20‐11‐2015 Psychosis: an illness of young Improving conditions for recovery: people low-dose antipsychotic treatment n First manifestations usually start at 15-25 years of strategies in first episode age psychosis n Incidence around 1.5 : 10,000 n Most important cause of functional problems: school, relationships, daily living Lex Wunderink, Roeline Nieboer, Durk Wiersma, Sjoerd Sytema, Fokko Nienhuis n Tending to persist and relapse through life n In all countries, in all social strata November 17, 2015 n Risk factors: living in bad neighbourhood, adverse First European Conference on Supported Education life events, being member of ethnic minority Groningen, The Netherlands Psychosis as a model of a mental Detection of early stages of illness disturbing social skills psychosis n Young people with vague feelings of distress n Insidious onset with social withdrawal, strange convictions, less interest in social activities n Socially isolated or withdrawn n Often: depression, lack of goals in life, bogging n Having few or no friends down in futile plans, having no inner compass n Feeling different, low self esteem n Social functioning and capacities are often n Decreasing school performance, low grades threatened to some degree n Experiencing psychic phenomena, like n Alternated with stormy episodes of emotional supernatural signs, hearing your own thoughts turmoil, fears, hallucinations and delusions: aloud, hearing others talking about you the first episode of psychosis 1
20‐11‐2015 Treatment in the early stages to Treatment of psychosis, once there prevent mental illness n Usually starts from the first stormy (psychotic) n No medication, no antipsychotics episode n Offering true support in daily life, particularly school- n Psychosocial treatments too much neglected performance n With antipsychotic drugs n Peer-group support n Usually recommended by doctors to be continued n Cognitive behavioural therapy for years n Trauma treatment if needed n In order to prevent relapse of symptoms Psychosocial interventions can reduce development n Presumed to help recovery and improve of severe mental illness with 50% (from >20% to 10%) functioning by reducing symptoms 2
20‐11‐2015 A true dilemma Significant cortical thinning • medicated patient group relative to the control group • medicated patient group relative to the unmedicated patient group No significant cortical thickness differences • unmedicated patient group relative to the control group However: better cognitive performance in medicated patients compared to unmedicated patients JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.2178 Published online January 14, 2015. What do antipsychotics do? About the role of dopamine n All antipsychotics block dopamine (D-2 receptors) n Gears drive, curiosity, attention, stamina n Antipsychotic effect is directly correlated with the n Important to executive behaviors, reaching goals, amount of dopamine blockade making sacrifices (reward system) n Reduce hallucinations and delusions n The dopamine system is recruted when situations n But have no effect, or even worsen negative ask for it: stress, chance of gaining rewards, when symptoms: lack of drive, indifference, apathy extra strong reaction to environmental stimuli is needed What is the purpose of the dopamine system? n Adds salience to selected sensory objects 3
20‐11‐2015 On the role of dopamine in Dopamine-derangement and psychosis, put simply psychosis Dopaminergic derangement might be caused by n n Too much dopamine activity is related to hyper - disregulation of the excitation/inhibition balance in cortical areas, caused by an as yet unknown primary disturbance salience and active psychosis: hearing voices, delusions Dopaminergic blockade might be considered a symptomatic n therapy targeting a consequence of a primary disturbance n Lack of dopamine activity is associated with lack of higher upstream drive and lack of being able to pursue goals: apathy, indifference, emotional flattening n Antipsychotics block dopamine, so: Hypothesis: you need dopamine blockade to stop and u Reduce symptoms: hallucinations and delusions prevent the production of positive symptoms, but it u Induce & worsen functional and cognitive impairments does not touch the underlying disorder that causes functional deficits, and might even worsen these. All or nothing phenomenon: too little or too much Vast amount of robust evidence on But what about functional the effectiveness of antipsychotics outcome? to stop and prevent delusions and hearing voices n Almost no experimental data on functional measures n Higher relapse rates were demonstrated in all trials n Having no symptoms does not automatically imply comparing placebo with active medication functional recovery n Robust evidence that longer duration of untreated n Negative symptoms might be worsened by psychosis has negative impact on prognosis dopamine blockade n Evidence that this includes relapse duration n Brain integrity might be further challenged by antipsychotics 4
20‐11‐2015 We did an RCT in remitted FEP Original discontinuation trial comparing dose-reduction and maintenance strategy Key question In dose-reduction/discontinuation compared to maintenance we hypothesized: Is maintenance treatment after remission of a first episode of psychosis really the best option? Better Quality of Life and Functioning levels Probably at the cost of: Higher relapse rates Consort flow chart Design of the study Oct 2001 through Dec 2002 257 eligible for trial 100 meeting criteria but refusing Onset Entry & Response Start experimental phase psychosis Selection or lost to follow-up Discontinuation Challenge 157 randomised 8 nonremitting Ta T0 T6 T15 T24 9 relapsing Maintenance Treatment 1 suicide 1 st assessment 2 nd assessment 3 rd assessment 4 th assessment 11 informed consent withdrawn Informed consent “Unblinding” Randomization randomization 128 trial group at T5 5
20‐11‐2015 What we found after 2 7-years follow-up years… Only 21.5% could be completely taken off drugs n n Aim: to compare rates of recovery No difference in quality of life between arms n No difference in functioning level, but better vocational n Long-term effects of early dose n functioning, bordering on significance reduction/discontinuation strategies on (35% vs. 17%, OR=2.4, P = .06) recovery have not been studied before Twice as many relapses in dose-reduction/discontinuation n strategy vs. maintenance treatment: 42% against 21% in n 103 (80,5%) of 128 patients were located and 18 months consented to follow-up assessment No gains, but more relapses, though benign and relatively n No controlled treatment during interim period mild; no impact on inpatient days or symptom severity Definitions of recovery, symptomatic and Recovery, symptomatic and functional functional remission remission after 7 years n Recovery = meeting criteria for symptomatic and DR (n=52) MT (n=51) Total functional remission during 6 months sample (n=103) n Symptomatic remission: meeting working group criteria (Andreasen et al, 2005) Recovery 21 (40.4%) 9 (17.6%) 30 (29.1) n Functional remission: no or only mild impairment on any of the social functioning domains, measured by Symptom 36 (69.2%) 34 (66.7%) 70 (68.0) remission the Groningen Social Disability Scale: self-care, housekeeping, family relationships, relationships Functional 24 (46.2%) 10 (19.6%) 34 (33.0) with peers, community integration, and vocational remission functioning 6
20‐11‐2015 Relapse rates over 7 years of follow-up Predictors of recovery, symptomatic and functional Kaplan Meier survival analysis of time to first relapse after first remission during 7 years of follow-up in patients receiving Guided Discontinuation (GD) or Maintenance Treatment (MT) from t6 (start of trial after 6 months of first remission, logistic regression remission) to t90 (final follow-up) Recovery: n u Negative symptoms OR = .845, df = 1, P = .007 u Living together OR = 4.444, df = 1, P = .011 u Trial arm (DR) OR = 3.489, df = 1, P = .014 Symptomatic remission n u DUP OR = .616, df = 1, P = .021 Functional remission n u Negative symptoms OR = .852, df = 1, P = .021 u Living together OR = 4.682, df = 1, P = .010 u Social functioning OR = .857, df = 1, P = .040 u Trial arm (DR) OR = 4.617, df = 1, P = .004 Antipsychotic dose during the last Dose-reduction is the best! 2 years of follow-up n Dose reduction/discontinuation strategy in remitted mean daily haloperidol equivalents after 7 years n FEP yields twice as many recovered patients u DR: 2.20 mg (SD 2.27) (40.4% vs. 17.6%) u MT: 3.60 mg (SD 4.01) u Significant difference: t = -2.185, P = .031 n No difference in symptom remission rates without patients who completely stopped antipsychotics (69.2% vs. 66.7%) n (11 in DR and 6 in MT) n Though relapse rates on the short term are twice u DR: 2.79 mg (SD 2.21) as high, on the long term they are equal (65% in 7 u MT: 4.08 mg (SD 4.03) years had at least 1 relapse) u Bordering on significance: t = -1.813, P = .073 7
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