Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

Correction to: Practical issues and limitations of brain attenuation correction on a simultaneous PET-MR scanner.

An amendment to this paper has been published and can be accessed via the original article.

Practical issues and limitations of brain attenuation correction on a simultaneous PET-MR scanner.

BACKGROUND: Despite the advent of clinical PET-MR imaging for routine use in 2011 and the development of several methods to address the problem of attenuation correction, some challenges remain. We have identified and investigated several issues that might affect the reliability and accuracy of current attenuation correction methods when these are implemented for clinical and research studies of the brain. These are (1) the accuracy of converting CT Hounsfield units, obtained from an independently acquired CT scan, to 511 keV linear attenuation coefficients; (2) the effect of padding used in the MR head coil; (3) the presence of close-packed hair; (4) the effect of headphones. For each of these, we have examined the effect on reconstructed PET images and evaluated practical mitigating measures. RESULTS: Our major findings were (1) for both Siemens and GE PET-MR systems, CT data from either a Siemens or a GE PET-CT scanner may be used, provided the conversion to 511 keV µ-map is performed by the PET-MR vendor's own method, as implemented on their PET-CT scanner; (2) the effect of the head coil pads is minimal; (3) the effect of dense hair in the field of view is marked (> 10% error in reconstructed PET images); and (4) using headphones and not including them in the attenuation map causes significant errors in reconstructed PET images, but the risk of scanning without them may be acceptable following sound level measurements. CONCLUSIONS: It is important that the limitations of attenuation correction in PET-MR are considered when designing research and clinical PET-MR protocols in order to enable accurate quantification of brain PET scans. Whilst the effect of pads is not significant, dense hair, the use of headphones and the use of an independently acquired CT-scan can all lead to non-negligible effects on PET quantification. Although seemingly trivial, these effects add complications to setting up protocols for clinical and research PET-MR studies that do not occur with PET-CT. In the absence of more sophisticated PET-MR brain attenuation correction, the effect of all of the issues above can be minimised if the pragmatic approaches presented in this work are followed.

Making decisions about antipsychotics: a qualitative study of patient experience and the development of a decision aid.

BACKGROUND: Shared decision making is a widely accepted standard of patient-centred care that leads to improved clinical outcomes, yet it is commonly underutilised in the field of mental health. Furthermore, little is known regarding patient decision making around antipsychotic medication, which is often poorly adhered to. We aim to explore psychiatric patients' experiences of antipsychotic medication decision making in order to develop a patient decision aid to promote shared decision making. METHODS: Focus groups were conducted with patients with chronic psychotic illnesses (n = 20) who had previously made a decision about taking or changing antipsychotic medication. Transcripts were coded and analysed for thematic content and continued until thematic saturation. These themes subsequently informed the development of a decision aid with the help of expert guidance. Further patient input was sought using the think aloud method (n = 3). RESULTS: Twenty-three patients participated in the study. Thematic analysis revealed that 'adverse effects' was the most common theme identified by patients surrounding antipsychotic medication decision-making followed by 'mode and time of administration', 'symptom control' and 'autonomy'. The final decision aid is included to provoke further discussion and development of such aids. CONCLUSIONS: Patients commonly report negative experiences of antipsychotic medication, in particular side-effects, which remain critical to future decision making around antipsychotic medication. Clinical encounters that increase patient knowledge and maximise autonomy in order to prevent early negative experiences with antipsychotic medication are likely to be beneficial.

Correction: Regulation of dopaminergic function: An [18F]-DOPA PET apomorphine challenge study in humans.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Correction: Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Correction: Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

The effects of serotonin modulation on medial prefrontal connectivity strength and stability: A pharmacological fMRI study with citalopram.

BACKGROUND: Static and dynamic functional connectivity are being increasingly used to measure the effects of disease and a range of different interventions on brain networks. While preliminary evidence suggests that static connectivity can be modulated by chronic antidepressants administration in healthy individuals and in major depression, much less is known about the acute effects of antidepressants especially on dynamic functional connectivity changes. Here we examine acute effects of antidepressants on dynamic functional connectivity within the default mode network. The default mode network is a well described network with many functions in which the role of serotonin is not clear. METHODS: In this work we measured acute pharmacological effects of an infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg) in a sample of thirteen healthy volunteers randomised to receive on two occasions the active compound or placebo in a cross over dosing. RESULTS: Acute citalopram administration relative to placebo increased static connectivity between the medial prefrontal cortex and right dorsolateral prefrontal cortex and posterior cingulate cortex. The SSRI also induced a reduction in variability of connectivity with the medial prefrontal cortex in the precuneus and posterior cingulate cortex. DISCUSSION: The measured changes are compatible with modified serotonin cortical availability.

Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia.

OBJECTIVE: Treatment resistance is a challenge for the management of schizophrenia. It is not always clear whether inadequate response is secondary to medication ineffectiveness, as opposed to medication underexposure due to non-adherence or pharmacokinetic factors. We investigated the prevalence of subtherapeutic antipsychotic plasma levels in patients identified as treatment-resistant by their treating clinician. METHOD: Between January 2012 and April 2017, antipsychotic plasma levels were measured in 99 individuals provisionally diagnosed with treatment-resistant schizophrenia by their treating clinicians, but not prescribed clozapine. Patients were followed up to determine whether they were subsequently admitted to hospital. RESULTS: Thirty-five per cent of plasma levels were subtherapeutic, and of these, 34% were undetectable. Black ethnicity (P = 0.006) and lower dose (P < 0.001) were significantly associated with subtherapeutic/undetectable plasma levels. Individuals with subtherapeutic/undetectable levels were significantly more likely to be admitted to hospital (P = 0.02). CONCLUSION: A significant proportion of patients considered treatment-resistant have subtherapeutic antipsychotic plasma levels, and this is associated with subsequent admission. The presence of subtherapeutic plasma levels may suggest a need to address adherence or pharmacokinetic factors as opposed to commencing clozapine treatment. While antipsychotic levels are not recommended for the routine adjustment of dosing, they may assist with the assessment of potential treatment resistance in schizophrenia.

The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders.

Ketamine is a non-competitive antagonist at the N-methyl-d-aspartate receptor. It has recently been found to have antidepressant effects and is a drug of abuse, suggesting it may have dopaminergic effects. To examine the effect of ketamine on the dopamine systems, we carried out a systematic review and meta-analysis of dopamine measures in the rodent, human and primate brain following acute and chronic ketamine administration relative to a drug-free baseline or control condition. Systematic search of PubMed and PsychInfo electronic databases yielded 40 original peer-reviewed studies. There were sufficient rodent studies of the acute effects of ketamine at sub-anaesthetic doses for meta-analysis. Acute ketamine administration in rodents is associated with significantly increased dopamine levels in the cortex (Hedge's g= 1.33, P<0.01), striatum (Hedge's g=0.57, P<0.05) and the nucleus accumbens (Hedge's g=1.30, P<0.05) compared to control conditions, and 62-180% increases in dopamine neuron population activity. Sub-analysis indicated elevations were more marked in in vivo (g=1.93) than ex vivo (g=0.50) studies. There were not enough studies for meta-analysis in other brain regions studied (hippocampus, ventral pallidum and cerebellum), or of the effects of chronic ketamine administration, although consistent increases in cortical dopamine levels (from 88 to 180%) were reported in the latter studies. In contrast, no study showed an effect of anaesthetic doses (>100 mg kg-1) of ketamine on dopamine levels ex vivo, although this remains to be tested in vivo. Findings in non-human primates and in human studies using positron emission tomography were not consistent. The studies reviewed here provide evidence that acute ketamine administration leads to dopamine release in the rodent brain. We discuss the inter-species variation in the ketamine induced dopamine release as well as the implications for understanding psychiatric disorders, in particular substance abuse, schizophrenia, and the potential antidepressant properties of ketamine, and comparisons with stimulants and other NMDA antagonists. Finally we identify future research needs.

Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis.

Animal models of psychosis propose that abnormal hippocampal activity drives increased subcortical dopamine function, which is thought to contribute to aberrant salience processing and psychotic symptoms. These effects appear to be mediated through connections between the hippocampus, ventral striatum/pallidum and the midbrain. The aim of the present study was to examine the activity and connectivity in this pathway in people at ultra high risk (UHR) for psychosis. Functional magnetic resonance imaging was used to compare neural responses in a hippocampal-basal ganglia-midbrain network during reward, novelty and aversion processing between 29 UHR subjects and 32 healthy controls. We then investigated whether effective connectivity within this network is perturbed in UHR subjects, using dynamic causal modelling (DCM). Finally, we examined the relationship between alterations in activation and connectivity in the UHR subjects and the severity of their psychotic symptoms. During reward anticipation, UHR subjects showed greater activation than controls in the ventral pallidum bilaterally. There were no differences in activation during novelty or aversion processing. DCM revealed that reward-induced modulation of connectivity from the ventral striatum/pallidum to the midbrain was greater in UHR subjects than controls, and that in UHR subjects, the strength of connectivity in this pathway was correlated with the severity of their abnormal beliefs. In conclusion, ventral striatal/pallidal function is altered in people at UHR for psychosis and this is related to the level of their psychotic symptoms.

Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors.

BACKGROUND: We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors. METHOD: The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance. RESULTS: From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset. CONCLUSIONS: The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression.

The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review.

Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration) and postsynaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor-binding potential and locomotor activity after amphetamine administration). Our findings show that many but not all DISC1 models display (1) increased locomotion after amphetamine administration, (2) increased dopamine levels after amphetamine administration in the nucleus accumbens, and (3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how DISC1, and potentially DISC1-interacting proteins such as AKT and GSK-3, could be used as novel therapeutic targets for schizophrenia.

Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans.

Dopaminergic function has a key role in normal brain function, dopaminergic dysfunction being implicated in numerous neuropsychiatric disorders. Animal studies show that dopaminergic stimulation regulates dopaminergic function, but it is not known whether this exists in humans. In the first study (study 1), we measured dopamine synthesis capacity (indexed as Kicer) to identify the relationship between baseline and change in Kicer under resting conditions for comparison with effects of dopaminergic stimulation. In the second study (study 2), we used a within-subjects design to test effects of dopaminergic stimulation on dopamine synthesis capacity. In study 1, eight volunteers received two 18F-DOPA scans on separate days, both at rest. In study 2, 12 healthy male volunteers received two 18F-DOPA positron emission tomographic (PET) scans after treatment with either the dopamine partial agonist apomorphine (0.03 or 0.005 mg kg-1) or placebo. In study 1, no significant correlation was found between baseline and change in dopamine synthesis capacity between scans (r=-0.57, n=8, P=0.17, two-tailed). In study 2, a significant negative correlation was found between baseline dopamine synthesis capacity and percentage change in dopamine synthesis capacity after apomorphine challenge (r=-0.71, n=12, P=0.01, two-tailed). This correlation was significantly different (P<0.01) from the correlation between baseline and change in dopamine synthesis capacity under unstimulated conditions. One-way repeated-measures analysis of variance showed a significant group (study 1/study 2) × time interaction (F(1,18)=11.5, P=0.003). Our findings suggest that regulation of dopamine synthesis capacity by apomorphine depends on baseline dopamine function, consistent with dopamine stimulation stabilizing dopaminergic function. Loss of this autoregulation may contribute to dopaminergic dysfunction in brain disorders such as schizophrenia, substance dependence, and Parkinson's disease.

Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization.

An interaction between external stressors and intrinsic vulnerability is one of the longest standing pathoaetiological explanations for schizophrenia. However, novel lines of evidence from genetics, preclinical studies, epidemiology and imaging have shed new light on the mechanisms that may underlie this, implicating microglia as a key potential mediator. Microglia are the primary immune cells of the central nervous system. They have a central role in the inflammatory response, and are also involved in synaptic pruning and neuronal remodeling. In addition to immune and traumatic stimuli, microglial activation occurs in response to psychosocial stress. Activation of microglia perinatally may make them vulnerable to subsequent overactivation by stressors experienced in later life. Recent advances in genetics have shown that variations in the complement system are associated with schizophrenia, and this system has been shown to regulate microglial synaptic pruning. This suggests a mechanism via which genetic and environmental influences may act synergistically and lead to pathological microglial activation. Microglial overactivation may lead to excessive synaptic pruning and loss of cortical gray matter. Microglial mediated damage to stress-sensitive regions such as the prefrontal cortex and hippocampus may lead directly to cognitive and negative symptoms, and account for a number of the structural brain changes associated with the disorder. Loss of cortical control may also lead to disinhibition of subcortical dopamine-thereby leading to positive psychotic symptoms. We review the preclinical and in vivo evidence for this model and consider the implications this has for treatment, and future directions.

Longitudinal alterations in motivational salience processing in ultra-high-risk subjects for psychosis.

BACKGROUND: Impairments in the attribution of salience are thought to be fundamental to the development of psychotic symptoms and the onset of psychotic disorders. The aim of the present study was to explore longitudinal alterations in salience processing in ultra-high-risk subjects for psychosis. METHOD: A total of 23 ultra-high-risk subjects and 13 healthy controls underwent functional magnetic resonance imaging at two time points (mean interval of 17 months) while performing the Salience Attribution Test to assess neural responses to task-relevant (adaptive salience) and task-irrelevant (aberrant salience) stimulus features. RESULTS: At presentation, high-risk subjects were less likely than controls to attribute salience to relevant features, and more likely to attribute salience to irrelevant stimulus features. These behavioural differences were no longer evident at follow-up. When attributing salience to relevant cue features, ultra-high-risk subjects showed less activation than controls in the ventral striatum at both baseline and follow-up. Within the high-risk sample, amelioration of abnormal beliefs over the follow-up period was correlated with an increase in right ventral striatum activation during the attribution of salience to relevant cue features. CONCLUSIONS: These findings confirm that salience processing is perturbed in ultra-high-risk subjects for psychosis, that this is linked to alterations in ventral striatum function, and that clinical outcomes are related to longitudinal changes in ventral striatum function during salience processing.

Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses.

BACKGROUND: Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated. METHOD: This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not. RESULTS: Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25-4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44-9.56); and patients of male gender (OR 3.13 95% CI 1.35-7.23). CONCLUSIONS: For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.