Managing the acute psychotic episodeBMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39148.668160.80 (Published 29 March 2007) Cite this as: BMJ 2007;334:686
- Peter Byrne, consultant psychiatrist
- Correspondence to:
People with a first or recurrent psychotic episode tend to present late for medical attention, and many do not present at all. Presentation is often initiated by others, not by patients themselves. Psychosis can also become apparent during a manic presentation, when patients act on their delusions in a public forum, or when they have the complications of substance misuse. Patients who experience intolerable symptoms (distressing delusions or voices; box 1) often seek medical help. In emergency settings, family members' concerns contrast with the patient's apparent indifference. The highest risk of suicide in people with schizophrenia occurs during the first five years of illness (“the critical period”), and interventions are most fruitful during this time. Importantly, patients experiencing their first episode should quickly be given competent assessments and access to appropriate services.
Acute psychosis is a common psychiatric emergency that may present to health services other than mental health practitioners
Comorbidities are common and increase with age—monitoring for hidden physical and other mental disorders is essential
Patients with a first episode (even those with substance misuse) are best treated by specialist multidisciplinary early intervention teams that deliver psychosocial interventions as essential adjuncts to drugs
Treatment achieves complete remission, without relapse, in 25% of patients
In general, a low dose, well tolerated atypical antipsychotic drug will increase medium term adherence and reduce future relapses
Sources and selection criteria
I searched HighWire and PubMed from 2002 to October 2006 for randomised controlled trials and systematic reviews of treatments for psychosis and schizophrenia. I reviewed the Cochrane Database of Systematic Reviews using both terms, across the age spans. Influential articles, key texts, and published treatment guidelines are also included.
Box 1 Positive psychotic symptoms
Clear symptoms (one or more needed for a diagnosis of schizophrenia)
Paranoid delusion: Any delusion that refers back to the self—in practice, most are persecutory delusions. Grandiose delusions (such as special powers or missions) occur in schizophrenia and bipolar affective disorder
Delusions of thought interference: Delusions that others can hear, read, insert, or steal the patient's thoughts
Passivity phenomena: Delusional beliefs or perceptions that others can control the patient's will, limb movements, bodily functions, or feelings
Thought echo: The patient hears their own thoughts spoken aloud ()
Third person auditory hallucinations (voices speaking about the patient): These may include a running commentary on the patient's actions; these are common in non-affective psychoses
Less clear symptoms (one or more needed for a diagnosis of schizophrenia)
Hallucinations in any modality without clear affective content
Second person auditory hallucinations (voices speaking to the patient): These may include command hallucinations (“run out the door”); these are common in depression, where they are demotivating or abusive (“you're useless”)
Thought disorder: Breaks in the train of thought (thought block), excessive attention to unnecessary detail (overinclusive thinking), and difficulties in abstract thinking (for example, cannot explain proverbs or common sayings)
How common is psychosis?
The one year prevalence of non-organic psychosis is 4.5 per 1000 community residents.1 Most new cases arise in men under 30 and women under 35, but a second peak occurs in people over 60 years. Psychotic symptoms had a 10.1% prevalence in a non-demented community population over 85 years.2 Schizophrenia has a one year prevalence of 3.3 per 1000 people, and a lifetime morbidity risk of 7.2 per 1000 people.w1 Independent of known associations with migration and ethnic origin, increased economic inequality in areas of high deprivation also predicts a higher incidence of schizophrenia.3 Some people who become depressed (one in five of us over a lifetime) also develop hallucinations and delusions, related to and “congruent with” their low mood. Bipolar affective disorder has a lifetime prevalence of 1.3-1.6%,4 and it is characterised by episodes of psychosis during both high (“manic”) and low (depressive) relapses. The misuse of substances, notably cannabis,5 raises the prevalence of psychotic symptoms further—substance misuse partly explains the 10 times higher prevalence of psychosis in prison populations.1 Psychosis occurs frequently in all forms of dementia including Parkinson's disease. Other causes of organic psychoses are neurological disorders (epilepsy, head injury, haemorrhage, infarction, infection, and tumours) and most causes of delirium. Taken together, therefore, acute psychosis is one of the most common psychiatric emergencies. There are explanations of psychotic “symptoms” other than the biomedical model of this review; medicalising psychosis as “an illness like any other” increases both public pessimism about outcome and the stigma attached to people with psychosis.6
Psychosis: A disorder of thinking and perception, where typically people do not ascribe their symptoms to a mental disorder
Positive symptoms: Positive psychopathology (delusions, hallucinations, thought disorder)
Negative symptoms: Symptoms that define the deficit state—what is not there (box 2)
Delusion: A false, unshakeable belief out of keeping with the patient's educational, cultural, and social background; it is held with extraordinary conviction and subjective certainty
Hallucination: A sensory perception experienced in the absence of a real stimulus; voices (the most common modality) are experienced as originating from outside the person and have the full force of real perception
Schizophrenia: Psychosis that develops a chronic course. A minimum of one clear symptom (box 1) or two less clear symptoms (boxes 1 and 2) must be present for most of the time for one month or more
Prodrome: A definable period before the emergence of psychotic symptoms during which functioning becomes impaired
Mania: The “high” relapses of bipolar affective disorder; hypomania is elevated mood without psychotic symptoms
How do I diagnose psychosis?
Diagnosis is based on clinical findings. No confirmatory laboratory or radiological tests are available, although investigations are needed to rule out organic psychosis. More information is gained on first assessment than at any subsequent time: even a few days' antipsychotic treatment can reduce the strength of delusions, and patients learn quickly that disclosing too many symptoms can have implications for the drugs they are prescribed or their liberty.
Carefully defining the psychotic processes clarifies their nature. Patients' trust can be gained by recording presenting complaints first and listening empathically to their accounts of troubling symptoms. Open questions (“How have things been for you lately?”) should be followed by progressively more closed questions (“Do you think something funny has been going on? Have you heard unusual noises or voices? Could someone be behind this?”). Patients rarely complain of negative symptoms (box 2), but they may have lost ambitions at school or work and social networks and activities may have been curtailed. Three core mood symptoms—mood, energy, and interest or pleasure—are reduced in depression and raised in manic states. The coexistence of psychosis and major alterations in mood may indicate bipolar or schizoaffective disorders.4
Many other aspects of the patient's history determine diagnosis and management:
• Symptoms in other systems, especially neurological and endocrine systems
• Past psychiatric symptoms, health service contacts, and treatments
• Medical history and medication history; these should be supplemented with a physical examination
• Family history of mental illness and suicide
• Alcohol and substance misuse. Use of cannabis increases the risk of psychosis in people predisposed to its effects5
• Allergies and adverse drug reactions, such as the extrapyramidal side effects of antipsychotics. These comprise early effects (akathesia and dystonic reactions), rare but fatal effects (neuroleptic malignant syndrome), and late and disabling effects (tardive dyskinesia).
Box 2 Negative psychotic symptoms (less clear symptoms; on their own, at least two of these symptoms are needed to diagnose schizophrenia)
Apathy (disinterest) manifested as blunted affect
Emotional withdrawal: flat affect
Odd or incongruous affect (for example, the patient smiles when recounting sad events, and vice versa)
Lack of attention to appearance or personal hygiene
Poor rapport: reduced verbal and non-verbal communication (for example, eye contact)
Lack of spontaneity and flow of conversation
Mental state examination
The primary diagnosis may be revised weeks or years later (box 3), and thorough documentation improves diagnostic accuracy now and later. The patient's general appearance and behaviour may indicate overarousal and hostility (as a result of positive symptoms) or irritability suggestive of elevated mood. Other motor signs (catatonia and negativism) are rare in Western settings. Altered consciousness is highly unusual in non-organic psychoses—intermittent clouding indicates delirium and this or other impairments require urgent medical investigation. Speech will be disorganised if thought disorder is present (box 1), and with predominant negative symptoms (box 2) conversation will be stilted and difficult. Random changes of the subject (loosening of associations) and new words (neologisms) are best written down verbatim. Fast or pressured speech suggests mania. Mood should be noted as normal, depressed, or elevated. Affect, the outward expression of mood, is unlikely to be normal in these patients: flat affect may be the most obvious sign of negative symptoms, but there may be others (box 2). An anxious or perplexed affect may impact on actual behaviour. Suicidality (thoughts, intentions, actions) must always be assessed by asking questions like, “Have the voices suggested suicide?” Other abnormalities of thought (obsessions, overvalued ideas) and perception (illusions, misinterpretations) are common. Cognitive impairment, tested at the bedside, can present in the early stages of psychosis, but gross abnormalities may alert the clinician to learning disability or organic pathology. Concentration is subjectively normal (patient unaware) but objectively impaired (for example, the patient cannot recite the months of the year backwards). Insight can change considerably over the course of a psychotic illness and its treatment.
Box 3 Psychiatric differential diagnosis
First episode psychosis or acute psychosis: includes drug induced, acute, and transient psychotic disorder; schizophrenia; and other non-affective psychotic disorders
Bipolar affective disorder: manic or depressed episode
Severe depressive episode with psychotic features
Post-traumatic stress disorder
Obsessive compulsive disorder
Schizotypal or paranoid personality disorder
Attention deficit hyperactivity disorder
Taking a collateral history is the third core component of assessments. Incomplete information can be gained from patients who are paranoid, and perhaps lack insight. Family and friends may have noticed them behaving strangely—responding to hallucinations or testing their delusions. Taking collateral details after clinical assessment is an opportunity to test the working diagnosis. The patient's family will clarify whether some beliefs are culturally sanctioned and are not therefore delusional. Collateral history may identify a prodrome or negative symptoms (box 2) as the main focus of carers' concerns. Insidious onset and prolonged psychotic symptoms during the first two years are both strong predictors of poorer long term outcome.7 If no prodrome has occurred and the episode has had a short duration (fewer than two weeks), with a clear stressful precipitant, the diagnosis might be one of an acute and transient psychotic disorder (box 3), which is best treated with support and without drugs. If the quality of collateral history is poor (for example, the patient is brought in by the police or is homeless), seek out anyone with prior contact before concluding your assessment. Integrate new information into further assessments of your patient: disclosure improves as a trusting relationship develops.
What else could it be?
Investigations (table 1⇓) are led by positive physical findings that suggest organic causes or comorbidities. Patients need to be given the results as soon as they are known. This reduces anxiety and paranoia, and it prevents excessive preoccupation with physical health. If the patient has organic psychosis, treat the underlying condition and unless the patient has epilepsy8 consider symptomatic short term treatment of the psychotic symptoms. If the underlying condition cannot be cured (for example, Alzheimer's dementia), consider giving low dose antipsychotics, but be aware that the benefits of these drugs in this situation may be outweighed by their adverse effects.w2 An identified physical cause is best treated in a general hospital with support from psychiatrists. Even in agitated patients who lack insight into their bizarre behaviour, mental health law allows for compulsory treatment of the mental disorder only, and physical treatments (antibiotics, intravenous fluids, surgery) cannot be forced on patients under this legislation.
From this point on, I will consider only psychiatric diagnoses. The first three diagnoses listed in box 3 should be treated in the same way because they are all a “first episode.” Decisions to prescribe mood stabilisers are usually made during subsequent episodes of bipolar affective disorder and schizoaffective disorder.4 10 Of the remaining diagnoses (box 3), depression is the most common and easily treated,11 and like all affective psychoses has a relatively good prognosis.12 Delusional disorder is a persistent, non-organic, non-affective psychotic disorder, without protracted hallucinations or negative symptoms. Post-traumatic stress disorder and obsessive compulsive disorder have prominent anxiety symptoms, driven by understandable (non-psychotic) processes. The last three possibilities are lifelong disorders, identified by collateral history. All can have episodes of psychosis, but residual disabilities of the underlying disorder persist beyond the treatment episode.
I find that having psychosis is horrible, but unless I'm acting strangely no one knows and I'm expected to seem normal. I hear very distressing voices all the time and occasionally get weird delusions and see things in a way that other people say are not real. I've been admitted to hospital and sectioned several times because of it.
When I first arrive at the hospital I hate the fact that my liberty has been curtailed, but after a while it's a relief not to have the responsibility of trying to take care of myself. I know it's time to go home when I start resenting the hospital again.
Finding the right medication can be difficult—I have the misfortune of getting terrible side effects from many of them. However, by trial and error I have eventually found something that doesn't make me too uncomfortable and makes the voices quieter. Now of course I'm reluctant to try the new ones in case they cause problems or don't work properly.
The most complicated thing in day to day life is trying to work out what sensory input is real without having to keep asking people. I also have to try to make sure I don't get tired or stressed.
Which treatment setting?
Non-organic psychoses are best treated by mental health services in the least restrictive setting. Even with sophisticated community services, more than 70% of patients with a first episode of psychosis are admitted to psychiatric hospital. Open discussion can achieve consensual admission. Patients with psychosis who decline further treatment are assessed under mental health legislation on the grounds of danger to self (suicide, unsafe behaviours, exploitation by others) or danger to others (overarousal, risk of acting on delusions, potential harm to others). In England and Wales, the Mental Health Act (1983) requires two independent doctors and an approved social worker to agree on involuntary committal to a psychiatric hospital. Psychosis is a disruptive and distressing experience; inpatient units need to be adapted to support rather than confront, and seclusion or “intensive care units” should be considered as last resorts. Accreditation for acute inpatient mental health services (www.rcpsych.ac.uk) sets out minimum and desirable standards. Older adults, adolescents, and postpartum women have complex needs and require admission to specialist units. Early detection, perhaps through specialised teams with allied strategies (public education, liaison with schools and general practitioners) have the potential to reduce admissions.13
Additional educational resources
Resources for healthcare professionals
Sims A. Symptoms in the mind. 3rd ed. London: Saunders, 1995
World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: WHO, 1992
Taylor D, Paton C, Kerwin RW. The Maudsley 2005-2006 prescribing guidelines. 8th ed. London: Taylor and Francis, 2005.
American Psychiatric Association Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 1997;154:1-63
American Psychiatric Association Practice guideline for the treatment of patients with bipolar disorder. Am J Psychiatry 1994;151:1-36
Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for the Treatment of Schizophrenia and Related Disorders. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders. Aust N Z J Psychiatry 2005;39:1-30
Resources for patients
If necessary, search within these sites for “early intervention” and “psychosis”
Early Prevention Psychosis Intervention Centre, Australia (www.eppic.org.au/)—This site sets out the gold standard for early intervention
National Institute for Mental Health in England (www.nimhe.csip.org.uk/)—Highlights patient care and carer information and other educational issues. The largest grouping in the Knowledge Community resource (http://kc.csip.org.uk/) is for psychosis. This links to NICE treatment guidelines on psychosis
Initiative to Reduce the Impact of Schizophrenia (www.iris-initiative.org.uk/)—This site offers a range of toolkits, protocols, and checklists to ensure best practice
Prevention and Early Intervention Programme for Psychosis (www.pepp.ca/)
Rethink, carers' and service users' organisation (www.rethink.org/)—Sets out practical advice, with excellent links; for example, the Early Psychosis Declaration, 2004
Royal College of Psychiatrists (www.rcpsych.ac.uk)—Help is at Hand leaflets and Accreditation for Acute Inpatient Mental Health Services are free to download
Psychosis sucks (www.psychosissucks.ca/)—This Canadian site has a wealth of plain English information for people with psychosis, with multiple translations
Schizophrenia (www.schizophrenia.com/)—An extensive, regularly updated news archive with interesting blogs
How do I manage a patient with acute psychosis?
One antipsychotic drug should be given at the lowest effective dose (table 2⇓). It is safer to achieve sedation with benzodiazepines (as required), rather than antipsychotics. Choosing a highly sedating antipsychotic drug at this stage can impede discharge later (box 4). All hospitals and trusts have clear guidelines on rapid tranquillisation of patients with psychosis; these monitor for side effects and complications.10 Typical antipsychotic drugs cause extrapyramidal side effects and raised prolactin (which causes sexual dysfunction and galactorrhoea) at therapeutic doses, as do most atypical antipsychotic drugs at higher doses. Typical antipsychotics have greater anticholinergic (dry mouth, tachycardia, urinary obstruction, etc) and antiadrenergic (postural hypotension, impotence) effects. All antipsychotics cause sedation to varying degrees and lower seizure threshold, especially clozapine. All antipsychotics, except for ziprasidone (not available in the UK) and aripiprazole,10 cause weight gain and impaired glucose tolerance. Typical and atypical antipsychotics probably increase the risk of thromboembolic disease equally.w3 Amisulpride and aripiprazole offer relatively lower risks of QTc prolongation on electrocardiography.10 Interactions between subclinical effects on the cardiovascular system and the metabolic syndrome are possible beyond the first episode, so body weight and blood monitoring (table 1⇑) should be repeated in three months, then yearly. The metabolic syndrome (box 5) is often seen in people with chronic psychoses given their unhealthy life styles,14 and is linked to all antipsychotics, most notably atypicals. The syndrome comprises a combination of insulin resistance and its physiological consequences—for example, a 20% increase in major coronary events over 10 years.15 Waist circumference (box 5) seems to be the best predictor of metabolic syndrome.
Box 4 Management principles in acute psychosis
Identify and change environmental factors16 that perpetuate psychotic symptoms
Listening to the patient's relatives is the best way to catch relapse earlier and identify harmful components of the ward environment
Consult with an early intervention team at the beginning of treatment, not the end
Test for, and persuade or intervene against, persistent substance misuse
For patients with mania use benzodiazepines with antipsychotics as adjuncts; for patients with schizophrenia use antipsychotics with benzodiazepines as adjuncts
Document frequency of nursing observations (blood pressure, temperature, pulse rate)
Monitor fluid balance (input and output) and body weight daily in acutely ill patients
When (not if) new symptoms occur, consider unwanted drug effects
Physical examination is an essential part of regular clinical review
Start psychosocial interventions at the earliest opportunity
Allied professionals—housing workers, peer workers (former patients who work with health professionals in early intervention teams), and other support workers—are invaluable in facilitating early discharge and preventing readmission
Box 5 Definition of metabolic syndrome15
Three or more of the following (the first three findings are the most common)
Abdominal obesity: waist circumference >102 cm in men, >88 cm in women
Hypertension: blood pressure ≥130/85 mm Hg
Serum triglycerides >1.69 mmol/l
Fasting plasma glucose >6.1 mmol/l
Serum high density lipoprotein <1.04 mmol/l in men, <1.29 mmol/l in women
One meta-analysis reported that five of seven atypical drugs had significant advantages over typical antipsychotics in the treatment of acute psychosis; quetiapine and aripiprazole did not achieve significance (table 2⇑).w4 The advantages of atypical drugs over typical drugs in the longer term are more marginal,w5 and one non-industry trial found no additional benefits of atypicals (excluding clozapine) for either patient preference or quality of life markers.w6 A multicentre trial of haloperidol and olanzepine measured brain volume in seven primary “magnetic resonance imaging regions of interest” over two years.9 Patients in the haloperidol group lost grey matter volume, mostly during the first 12 weeks of treatment, and these losses correlated with negative clinical outcomes. They could not conclude that haloperidol failed to prevent volume loss, or caused it, or that olanzepine halted loss.9 The choice of antipsychotic drug is best made in consultation with the patient, in the context of psychosocial interventions that promote recovery. Clozapine should be considered earlier in patients who do not respond to two antipsychotics, but many patients decline clozapine because weekly blood tests are needed to detect early signs of a low white blood cell count. Fish oils are a worthwhile option, but only as an addition to standard treatment.10
Given the adverse effects of antipsychotic drugs, non-pharmacological treatments (table 3⇓) should be more widely available, but this seems to be limited by ward culture and lack of suitably trained staff. Evidence supporting psychological interventions is strong enough to recommend their use in all treatment guidelines.17 Cognitive behaviour therapy reduces the impact of symptoms,w25 and family interventions prevent relapse.w26 Both achieve an agreed, individualised plan to recognise relapse earlier. Practitioners of cognitive behaviour therapy have challenged traditional assumptions about delusions to gain a shared understanding of the origins of beliefs and explore alternative explanations: disturbances in intrinsic thinking and subcultural beliefs (ideas common in the young adult age group most likely to develop non-organic psychosis) may underlie delusions.18 Family interventions are best carried out early in the course of illness, while the patient still lives at home. Family interventions have the advantage of benefits for other family members and greater acceptability and than drug treatments (drop-out rates are lower). Psychoeducational interventions are brief, cheap, and require less staff training. Most patients with a first episode of psychosis have misused substances; abstinence improves their prognosis, and if they continue to abstain their outcomes at 18 months are better than those for patients who have never misused substances.19
Role of the general practitioner in diagnosis and treatment
Psychosis subtly changes how patients you know well interact with you
The extent of symptoms and changes in social functioning determine the diagnosis and predict recovery
First episode psychosis is a useful diagnosis in itself; time will determine the final diagnosis
Key risks are suicide and aggression, especially in over-aroused patients bewildered by their symptoms
All patients with new psychosis need mental health referral; patients at risk should be referred that day
Joint care monitors physical health needs and the effects of drugs, and looks out for deteriorations in function and other signs of relapse
What happens next?
Box 6 shows possible outcomes of standard care, on the basis of two reviews.7 20 Between 30% and 60% of patients with a first episode of psychosis receiving interventions from UK community mental health teams had a good outcome at three years.12 Among those patients who do not respond to treatment initially, 16% have a good recovery at 15 years.7 These patients, who have a complex long term illness and a high risk of relapse, are best managed in specialist settings. Early intervention teams provide phase specific treatments, integrated case management, and cognitive behaviour therapy interventions.13 A randomised clinical trial has shown the value of integrated care in patients with a first episode of psychosis.21 Patterns of symptoms change over time and a modular form of cognitive behaviour therapy meets people's needs most effectively. Early intervention teams reduce the duration of untreated psychosis.13 22 Despite early misgivings among researchers, duration of untreated psychosis is a remediable, independent predictor of worse outcome.w35 Social functioning and vocational outcomes at 18 months are significantly improved by early intervention teams.23 Excess deaths including suicide are seen in all patients with a first episode of psychosis,7 but a fall in suicide rates in people with schizophrenia has been attributed to reduced access to lethal methods and better treatment (from early intervention teams).24 The evidence supporting early intervention teams is better than that justifying the current practice of standard care.w36 One key research question remains: “Do specialised early intervention teams offer improvements in outcome over and above those provided by phase-specific interventions alone?”w36
Box 6 Relapse and recovery after a psychotic episode
Relapse at one year20
Antipsychotic drug treatment but no psychosocial interventions
40% of all patients; 62% if in a stressful environment
27% of patients with a first episode of psychosis; 48% of patients with five or more previous episodes
Placebo treatment and no psychosocial interventions
61% of patients with a first episode of psychosis; 87% of patients with five or more previous episodes
Antipsychotic drug treatment and psychosocial intervention(s)
19% with family education; 20% after social skills training; 0% with both interventions; 38% for controls (antipsychotic drug treatment alone). A total of 103 patients from stressful environments were studied
Recovery (defined as global assessment of function >60) at 15-25 years' follow-up7
37.8% of patients with schizophrenia
54.8% of patients with other psychoses
After recovery (full or partial), a single antipsychotic drug is given prophylactically, usually at a lower dose than that needed for treating acute illness (table 2⇑). Treatment of a first episode is recommended for one year, followed by gradual cessation in asymptomatic patients at low risk. Risk of relapse is indicated by residual disability, family history of psychosis, or current substance misuse. Patients at risk and those with multiple psychotic episodes require longer prophylaxis. Patients with a history of violence need more intensive case management to reduce risk, and this may include prolonged medication under supervision. Given the high personal and health service costs of relapse, decisions about discontinuation and prophylaxis should be agreed with early intervention teams. Several early models for intervention teams have been described, with varying resource implications.25 The subject of treatment resistant psychosis has been discussed by others.10 26 Multiple coordinated interventions at adequate doses with verified adherence, including clozapine as a third line drug, must be applied before “treatment failure” is confirmed.
Early intervention teams accommodate diagnostic uncertainty in some patients, and for most patients coordinated interventions maximise functioning and prevent relapse. These teams and their advocates (users, carers, and people outside the health professions) have brought enthusiasm and innovation to a large number of patients in whom “cure” was previously the exception rather than the rule. We still await the “perfect” antipsychotic drug, where improved efficacy is not undermined by disabling, initially hidden, side effects. Trials of cognitive behaviour therapy and family interventions, with more sophisticated treatments than used heretofore, will identify specific components that improve recovery and reduce relapse further.
Competing interests: None declared.
Provenance and peer review: Commissioned; peer reviewed.