drug treatment sector needs to grow significantly to allow it to respond to those who need intensive treatment and to be available to support primary care. The announced introduction of Medicare item numbers for addiction medicine specialists8 will facilitate development of the workforce in this area. The use of a national planning model that assesses needs according to population prevalence, estimates the demand for treatment, and calculates the amount of resources required to respond effectively has been used to develop mental health services. A similar plan should be a matter of priority as a blueprint for national drug and alcohol service development.9 Western Australia has used modelling to develop one version of such an approach, focusing on system integration because this “ensures service delivery is comprehensive, cohesive, accessible, responsive, and optimises the use of limited resources”.10

The release of the Final Report of the National Ice Taskforce provides an opportunity for action. However, many key issues raised in the report still require adequately resourced strategies; this applies especially to specific plans for Indigenous communities. Mixed funding by the federal and state governments makes it challenging to achieve the necessary coherence of response. The Primary Health Networks will need to rapidly develop the capacity to engage with GPs, and specialist drug and alcohol services if they are to play a key role. Governments, health services and the general community must seize this opportunity to respond to the problems associated with methamphetamine use.