August 2013 – Issue 8 Dr Andrew Amos Gold Coast University Hospital

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Hello, I’m Andrew Amos, and this is the August 2013 episode of Australian Psychiatry Review. This month APR closes with a summary of the main trends in psychosis research over the last year, associated with an online quiz for CME points. The summary describes the main changes affecting psychotic disorders in the DSM-5, advances in the treatment and understanding of psychotic illness, and health system factors affecting people with psychosis. The regular monthly roundup of the psychiatric literature includes a comprehensive review of the rapid antidepressant effect of ketamine by Katalinic and colleagues; evidence of the high prevalence of psychotic experiences in people without psychotic disorders reported by Zammit and colleagues; and a bidirectional relationship between trauma and psychosis in adolescents detected by Kelleher and colleagues.

The August issue of the Australian and New Zealand Journal of Psychiatry gathers viewpoints on mental health policy ahead of the Australian General Election called for September. On the basis of changes in the prevalence, treatment, morbidity, and care

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systems for psychotic illness revealed by the population-wide Survey of High Impact Psychosis, Carr and Waghorn identify employment and social integration as two priorities for mental health policymakers.1 Castle argues that effective support of patient and caregiver autonomy is central to the recovery ideal, and proposes linking health funding to individual patients.2 Whiteford and colleagues suggest a systematic approach to mental health policy that identifies and measures the burden of mental illness, organises interventions into a service delivery framework, and adapts policy settings to implement this framework.3 They refer to the National Health and Medical Research Council’s aspiration to ameliorate the maximum burden of mental illness at the lowest cost and suggest three mechanisms for achieving this; increasing coverage where disease burden is high and treatment is low, such as major childhood mental disorder; translating research of effective treatments into practice, such as internet delivery of psychological interventions; and integrating complementary systems, such as physical and mental health treatment.

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Hui and colleagues show that close to 50% of first-episode psychosis (FEP) patients in a Hong Kong cohort relapsed within three years, with higher rates of relapse in smokers.4 Kim and colleagues report that psychosocial function is impaired in patients at ultra high risk of psychosis (UHR), with reduced adaptation and resilience.5 Exploratory data analysis suggested resilience was lower in UHR patients who converted to psychotic illness than those who did not.

Katalinic and colleagues provide a comprehensive review of evidence for the rapid antidepressant effect of ketamine in patients with treatment resistant depression.6 They note limitations of the literature, primarily open-label studies, with a single RCT using a parallel-group design, but conclude that most studies found significant rapid antidepressant effects of ketamine for a substantial subset of patients. They suggest future research should examine the optimal frequency and dose for achieving and sustaining response, given evidence of rapid relapse in ketamine treated patients.

Inside this issue: 2. International Psychiatric Journals

4. International Medical Journals

5. FOCUS SECTION – Trends in Psychosis Research

Australian Psychiatry Review A monthly summary of psychiatric research from high impact journals.

In August APR reviews trends in psychosis research over the last year; and reports on rapid anti-depressant effects of ketamine; high prevalence of psychotic experiences in general population, and the relationship between trauma and psychosis. RANZCP CME points are available with an online quiz.

Australian Psychiatry Review – August 2013

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AJP - July 2013

In the July issue of the American Journal of Psychiatry, Zammit and colleagues report a longitudinal birth cohort study of close to 5000 people assessed for psychotic experiences and illness at ages 12 and 18 years.7 At 18 years 9% had suspected or definite psychotic experiences, with 1.7% meeting criteria for a psychotic disorder. Only 50% with a psychotic disorder sought professional help. 80% of patients with psychotic experiences at age 12 had remitted by age 18. The positive predictive value of psychotic experiences at age 12 for psychotic disorders at age 18 was estimated at between 5.5 and 22.8%, which the authors conclude is too low to justify targeted interventions.

Commenting on this article, van Os suggested that psychotic illness is phenomenologically and temporally continuous with subthreshold states of psychopathology, which he describes as extended phenotypes.8 He adds that normal variation shares genetic and environmental causes with the extreme ends of psychopathology which are labeled with psychiatric diagnoses. van Os is careful to distinguish subthreshold extended phenotypes from the UHR-state proposed as a transition point to definitive psychotic illness, noting that help-seeking characterises people with more severe symptoms and less resilient natures. He attributes the decision to exclude from the DSM-5 the attenuated psychosis syndrome, and similar risk syndromes predisposing to other specific diagnoses, to growing evidence that early

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psychopathology across diagnoses is relatively non-specific. He poses the challenge of understanding how early non-specific subthreshold psychopathology interacts in a dynamic circuit and gradually differentiates into more specific but overlapping syndromes.

Kelleher and colleagues explore whether the association between childhood trauma and psychosis is causal.9 They report a longitudinal prospective cohort study of over 1000 adolescents, which showed a bidirectional relationship between trauma, represented by physical assault and bullying, and psychosis. Even after correcting for the bidirectional relationship, trauma strongly predicted psychotic experiences, with a dose-response relationship between severity of bullying and psychotic experiences. They also found that the end of bullying predicts the end of psychosis.

AJP - August 2013

In August the American Journal of Psychiatry includes a clinical guidance article by Rose and Behm suggesting that patients seeking abstinence from smoking who do not reduce daily cigarettes in the week before the quit date can benefit from either bupropion augmentation of nicotine patch treatment, or from switching from patch to varenicline.10 They note that patients accurately self-report smoking levels, reducing the need for measurement of expired carbon monoxide as an index of adherence. Rose and Behm conclude that it may be possible to identify a group of patients who will not be successful with

International Psychiatric Journals American Journal of Psychiatry, British Journal of Psychiatry JAMA Psychiatry, Molecular Psychiatry, Psychiatric Services

Schizophrenia, “Just the facts” - Tandon et al, Schizophr Res, 100(1):4-19

Epidemiology

Incidence 8-40/100,000/year

Higher incidence with urbanicity

Higher incidence with migration

Lifetime risk = 0.7%

Greater lifetime risk in males

Point prevalence 2-10/1000

Higher prevalence with lower socioeconomic class

Genetic factors contribute 80% of liability

Genetic heterogeneity with multiple genes of small effect

Several environmental factors of small effect (cannabis, birth season, perinatal infection)

Neurobiology

Reduced brain volume, larger lateral/third ventricles

Reduced grey matter (medial/superior temporal lobe structures, prefrontal cortex, thalamus)

Structural alterations in cortico-cortical tracts

Reduced cerebral asymmetry

Basal ganglia enlargements after treatment

Structural brain abnormalities at illness onset - abnormalities may progress in subset of patients

Structural brain abnormalities in unaffected family members

Hypofrontality - decreased activity of prefrontal cortex at rest and during cognitive challenge

Abnormal activation patterns in multiple brain regions during imaging of cognitive tasks

Reduced n-Acetyl Aspartate in frontal/temporal cortex

Reduced phosphomonoesters in prefrontal cortex

Absence of gliosis at post-mortem

Reduced neuropil

Altered neuronal elements in cortical/limbic structures

Altered sleep architecture (delta sleep deficits, shortened REM latency)

Smooth pursuit eye movement abnormalities in patients and relatives

Abnormalities in event related potentials (P50, P300, N100, mismatch negativity)

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nicotine patch and switch them early to more effective treatments, while avoiding the side effects associated with bupropion and varenicline for most patients.

Hasin and colleagues provide a review of DSM-5 substance related and addictive disorders, which notes the elimination of the distinction between substance abuse and dependence, standardisation of tobacco use disorder with other substance use disorders, incorporation of gambling disorder with substance use disorders, and the addition of cannabis and caffeine withdrawal disorders.11 They also describe the rationale for the addition of the new substance use criterion of craving, with reference to imaging, pharmacological, and genetic studies.

Torrent and colleagues describe a 21-week remediation program for patients with bipolar disorder which improved overall function, including higher rates of employment.12 They randomized 239 outpatients to a program of functional remediation, psychoeducation, or treatment as usual (TAU), and found the active arms showed improvement on the Functioning Assessment Short Test compared to TAU.

Cullen and colleagues provide a case report and discussion of an adolescent with nonsuicidal self-injury, defined as harming one’s own body tissue without intent to die.13 They describe neurobiological research which links emotional dysregulation to disturbed function in limbic and frontal brain regions, the autonomic nervous system, the hypothalamic-pituitary-adrenal axis, and disordered serotonin release and uptake. Cullen and colleagues conclude that research and clinical experience both indicate that the combination of SSRI and dialectical behaviour therapy most effectively helps maintain safety, build self-soothing strategies of emotional regulation, and reduce interpersonal sensitivity.

BJP - August 2013

The August issue of the British Journal of Psychiatry includes two articles suggesting genetic links between ADHD and schizophrenia. Larsson and colleagues use longitudinal evidence from Swedish national registers to demonstrate increased risk of bipolar disorder and schizophrenia amongst relatives of ADHD probands, including lower risks in half- than in full siblings.14 Hamshere and colleagues found that schizophrenia risk alleles identified by the Psychiatric Genome-wide Association Study Consortium differentiated children with ADHD from controls.15 Oosterbaan and colleagues report a cluster-randomised controlled trial of collaborative stepped care provided by a psychiatric nurse in a primary care setting augmenting

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antidepressants and CBT.16 They found evidence of earlier response to treatment at 4 months which was no longer significant at 8- and 12-month follow-up. An editorial by Roy-Byrne highlights the difficulty of implementing collaborative care in the United States, particularly due to fragmentation of care systems into separate streams for substance abuse, mental health, and medical health.17 Attempts to introduce collaborative care between specialist psychiatric and primary care services are most likely to be introduced for the least effective models, such as simple co-location of mental health and primary care workers; while more effective models, such as multi-disciplinary teams including primary care and specialist psychiatric clinicians working together, are rarely taken up.

JAMA Psychiatry - July 2013; awaiting August

An exciting article published online in JAMA Psychiatry by Wunderink and colleagues reports a follow-up of 128 patients up to 7 years after they achieved remission from FEP and were randomised to maintenance antipsychotic treatment or dose-reduction or discontinuation.18 The authors report that 40% of the dose-reduction patients achieved recovery over 7 years, significantly more than the 18% of maintenance patients. Over the 18 months of initial treatment the dose-reduction patients showed a higher rate of relapse, though relapse rates were no longer different at three years, suggesting maintenance treatment delays rather than prevents relapse. Hallak and colleagues report a randomised, double-blind trial assigning twenty inpatients with schizophrenia to a single nitroprusside dose or placebo control.19 The glutamate hypothesis of schizophrenia draws on several lines of evidence, including dysfunction in the glutamate-nitric oxide-cyclic guanosine monophosphate pathways of patients with schizophrenia, reproduction of positive and negative psychotic symptoms with glutamate antagonists, and animal models. Sodium nitroprusside is used to rapidly lower blood pressure in acute hypertensive episodes, though it requires higher doses to affect the blood pressure of normotensive patients. Hallak and colleagues report that a single low dose of nitroprusside reduced positive and negative symptoms of inpatients with schizophrenia within 4 hours, and improvements persisted over four week

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follow-up. There were no significant side-effects noted. A related editorial by Coyle sounds several notes of caution, particularly the small numbers and possible neurotoxic effects, though concludes nitroprusside remains promising.20 Parboosing and colleagues report that maternal influenza during pregnancy is associated with a 4-fold increase in the likelihood of bipolar affective disorder.21 Ilgen and colleagues found an association between non-cancer pain disorders and suicide, which remained significant after controlling for comorbid psychiatric conditions.22 Weisz and colleagues provide a meta-analysis of randomised controlled trials comparing evidence-based psychotherapies to usual care, which provided only modest support for the psychotherapies, and was particularly weak for clinically referred youths and clinically diagnosed samples.23

Molecular Psychiatry - August 2013

An editorial by Licinio and Wong in the August edition of Molecular Psychiatry proposes a novel framework for understanding psychiatric nosology.24 They suggest that much of the heat and light associated with criticisms of the DSM-5 is sparked by the mistaken belief that the diagnostic categories represent distinct biological entities, despite the explicit aetiological neutrality of the DSM. They develop the themes of redundancy, meaning that the symptomatic clusters comprising psychiatric diagnoses can each have multiple causes, and pleiotropism, meaning that individual risk factors can be associated with multiple psychiatric outcomes. An example of redundancy is seen in discordance for diagnosis of major depression in monozygotic twins; while pleiotropism can be detected in genetic studies which show specific alleles associated with increased rates of both schizophrenia and bipolar disorder. They argue that it is a mistake to insist upon conceptual purity where this does not exist in psychopathology. Instead, understanding should be sought by integration of research from cell biology through animal models and clinical trials, with theoretical knowledge of biological pathways such as inflammation and neuroendocrine processes. Martinowich and colleagues discuss ketamine in the context of other putative rapidly-acting antidepressant treatments, such as sleep-deprivation, ECT, and other glutamatergic antagonists.25 They propose a series of physiological stages in antidepressant treatments, beginning with acute alterations in brain function, which lead to activation of

Australian Psychiatry Review – August 2013

Schizophrenia, “Just the facts” - Tandon et al, Schizophr Res, 100(1):4-19

(cont…)

Dopamine agonists exacerbate and D2 antagonists alleviate schizophrenic symptoms

NMDA antagonists (eg phencyclidine) cause psychotic symptoms similar to schizophrenia

Abnormalities in central GABA neurotransmission

Abnormalities in cholinergic/serotonergic systems

Hypothalamo-pituitary-adrenal axis dysregulation including hypercortisolaemia

Clinical features

Nosological boundaries with other psychiatric disorders are indistinct

No pathognomonic symptoms

Diagnosis based on symptom profile and course

Significant heterogeneity in neurobiology, clinical manifestations, course, and treatment response

Chronic and relapsing disorder

Mix of positive, negative, cognitive, mood symptoms

Severity of symptoms varies across patients and through the course of the illness

Generalised intellectual impairment

Specific impairment in particular cognitive functions

Cognitive deficits present prior to onset of illness

Less severe cognitive deficits occur in relatives

Increased prevalence of minor physical, dermatoglyphic, and neurological abnormalities

Higher prevalence of obesity and cardiovascular disease

Reduced occurrence - rheumatoid arthritis - cancer

Increased – suicide - smoking and substance abuse - violent behavior

International Medical Journals JAMA, Lancet, NEJM

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JAMA

The July 24 issue of JAMA includes a Continuing Medical Education section by Naomi Simon on treating complicated grief, focused on a case report of a 60 year old woman dealing with the sudden death of her husband after the diagnosis of oesophageal cancer.28 A news article in the same issue reports that the typical antipsychotic thioridazine helps kill drug-resistant staphylococci by attacking the bacterial cell wall. Kuehn refers to an FDA investigation of two unexplained deaths within four days of administration of Olanzapine pamoate depot.29 The dead

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patients were found to have high levels of olanzapine in their blood stream.

Lancet

In June the Lancet published online an article by Leucht and colleagues reporting a Bayesian meta-analysis of randomised controlled trials ranking the efficacy and tolerability of 15 antipsychotics.30 They report that all were significantly more effective than placebo at reducing psychotic symptoms, with the largest effect sizes for clozapine, amisulpride, and olanzapine. Haloperidol was worst for all-cause discontinuation and extrapyramidal side-effects, while clozapine

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homeostatic mechanisms involving cellular signaling cascades, which then re-establish a new homeostasis in the brain’s patterns of activity. Rapid-acting antidepressant treatments may directly affect downstream targets of these cellular signaling cascades. Martinowich and colleagues review evidence suggesting that brain-derived neurotrophic factor (BDNF) and changes in synaptic function may be important downstream factors.

Psychiatric Services

In the May issue of Psychiatric Services Addington and colleagues attempt to systematically identify all potential components of FEP services and assess which are essential based on existing evidence.26 They detail a comprehensive search for literature between 1980 and 2010, followed by a multi-stakeholder consensus process known as Delphi

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involving communication protocols allowing experts to iteratively select the most important elements of a complex set. The panel of experts proposed 32 essential components of FEP treatment ranked for level of evidence, with strong evidence for 6 components: antipsychotic selection, slow titration, clozapine for treatment resistance, monotherapy, supported employment, and multifamily group psychoeducation. A related article by Goldman and colleagues examines the financial framework of FEP services in the US, most frequently capitated Medicaid insurance, supplemented with local and federal funding to cover insurance gaps.27 Because President Obama’s Affordable Care Act is likely to significantly increase Medicaid coverage for people with psychotic illness, it is also likely to significantly increase the possibility of functional FEP services across the US.

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TRENDS IN PSYCHOSIS RESEARCH Diagnosing psychotic illness

Treatment of psychosis Understanding of psychosis

Health systems surrounding psychosis

Schizophrenia, “Just the facts” - Tandon et al, Schizophr Res, 100(1):4-19

(cont…)

Onset usually during adolescence or early adulthood

Age of onset earlier in males

Significant premorbid impairments in many patients Doubling of age-standardised mortality

Poor outcome predicted by male gender - early age of onset - prolonged period of untreated illness - severity of cognitive and negative symptoms

Outcome has improved modestly over 20th Century

Prevention and treatment

Dopamine-2 antagonists are only effective therapeutic agents currently available

Clozapine most effective agent for atypical-resistant positive symptoms and suicidality

All other antipsychotics similarly efficacious

Antipsychotics have limited effectiveness for negative symptoms and cognitive deficits

EPS not necessary for antipsychotic effect and compromise cognitive/negative mood

Antipsychotics vary widely in adverse effects

Antidepressants effective in treating depressive symptoms

ECT may be effective

rTMS can be effective

Family and patient psycho-education reduce relapse rates

CBT reduces psychotic symptoms

Social skills training improves outcomes

Assertive community treatment reduces hospitalization

Cognitive remediation reduces cognitive deficits

Early intervention in UHR delays transition to psychotic illness

Intervention during first episode of psychosis improves outcomes

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The release of the DSM-5 in May was the major event in the psychosis literature over the last year. Despite increasing resources devoted to new pharmacotherapies, cognitive interventions, and social supports, advances in practice and knowledge continue to be incremental rather than revolutionary. This focus section will first consider diagnostic changes affecting psychotic disorders in the DSM-5, research on interventions for psychosis, advances in our understanding of illness phenomena and mechanisms, and health systems research.

Diagnosing psychotic illness While the designers of the DSM-5 intended that the diagnostic approach

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start to include biomarkers, no viable markers have been demonstrated. In part, as Hardy observed in the July issue of JAMA Psychiatry, this is because the early promise of psychiatric genetics and molecular psychiatry has not been fulfilled.32 Thus, the main changes to the treatment of psychosis in the DSM-5 were based on empirical rather than theoretical or aetiological grounds. The diagnosis of schizophrenia saw several changes, including the elimination of the special status of bizarre delusions and Schneiderian first-rank auditory hallucinations, meaning at least two criterion A symptoms are required for any diagnosis of schizophrenia. It is now also required that at least one criterion A symptom be a delusion, hallucination, or disorganised speech. Schizophrenia subtypes have been eliminated because of limited diagnostic

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was best for EPS and worst for sedation. The authors conclude that received ideas such as the division into typical and atypical antipsychotics, and the equivalent efficacy of most antipsychotics, are not supported by efficacy or side-effect data.

NEJM

The July 4 issue of the New England Journal of medicine includes an editorial by Becker and Kleinman which summarises the global implications of the World Health Organization’s slogan “No health without mental health”.31 The authors report that the aggregate global burden of mental illness is higher than that of any other disease category. Less than 25% of people with serious mental illness in less-developed

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countries receive any treatment, and the effectiveness of the treatment that is received is poorly known. Becker and Kleinman outline various limiting factors, including lack of mental health workers, but also note the absence of mental health research in less-developed settings, preventing appropriate resource allocation or estimates of the potential outcomes of different interventions. They propose a collaborative care model, in which mental health specialists provide training, supervision, and tertiary care with the bulk of direct service delivery provided by primary care professionals. And that’s it for the monthly roundup. Next, we will focus on trends in psychosis research over the last year.

Australian Psychiatry Review – August 2013

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References

Australian and New Zealand Journal of Psychiatry

1. Carr VJ, Waghorn G. To love and to work: The next major mental health reform goals. Australian and New Zealand Journal of Psychiatry. 2013;47(8):696–8.

2. Castle DJ. Where to for Australian mental health services? Promoting self-efficacy. Australian and New Zealand Journal of Psychiatry. 2013;47(8):699–702.

3. Whiteford H, Harris M, Diminic S. Mental health service system improvement: Translating evidence into policy. Australian and New Zealand Journal of Psychiatry. 2013;47(8):703–706.

4. Hui CL-M, Tang JY-M, Leung C-M, et al. A 3-year retrospective cohort study of predictors of relapse in first-episode psychosis in Hong Kong. Australian and New Zealand Journal of Psychiatry. 2013;47(8):746–53.

5. Kim KR, Song YY, Park JY, et al. The relationship between psychosocial functioning and resilience and negative symptoms in individuals at ultra-high risk for psychosis. Australian and New Zealand Journal of Psychiatry. 2013;47(8):762–71.

6. Katalinic N, Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK. Ketamine as a new treatment for depression: A review of its efficacy and adverse effects. Australian and New Zealand Journal of Psychiatry. 2013;47(8):710–27.

American Journal of Psychiatry

7. Zammit S, Kounali D, Cannon M, et al. Psychotic experiences and psychotic disorders at age 18 in relation to psychotic experiences at age 12 in a longitudinal population-based cohort study. American Journal of Psychiatry. 2013;170(7):742–50.

8. Van Os J. The dynamics of subthreshold psychopathology: implications for diagnosis and treatment. American Journal of Psychiatry. 2013;170(7):695–8.

9. Kelleher I, Keeley H, Corcoran P, et al.

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stability, with low reliability and poor validity. Healy provides a potted history of changing conceptualisations of catatonia, and particularly the error of thinking of this non-specific syndrome as a subtype of schizophrenia.33 A number of changes have occurred outside the schizophrenia diagnosis. A dimensional approach to measuring the severity of core psychotic symptoms has been added which applies across the spectrum of psychotic disorders. Schizoaffective disorder has been conceptualised as a longitudinal rather than a cross-sectional diagnosis, and delusional disorder no longer requires non-bizarre delusions, although a specifier for bizarre delusions has been added. The criteria for catatonia are now defined uniformly across DSM-5.

Treatment of psychosis There is little evidence of rapid advances in treatment of psychotic illness. While there were isolated reports of relatively novel antipsychotic agents such as lurasidone34 and asenapine,35 outcomes do not appear to be greatly different from more established agents. Papanastasiou and colleagues report that glutamatergic treatments for psychosis continue to show promise without real delivery.36 Rapid reduction of psychotic symptoms with a single dose of nitroprusside has been discussed earlier in this podcast. In the absence of major breakthroughs the literature appears to have focused on reanalysis of specific questions, particularly regarding clozapine. Patel pointed out an underutilisation of clozapine which might be driven by clinicians exaggerated fears of the possibility of fatal side-effects.37 Howes and colleagues showed that despite

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protocols suggesting second-line use of clozapine for treatment-resistant schizophrenia, most initiations occurred after several years delay involving unsuccessful trials of more than two alternative antipsychotics, and frequently involved high-dose treatment and polypharmacy.38 Remington and colleagues noted that while most protocols suggest a clozapine trial after adequate trial of two other antipsychotics, the evidence suggests it would be reasonable to try clozapine after a single unsuccessful trial.39 Nielsen and colleagues found that the majority of clozapine discontinuations for medical reasons were unwarranted, and that many side-effects of clozapine could safely be managed with dose modification, or addition of other agents, without the need to discontinue clozapine.40 Cohen and Monden note only 17 patients are known to have developed agranulocytosis after the first year of clozapine treatment, with morbidity similar to that of chlorpromazine.41 They suggest it may be reasonable to move to quarterly blood tests after one year of stable treatment with clozapine. Over the last year there has been an extension of the growing focus on the need for treatments for negative symptoms of schizophrenia. Marder provided a continuing medical education exercise in the January issue of the Journal of Clinical Psychiatry to help clinicians develop their skills in this area.42 Kring and colleagues presented the biologically motivated Clinical Assessment Interview for Negative Symptoms (or CAINS) dividing motivational systems into dopaminergic networks anticipating reward, and GABAergic and opioid systems mediating the experience of pleasure.43 Several items of conventional wisdom regarding treatment of psychosis have been re-examined over the last year. Kirson and colleagues reported that increased efficacy of

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depot versus oral medication in non-adherent patients disappeared with more rigorous methodologies such as randomised controlled trials.44 Continuing the re-evaluation of the relative merits of typical and atypical medications of the last few years, Kishimoto and colleagues reported a meta-analysis suggesting that second-generation antipsychotics are better at preventing relapse than first-generation antipsychotics.45 As described earlier in the podcast, Wunderink and colleagues found that long-term outcomes of patients with FEP may be better with dose-reduction or discontinuation than with maintenance antipsychotics. An article by Scott and colleagues in the April issue of the British Journal of Psychiatry reported that the clinical staging model pioneered in early intervention in psychosis programs is now being extended to the rest of psychiatry, as clinicians realise that it may be possible to avoid the loss of function and socioeconomic drift associated with long-standing mental illness.46 Evidence for the prevention of transition to psychosis amongst patients at ultra-high risk of psychosis continues to be mixed at best.47 Based on research that psychotic experiences are highly prevalent and non-specific risk factors, van Os suggested that the relevant goal of treatment for people with sub-threshold psychotic symptoms might be reduction of distress rather than prevention of transition.48 Warner suggested that early intervention efforts should focus on the mode of onset rather than the duration of untreated psychosis, with worse illness requiring more intensive intervention associated with slow insidious onset.49 One of the principles of clinical staging in psychosis has been the early introduction of cognitive and social interventions to prevent functional decline and maintain or develop skills and resources. Alongside this has been an effort to implement a patient-centred focus, including measurement of patient-reported outcomes. In the October 2012 issue of the British Journal of Psychiatry Reininghaus and colleagues found significant methodological limitations of existing patient-reported outcome instruments and suggested development of short, clinically relevant measures.50 Harvey and colleagues review the literature and conclude that placing patients with severe mental illness in work then supporting them, known as individual placement and support, is more effective

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than training patients for work and then trying to place them, a more traditional model of vocational support.51 Alvarez-Jiminez and Gleeson reviewed exciting prospects for the greater use of internet technologies in the treatment of psychotic illness using social media to connect and empower patients.52 Evidence on CBT for psychosis and cognitive remediation therapy continued to accumulate,53 while Leff and colleagues reported an intriguing intervention where patients could develop computer-based representations of delusional identities, called avatars.54 The authors speculated that reduced patient distress may have been associated with the actualisation of persecutory voices, validating patients’ experiences and allowing them a measure of control and safe experimentation with resistance to delusional ideas. While clozapine appears to be underutilised because of unrealistic fears, multiple authors have reported the dangerous overuse of antipsychotic medications in older patients with dementia and behavioural disturbance. Barnes and colleagues reported an audit of British trusts which showed 16% of dementia patients without a psychotic illness were prescribed antipsychotics, with a large proportion continued for 6 months without a documented therapeutic response.55 There has been a significant increase in research on medical comorbidities amongst people with psychotic illness over the last year. Kisely and colleagues demonstrated that psychiatric patients don’t have a higher prevalence of cancer, but have a 30% higher cancer fatality rate, which may be associated with reduced detection or reduced treatment associated with clinician preconceptions about these patients.56 Crump and colleagues reported a national cohort study of Swedish adults which showed that people with schizophrenia die 12 to 15 years earlier than the general population.57 They attributed most of the excess mortality to ischaemic heart disease and cancer, with a significant underdiagnosis of illness. Chen and colleagues reported that metformin significantly reduced body weight, BMI, and fasting glucose in patients on clozapine, with returned to control levels after metformin was discontinued.58

Understanding of psychosis

In the absence of major advances in our understanding of the causes or trajectory of psychotic illness, the literature has tended to focus attention on multiple factors of small effect. For example, Collip and colleagues reported that the relationship between trauma and psychosis might be mediated by genetic variation in the FKBP5 protein affecting the

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Childhood trauma and psychosis in a prospective cohort study: cause, effect, and directionality. American Journal of Psychiatry. 2013;170(7):734–41.

10. Rose JE, Behm FM. Adapting Smoking Cessation Treatment According to Initial Response to Precessation Nicotine Patch. American Journal of Psychiatry. 2013;170(8):860–867.

11. Hasin DS, O’Brien CP, Auriacombe M, et al. DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale. American Journal of Psychiatry. 2013;170(8):834–851.

12. Torrent C, Bonnin C del M, Martínez-Arán A, et al. Efficacy of Functional Remediation in Bipolar Disorder: A Multicenter Randomized Controlled Study. American Journal of Psychiatry. 2013;170(8):852–859.

13. Cullen KR, Westlund MK, Lariviere LL, Klimes-Dougan B. An Adolescent With Nonsuicidal Self-Injury: A Case and Discussion of Neurobiological Research on Emotion Regulation. American Journal of Psychiatry. 2013;170(8):828–831.

British Journal of Psychiatry

14. Larsson H, Rydén E, Boman M, Långström N, Lichtenstein P, Landén M. Risk of bipolar disorder and schizophrenia in relatives of people with attention-deficit hyperactivity disorder. British Journal of Psychiatry. 2013;203:103-106.

15. Hamshere ML, Stergiakouli E, Langley K, et al. A shared polygenic contribution between childhood ADHD and adult schizophrenia. British Journal of Psychiatry. 2013;203:107-111.

16. Oosterbaan DB, Verbraak MJPM, Terluin B, et al. Collaborative stepped care v. care as usual for common mental disorders: 8-month, cluster randomised controlled trial. British Journal of Psychiatry. 2013;203:132–139.

17. Roy-Byrne P. Collaborative care at the crossroads. British Journal of Psychiatry. 2013;203:86–7.

JAMA Psychiatry

18. Wunderink L, Nieboer RM, Wiersma D,

Australian Psychiatry Review – August 2013

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cortisol feedback loop active in responses to stress, discussed at the phenotype level as resilience.59 As previously discussed, Kelleher and colleagues reported evidence of a causal relationship between childhood trauma and psychotic illness, along with evidence that life events can trigger psychotic episodes;9 Beards and colleagues have also suggested that life events can be associated with the onset of psychotic illness.60 van Os and colleagues have continued to document a high prevalence of stable subthreshold psychotic experiences in up to 10% of the population.48 van Os has suggested that subthreshold psychosis is temporally and psychopathologically continuous with psychotic illness, rather than being categorically distinct.8 An article by most of the major researchers in the ultra-high risk of psychosis paradigm acknowledged the poor reliability of the attenuated psychosis syndrome rejected by the DSM-5.61 These authors proposed that prior to definitive psychotic illness, psychotic symptoms could be considered a pluripotent risk factor that might develop into psychotic, affective, or behavioural disturbances in later life. They also acknowledged an ongoing absence of evidence that prodromal treatment can prevent transition to frank psychotic illness. Gaudiano and Zimmerman reported that 28% of treatment-seeking outpatients reported psychotic experiences, even after excluding those with frank psychotic disorders.62 They could not identify any patients clearly meeting criteria for attenuated psychosis syndrome alone, and concluded that psychotic experiences represent non-specific indicators of psychopathology. They speculated that attenuated psychosis syndrome could result in high false-positives and lead to increased use of antipsychotic medication without clear need. The neuroscience of psychosis continues to be plagued by complex, contradictory results with limited replication and little to no relevance for clinical practice. Over the last year there has been significant interest in the interaction between the immune system and psychiatric illness. Najjar and colleagues provide an open-access and comprehensive overview of this growing field, describing autoimmune mechanisms in neuropsychiatric syndromes, as well as neuroimmunologic abnormalities in classical psychiatric disorders including schizophrenia.63 They conclude that innate inflammation may be mechanistically linked

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to monoaminergic and glutamatergic abnormalities and oxidative injury in psychiatry illnesses.

Psychosis and health systems Associated with ongoing reform of the health system in the US with President Obama’s Affordable Care Act, and increasing financial pressure on public expenditures in the US and across the developed world since the Global Financial Crisis in 2007, there has been a growing effort to calculate the cost and cost-effectiveness of treatment for psychotic illness. At the same time there has been an effort to describe the systems that support patients with psychotic illness, to identify areas of unmet need and assess the success of the changing approach to psychosis over the last decade. Attempts to demonstrate the cost-effectiveness of early intervention in psychosis have continued over the last year. Hastrup and colleagues reported that the total costs of the OPUS early intervention paradigm in Denmark were not different from those of TAU, and were likely to be cost-effective interventions.64 The nation-wide Survey of High-Impact Psychosis across Australia generated a number of intriguing results, particularly when compared to the most recent survey in 1998. Morgan and colleagues reported that between 1998 and 2010 public and private mental health systems in Australia increased the proportion of the population entering care, with large shifts from inpatient to outpatient care, and from typical to atypical antipsychotics.65 At the same time there was a significant increase in the proportion of substance and alcohol abuse among patients treated for psychotic illness. While stable accommodation rates improved there remained a large unmet need amongst this vulnerable population. And that’s it for the special summary of trends in psychosis research. CME points can be achieved by logging on to the College’s CPD Online section and completing a brief quiz. The password to enter the quiz is ‘early’. See

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Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy Long-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psychiatry. 2013;Jul 3:1–8 [Epub ahead of print].

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AUSTRALIAN PSYCHIATRY REVIEW AUGUST 2013

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Two things fill the mind with ever-increasing wonder and awe, the more often and the more intensely the mind of thought is drawn to them: the starry heavens above me and the moral law within me. – Immanuel Kant, 1788

Dr Andrew Amos Early Psychosis Gold Coast Robina Hospital 2 Bayberry Lane Robina, QLD, 4226