Research underscores importance of early intervention in psychosis

A newly published study by Irish clinicians suggests that the advantages of early detection and intervention for psychosis endure for at least 20 years. Senior Author and Consultant Psychiatrist Prof Mary Clarke spoke to Catherine Reilly about the findings

Anew study by Irish clinicians, published in April in the American Journal of Psychiatry, has provided “important and sound support” for the long-term impact of duration of untreated psychosis (DUP) on clinical, functional, and quality-of-life outcomes. That is according to an editorial in the journal by Prof Ashok Malla, Professor of Psychiatry at McGill University, Canada, and a leading global expert on psychosis.

The longitudinal study, led by researchers at the DETECT (Dublin and East Treatment and Early Care Team) Early Intervention in Psychosis Service, and the RCSI University of Medicine and Health Science, suggested that the advantages of early detection and intervention for psychosis endure for at least 20 years.

It established that people with longer delays in treatment had worse outcomes 20 years later in terms of symptoms (eg, hallucinations and social withdrawal), functioning (eg, employment status), and quality-of-life (eg, satisfying interpersonal relationships).

The authors found that while associations between delayed treatment and worse long-term outcome can vary depending on what outcome is measured, they are sustained across decades in a way that could not be explained by other factors.

“There were questions as to whether that relationship endured over the 20-year period, and we certainly found that it did,” Prof Mary Clarke, Senior Author, Clinical Professor of Psychiatry at University College Dublin and Consultant Psychiatrist at DETECT Early Intervention in Psychosis Service, told the Medical Independent (MI)

The study is believed to be the first to systematically examine DUP-outcome relationships among a first-episode psychosis (FEP) incidence cohort, at multiple, sequential time points, over a 20-year period. It was supported by the St John of God Research Foundation through funding from the Health Research Board and the Stanley Medical Research Institute, US.

Participants

The research involves 171 participants who first presented with psychosis to Cluain Mhuire Mental Health Service or St John of God Hospital in Dublin between 1995 and 1999. Of these 171 participants, outcome measures were provided by 170 at baseline, 116 at six-month, 136 at four-year, 113 at eight-year, 136 at 12-year, and 80 at 20year follow-ups.

Prof Clarke was also involved in the initial study in 1995. She said the research team has been fortunate to have supportive funders and participants who demonstrated great altruism. “Because these kinds of studies are very hard to do. And increasingly, with data protection legislation, they do become trickier,” she told MI “But I think it was a great reflection on the altruism of people who came back time after time, in the knowledge that they were not necessarily going to benefit from the study, but were hoping to help others.”

She said the results highlighted the importance of ensuring that people with a diagnosis of psychosis have timely access to evidence-based treatments. The findings also underscored the importance of investing in research that aims to improve the outcome of psychotic illnesses.

Earlier findings from this study provided the rationale and evidence-base to establish the DETECT Early Intervention in Psychosis Service at St John of God community services, which was the first early detection and intervention service for psychosis in Ireland.

In 2019 the HSE National Clinical Programme for

Early Intervention in Psychosis (EIP) published a model of care document, which noted extensive evidence showing that intervening early in psychotic disorders was associated with numerous benefits. These included lower levels of symptom severity, suicidality, and death; lower risks of progression to more enduring stages of psychosis; and better rates of remission, recovery, and relapse prevention.

Under the model of care, EIP services should be established throughout the HSE mental health system to ensure everyone aged 14 to 65, presenting with FEP to mental health services, has access to EIP services for up to three years. The development of EIP services nationally is ongoing.

Holistic

Evidence-based interventions for FEP include pharmacotherapy; physical health monitoring and lifestyle interventions; psychological therapies; family interventions; and social, occupational, and educational interventions.

According to Prof Clarke, the evidence now supports a “more holistic” approach to treatment of psychosis. Medication remains an important intervention, particularly at the initial stages.

“I think over the past 20 years [internationally] we have seen a huge interest and expansion in psychological services, particularly cognitive behavioural therapy for the treatment of psychosis,” she noted.

There is increased recognition of the physical healthcare requirements of patients. In Ireland, the area of physical health monitoring requires ongoing improvement, confirmed Prof Clarke.

“A lot of the evidence is showing that people with psychosis have poor physical health and tend to die 10 to 15 years earlier than the general population, despite improvements in the general population healthcare, and the biggest cause of mortality in psychosis actually is cardiovascular disease.”

There is a “big emphasis” on ensuring people are educated and informed about the importance of looking after their cardiovascular health, the benefits of exercise, and potential side-effects of medication.

Medication for psychosis has the potential to raise glucose and cholesterol and cause weight gain. These changes “can happen quite quickly and can happen at an early stage, so that is the emphasis from the beginning, to be aware of it and educate people about it and also to educate the families about it”. Some of the medications are more prone to causing weight gain than others and it is important that this is monitored.

Physical activity has several benefits for people affected by psychosis. There is evidence that exercise can help with anxiety and mood symptoms, while research is ongoing into whether it can have a positive impact on some symptoms of psychosis. In addition, physical activity has a social aspect and helps with integration into the community.

“We have our own physical health programme here, which is tailored for people with serious mental illness, which we run within our mental health services in partnership with Dún Laoghaire-Rathdown Sports Partnership,” stated Prof Clarke.

Psychotic disorders, such as schizophrenia and mood disorders (with psychosis), affect about 3 per cent of the population in their lifetime. Each year in Ireland, approximately 1,300 adults and 230 adolescents develop a psychotic disorder for the first time.

The three years after FEP is regarded as a crucial period in terms of maximising improvement.

Some people develop psychosis very acutely and it is evident they are unwell. However, the signs may be subtle for many others. “Making a diagnosis of psychosis, particularly in the initial stages, can be quite complicated,” noted Prof Clarke.

On whether there were additional training requirements for GPs, Prof Clarke said: “I think the GPs do a fantastic job in picking up people with the signs and symptoms of psychosis and referring them on to the mental health services.” She said services, such as the DETECT Early Intervention in Psychosis Service and the national clinical programme, were conscious of the need to do more educational work with GP colleagues, “who do a great job.”

Another important message involves recovery. At 20year follow-up in the study, 26 of the 80 participants were not receiving any antipsychotic treatment and, according to Prof Clarke, this reflected the fact that many people recover from psychosis.

“The key message is at least a third of people will have one psychotic episode and make a full recovery, so it was not surprising that there were people taking no medication and who had fully recovered.”

Prof Clarke underlined that the earlier a person receives treatment for psychosis, the better the outcomes, as has been accepted for many physical illnesses. She said this is important to communicate to people.

PRESCRIBING INFORMATION (PI)

RINVOQ® (upadacitinib) 15 mg and 30mg prolonged-release tablets. Refer to Summary of Product Characteristics (SmPC) for full prescribing information. PRESENTATION: Each 15 mg prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15mg of upadacitinib. Each 30mg prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg of upadacitinib. INDICATION: Treatment of moderate to severe active rheumatoid arthritis (RA) and active psoriatic arthritis (PsA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate. Treatment of active ankylosing spondylitis (AS) in adult patients who have responded inadequately to conventional therapy. Treatment of moderate to severe atopic dermatitis (AD) in adults and adolescents 12 years and older who are candidates for systemic therapy. DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of conditions for which upadacitinib is indicated. Dosage: RA, PsA and AS: The recommended oral dose is 15mg once daily. Consideration should be given to discontinuing treatment in patients with AS who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. AD (adults): The recommended oral dose is 15 mg or 30 mg once daily based on individual patient presentation. 30 mg once daily dose may be appropriate for patients with high disease burden and for patients with an inadequate response to 15 mg once daily. The lowest effective dose for maintenance should be considered. For patients ≥ 65 years of age, the recommended dose is 15mg once daily. AD (adolescents from 12 to 17 years): The recommended oral dose is 15mg once daily for adolescents weighing at least 30 kg. Adults and adolescents 12 years and older: Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used for sensitive areas such as the face, neck, and intertriginous and genital areas. Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment. Special Populations: Elderly: For AD, doses higher than 15mg once daily not recommended in patients aged 65 years and older. Limited data for patients aged 75 and older. Renal: No dose adjustment required in mild-moderate renal impairment. Upadacitinib 15mg once daily should be used with caution in patients with severe renal impairment. Upadacitinib 30 mg once daily is not recommended for patients with severe renal impairment. Upadacitinib has not been studied in subjects with end stage renal disease. Hepatic impairment: No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Should not be used in patients with severe (Child Pugh C) hepatic impairment. Paediatric Population: No data available in the following paediatric patient populations: children with AD below the age of 12 years; children and adolescents with RA, PsA and AS aged 0 to less than 18 years. CONTRAINDICATIONS: Hypersensitivity to active substance or excipients. Active tuberculosis (TB) or active serious infections. Severe hepatic impairment. Pregnancy. SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as the risk of additive immunosuppression cannot be excluded. Serious infections: Serious and fatal infections have been reported. Caution when treating patients ≥65 years. Frequently reported – pneumonia and cellulitis. Bacterial meningitis has been reported. Opportunistic infections reported –TB, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis. Do not initiate treatment in patients with active, serious infection, including localised infections. Consider the risk/benefit of treatment in patients with: chronic or recurrent infection, history of serious or opportunistic infection, those exposed to TB, those who have resided or travelled in areas of endemic TB or endemic mycoses, those with underlying conditions that may pre-dispose patients to infection. Closely monitor patients and interrupt treatment if there are signs and symptoms of infection pre and post treatment. Tuberculosis: Pre-screen patients for active or latent TB. RINVOQ should not be given to patients with active TB. Consider anti-TB therapy in patients with previously untreated latent TB or in patients with risk factors for TB infection. Consult with a physician with experience in TB therapy to assess whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Viral reactivation: Cases of herpes virus reactivation have been reported e.g. herpes zoster. If herpes zoster is reactivated, consider interruption of upadacitinib therapy until the episode resolves. Screen for viral hepatitis and monitor regularly for reactivation before starting and during therapy with upadacitinib. Patients, positive for hepatitis C antibody/hepatitis C virus RNA and hepatitis B surface antigen/hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted. Vaccination: Use of live, attenuated vaccines during or immediately prior to therapy is not recommended. It is recommended that patients be brought up to date with all immunisations, including

THE ITCH & RASH OF MODERATE TO SEVERE ATOPIC DERMATITIS

RINVOQ demonstrated in an integrated analysis of the MEASURE UP 1 & 2 monotherapy studies at Week 16:

• EASI 75 skin clearance rates of 76% and 65% for patients treated with RINVOQ 30 mg QD and 15 mg QD, respectively, vs 15% with placebo (p<0.001 for both comparisons)2

• Itch reduction (mean percent change from baseline in Worst Pruritus NRS) of –70% and –58% for RINVOQ 30 mg QD and 15 mg QD, respectively, vs –24% with placebo (p<0.001 for both comparisons)2 prophylactic zoster vaccinations prior to starting therapy, in agreement with current immunisation guidelines. Malignancy: Immunomodulatory therapies may increase the risk of malignancies including lymphoma and nonmelanoma skin cancer in RA patients. Malignancies were observed in clinical studies. Periodic skin examination recommended for patients who are at increased risk for skin cancer. See SmPC for full details. Haematological abnormalities: Do not start therapy if Absolute Neutrophil Count <1 x 109 cells/L, Absolute Lymphocyte Count <0.5 x 109 cells/L and Hb <8 g/dL. Monitor patients and temporarily stop therapy if abnormal haematological parameters as specified are detected during routine patient management. Diverticulitis: Events of diverticulitis have been reported in clinical trials and post-marketing. Upadacitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis to prevent gastrointestinal perforation. Cardiovascular Risk: RA patients have an increased risk for cardiovascular disorders. Manage patient’s risk factors for e.g. hypertension, hyperlipidaemia as per usual standard of care. Lipids: Monitor total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) at 12 weeks and thereafter according to international guidelines. Elevated LDL in clinical trials decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Hepatic transaminase elevations: Monitor liver enzymes at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. In such cases therapy should be interrupted until this diagnosis is excluded. Venous thromboembolism: Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAKi, including upadacitinib. Use therapy with caution in patients at high risk for DVT/PE. Risk factors should be determined by patients age, obesity and medical history of DVT/PE, patients undergoing major surgery and prolonged immobilisation. If clinical features of DVT/PE occur discontinue therapy, evaluate and treat promptly. INTERACTIONS: Upadacitinib is metabolised mainly by CYP3A4 and plasma exposures may be affected by CYP3A4 inhibitors or inducers. Upadacitinib 15 mg once daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Upadacitinib 30 mg once daily dose is not recommended for patients receiving chronic treatment with strong CYP3A4 inhibitors. See SmPC for full details. FERTILITY, PREGNANCY AND LACTATION: Upadacitinib is contraindicated during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment and for 4 weeks following the final dose of upadacitinib. Female paediatric patients and/or their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib. Upadacitinib should not be used during breast-feeding. The effect of upadacitinib on human fertility has not been evaluated. ADVERSE REACTIONS: Refer to SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): upper respiratory tract infections, acne. Common adverse reactions (≥1/100 to <1/10): bronchitis, herpes zoster, herpes simplex, folliculitis, influenza, anaemia, neutropaenia, hypercholesterolaemia, cough, abdominal pain, nausea, urticaria, fatigue, pyrexia, increased blood CPK/ALT/AST, increased weight and headache. This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; website: www.hpra.ie.

LEGAL CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBER/ PRESENTATION: EU/1/19/1404/001 and EU/1/19/1404/006 – Calendar blister packs containing 28 prolonged-release tablets. MARKETING

AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany. Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland.

DATE OF REVISION: December 2021. PI-1404-005

Abbreviations: EASI – eczema activity and severity index; NRS – numerical rating scale; QD – once daily; EU – European Union.

* The recommended dose of RINVOQ is 15mg once daily for adolescents weighing at least 30kg. The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years have not been established. No data are available. No clinical exposure data are available in adolescents <40kg. The posology in adolescent patients 30kg to <40kg was determined using population pharmacokinetic modelling and simulation.2

Reference: 1. Langan S. et al. Atopic dermatitis. The Lancet. 2020;396(10247):345-360. DOI: https://doi.org/10.1016/ S0140-6736(20)31286-1.

2. RINVOQ Summary of Product Characteristics, available on www.medicines.ie

3. Baricitinib Summary of Product Characteristics, available on www.medicines.ie 4. Abrocitinib Summary of Product Characteristics, available on www.medicines.ie