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Case Study Illustrates How Schizophrenia Can Often Be Overdiagnosed

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Study shows how schizophrenia can often be over diagnosed. Learn how. Click to Tweet

Study author Russell Margolis, director of the Johns Hopkins Schizophrenia Center, answers questions on misdiagnosis of the condition and reiterates the importance of thorough examination.

It’s not uncommon for an adolescent or young adult who reports hearing voices or seeing things to be diagnosed with schizophrenia, but using these reports alone can contribute to the disease being overdiagnosed, says  Russell Margolis , clinical director of the Johns Hopkins Schizophrenia Center. 

Many clinicians consider hallucinations as the sine qua non, or essential condition, of schizophrenia, he says. But even a true hallucination might be part of any number of disorders — or even within the range of normal. To diagnose a patient properly, he says, “There’s no substitute for taking time with patients and others who know them well. Trying to [diagnose] this in a compressed, shortcut kind of way leads to error.”

A case study he shared recently in the  Journal of Psychiatric Practice  illustrates the problem. Margolis, along with colleagues Krista Baker, schizophrenia supervisor at Johns Hopkins Bayview Medical Center, visiting resident Bianca Camerini, and Brazilian psychiatrist Ary Gadelha, described a 16-year-old girl who was referred to the Early Psychosis Intervention Clinic at Johns Hopkins Bayview for a second opinion concerning the diagnosis and treatment of suspected schizophrenia.

The patient made friends easily but had some academic difficulties. Returning to school in eighth grade after a period of home schooling, she was bullied, sexually groped and received texted death threats. She then began to complain of visions of a boy who harassed her, as well as three tall demons. The visions waxed and waned in relation to stress at school. The Johns Hopkins consultants determined that this girl did not have schizophrenia (or any other psychotic disorder), but that she had anxiety. They recommended psychotherapy and viewing herself as a healthy, competent person, instead of a sick one. A year later, the girl reported doing well: She was off medications and no longer complained of these visions.

Margolis answers  Hopkins Brain Wise ’s questions.

Q: How are anxiety disorders mistaken for schizophrenia?

A:  Patients often say they have hallucinations, but that doesn’t always mean they’re experiencing a true hallucination. What they may mean is that they have very vivid, distressing thoughts — in part because hallucinations have become a common way of talking about distress, and partly because they may have no other vocabulary with which to describe their experience. 

Then, even if it  is  a true hallucination, there are features of the way psychiatry has come to be practiced that cause difficulties. Electronic medical records are often designed with questionnaires that have yes or no answers. Sometimes, whether the patient has hallucinations is murky, or  possible —  not yes or no. Also, one can’t make a diagnosis based just on a hallucination; the diagnosis of disorders like schizophrenia is based on a constellation of symptoms. 

Q: How often are patients in this age range misdiagnosed?

A:  There’s no true way to know the numbers. Among a very select group of people in our consultation clinic where questions have been raised, about half who were referred to us and said to have schizophrenia or a related disorder did not. That is not generalizable.

Q:   Why does that happen?

A:  There is a lack of attention to the context of symptoms and other details, and there’s also a tendency to take patients literally. If a patient complains about x, there’s sometimes a pressure to directly address x. In fact, that’s not appropriate medicine. It is very important to pay attention to a patient’s stated concerns, but to place these concerns in the bigger picture. Clinicians can go too far in accepting at face value something that needs more exploration. 

Q: What lessons do you hope to impart by publishing this case?

A:  I want it to be understood that the diagnosis of schizophrenia has to be made with care. Clinicians need to take the necessary time and obtain the necessary information so that they’re not led astray. Eventually, we would like to have more objective measures for defining our disorders so that we do not need to rely totally on a clinical evaluation. 

Learn more about Russell Margolis’ research regarding the challenges of diagnosing schizophrenia .

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Standardized uptake value (SUV) ratios of the bilateral ACC and hippocampus were compared between patients with schizophrenia and healthy controls. Statistical significance was determined as a false discovery rate (FDR)–corrected P < .05. The center horizontal bars indicate means; the outer horizontal bars indicate 95% CIs.

Pearson correlation analysis between standardized uptake value (SUV) ratios of the bilateral anterior cingulate cortex (ACC) and positive symptom scores on the Positive and Negative Syndrome Scale (PANSS; range, 7-49, with higher scores indicating the greater severity of positive symptoms) was performed. Statistical significance was determined as a false discovery rate (FDR)–corrected P < .05.

The orange lines indicate regression lines.

eMethods. Sample Size Determination and Fluorine 18–Labeled THK 5351 Preparation

eTable 1. Pearson Correlation Analysis Between the Altered Standardized Uptake Ratio of Fluorine 18– Labeled THK5351 in Primary Regions of Interest and Positive Symptom Severity in Patients With Schizophrenia

eTable 2. Group Comparison Results of the Standardized Uptake Value Ratio of Fluorine 18– Labeled THK5351 in Secondary Regions of Interest

eTable 3. Pearson Correlation Analysis Between Altered Standardized Uptake Ratio of Fluorine 18– Labeled THK5351 in Primary Regions of Interest and Olanzapine-Equivalent Dose of Antipsychotics as Well as Duration of Illness in Patients With Schizophrenia

eFigure 1. Schematic Diagram of Fluorine 18– Labeled THK 5351 Positron Emission Tomography Analysis

 eFigure 2. Group Comparison of Fluorine 18– Labeled THK5351 Standardized Uptake Value Ratios

eReferences

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Kim M , Choi W , Choi S, et al. In Vivo Reactive Astrocyte Imaging in Patients With Schizophrenia Using Fluorine 18–Labeled THK5351. JAMA Netw Open. 2024;7(5):e2410684. doi:10.1001/jamanetworkopen.2024.10684

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In Vivo Reactive Astrocyte Imaging in Patients With Schizophrenia Using Fluorine 18–Labeled THK5351

• 1 Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Republic of Korea
• 2 Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
• 3 Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, Seoul, Republic of Korea
• 4 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
• 5 Department of Radiology, Seoul National University College of Medicine, Seoul, Republic of Korea
• 6 Department of Public Health Medical Services, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
• 7 Department of Psychiatry, Seoul Metropolitan Government–Seoul National University Boramae Medical Center, Seoul, Republic of Korea
• 8 Institute of Human Behavioral Medicine, Seoul National University–Medical Research Center, Seoul, Republic of Korea

Question   Can region-specific reactive astrocytes in vivo associated with positive symptoms in patients with schizophrenia be measured using fluorine 18–labeled THK5351 ([ 18 F]THK5351) positron emission tomography?

Findings   In this case-control study of 68 participants, standardized uptake value ratios (SUVrs) of [ 18 F]THK5351 in the bilateral anterior cingulate cortex and left hippocampus were greater in patients with schizophrenia than in healthy controls. Increased [ 18 F]THK5351 SUVrs were correlated with positive symptom severity in patients with schizophrenia.

Meaning   Considering the role of astrocytes in brain development, neurotransmission, and immune reactions, reactive astrocytes in the bilateral anterior cingulate cortex and left hippocampus may be strong biomarkers for schizophrenia pathophysiology and treatment.

Importance   In vivo imaging studies of reactive astrocytes are crucial for understanding the pathophysiology of schizophrenia because astrocytes play a critical role in glutamate imbalance and neuroinflammation.

Objective   To investigate in vivo reactive astrocytes in patients with schizophrenia associated with positive symptoms using monoamine oxidase B (MAO-B)–binding fluorine 18 ([ 18 F])–labeled THK5351 positron emission tomography (PET).

Design, Setting, and Participants   In this case-control study, data were collected from October 1, 2021, to January 31, 2023, from the internet advertisement for the healthy control group and from the outpatient clinics of Seoul National University Hospital in Seoul, South Korea, for the schizophrenia group. Participants included patients with schizophrenia and age- and sex-matched healthy control individuals.

Main Outcomes and Measures   Standardized uptake value ratios (SUVrs) of [ 18 F]THK5351 in the anterior cingulate cortex (ACC) and hippocampus as primary regions of interest (ROIs), with other limbic regions as secondary ROIs, and the correlation between altered SUVrs and Positive and Negative Syndrome Scale (PANSS) positive symptom scores.

Results   A total of 68 participants (mean [SD] age, 32.0 [7.0] years; 41 men [60.3%]) included 33 patients with schizophrenia (mean [SD] age, 32.3 [6.3] years; 22 men [66.7%]) and 35 healthy controls (mean [SD] age, 31.8 [7.6] years; 19 men [54.3%]) who underwent [ 18 F]THK5351 PET scanning. Patients with schizophrenia showed significantly higher SUVrs in the bilateral ACC (left, F = 5.767 [false discovery rate (FDR)–corrected P = .04]; right, F = 5.977 [FDR-corrected P  = .04]) and left hippocampus ( F = 4.834 [FDR-corrected P  = .04]) than healthy controls. Trend-level group differences between the groups in the SUVrs were found in the secondary ROIs (eg, right parahippocampal gyrus, F = 3.387 [ P  = .07]). There were positive correlations between the SUVrs in the bilateral ACC and the PANSS positive symptom scores (left, r  = 0.423 [FDR-corrected  P = .03]; right, r  = 0.406 [FDR-corrected  P = .03]) in patients with schizophrenia.

Conclusions and Relevance   This case-control study provides novel in vivo imaging evidence of reactive astrocyte involvement in the pathophysiology of schizophrenia. Reactive astrocytes in the ACC may be a future target for the treatment of symptoms of schizophrenia, especially positive symptoms.

Glutamatergic imbalance and neuroinflammation are believed to be important in schizophrenia pathophysiology. The glutamate hypothesis suggests that psychotic symptoms are caused by N -methyl- d -aspartate receptor hypofunction-mediated abnormal glutamatergic neurotransmission with a dysfunctional thalamic filter system. 1 - 3 Furthermore, excessive glutamate activity might lead to excitotoxic damage and oxidative stress–related neuroinflammation, which further explains the pathophysiology. 4 , 5 This finding is consistent with the immune hypothesis suggesting the involvement of neuroinflammation caused by microglial overactivation in the development and progression of schizophrenia. 6 - 9

Previous magnetic resonance (MR) spectroscopy studies have revealed that patients with schizophrenia exhibit altered glutamate and/or glutamine levels in several brain regions, including the anterior cingulate cortex (ACC) and hippocampus, although the direction and degree of alterations have been inconsistent. 10 - 13 Among individuals at clinically high risk for psychosis, the baseline hippocampal glutamate level was suggested to be associated with the transition to psychotic disorder. 14 In vivo microglial imaging studies using 18-kDa translocator protein positron emission tomography (PET) to detect neuroinflammation in the frontal cortex, ACC, temporal cortex, and hippocampus of patients with schizophrenia have also provided inconsistent results. 15 - 18 These inconsistencies may be due to the simple approach of using individual glutamate or neuroinflammation markers in a rather complex, mutually influencing system. However, investigations aimed at integrating glutamate imbalance and neuroinflammation in the pathophysiology of schizophrenia are limited, and only 1 study 5 has attempted to bridge the gap between the 2 hypotheses by showing that the levels of the antioxidant glutathione and excitotoxic glutamate and/or glutamine are lower in patients with schizophrenia who are in stable clinical condition.

Reactive astrocytes are promising candidates for achieving a comprehensive understanding of glutamate imbalance and neuroinflammation in the pathophysiology of schizophrenia because astrocytes play an important role in glutamate recycling, neurotransmission (including dopamine), and the neuroimmune system, in addition to their basic role in supporting neurons. 19 - 21 Reactive astrocytes are remodeled in response to injury, disease, or infection of the brain and can be measured in vivo by detecting overexpressed monoamine oxidase B (MAO-B) on the outer mitochondrial membrane. 22 In patients with schizophrenia, abnormal astrocyte-neuronal interactions have been suggested to be the mechanism of psychotic symptom development, 2 and alterations in the expression of astrocyte-related genes and their products in patients’ postmortem brains have been reported. 23 However, in vivo reactive astrocyte imaging has not yet been reported in patients with schizophrenia.

In this study, we investigated the in vivo imaging of reactive astrocytes and their association with positive symptoms in patients with schizophrenia using validated MAO-B–binding fluorine 18 ([ 18 F])–labeled THK5351 PET 24 - 26 to obtain a more comprehensive understanding of the role of reactive astrocytes in schizophrenia pathophysiology. The primary regions of interest (ROIs) were the ACC and hippocampus based on previous studies of glutamate imbalance, neuroinflammation, and positive symptom development in patients with schizophrenia. 10 , 13 , 16 , 27 The secondary ROIs included other limbic regions, such as the posterior cingulate cortex (PCC), parahippocampal gyrus, amygdala, insula, and nucleus accumbens, based on previous studies 28 , 29 that reported the association between glutamate alterations and positive symptoms in these regions in patients with schizophrenia.

This case-control study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline. All participants provided written informed consent after receiving a thorough explanation of the study procedure. The study was conducted in accordance with the Declaration of Helsinki 30 and was approved by the Institutional Review Board of Seoul National University Hospital.

A total of 33 patients with schizophrenia and 35 age- and sex-matched healthy controls participated in this study. All study participants were of East Asian descent. Information regarding the sample size calculation is provided in the eMethods in Supplement 1 . Patients with schizophrenia were recruited from the outpatient office of the Department of Neuropsychiatry at Seoul National University Hospital. The diagnosis of schizophrenia was confirmed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) Axis I Disorders (SCID-I) by board-certified psychiatrists (M.K., S.-Y.M., and S.K.L.). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). 31 The Hamilton Rating Scale for Depression 32 and the Hamilton Rating Scale for Anxiety 33 were used to measure the severity of depression and anxiety, respectively. The healthy controls were recruited via internet advertisement and were screened using the SCID-I Nonpatient Edition. Healthy controls were excluded if they had any past or current diagnosis of a psychiatric disorder and any first- to third-degree biological relatives with a psychotic disorder. In all participants, general functional status was evaluated using the modified Global Assessment of Functioning, and intelligent quotient (IQ) was measured with the Korean version of the Wechsler Adult Intelligence Scale. 34 The exclusion criteria included substance abuse or dependence (except nicotine), neurological disease or significant head trauma, medical illness that could accompany psychiatric symptoms, and intellectual disability (IQ < 70).

A PET-MR machine (Biograph mMR; Siemens Healthcare) was used to obtain dynamic 3-dimensional PET images. Immediately after an intravenous bolus injection of 185 MBq (5 mCi) of [ 18 F]THK5351, 27 frames of emission scans (8 × 15 seconds, 3 × 60 seconds, 5 × 120 seconds, and 11 × 300 seconds) and a total 70-minute PET scan were acquired while the participant was at rest. Fluorine 18–labeled THK5351 was synthesized and radiolabeled at Seoul National University Hospital, and details are provided in the eMethods in Supplement 1 . Each participant was fitted with an MR imaging coil and supporting cushion to reduce head motion during the PET scan, and the participants were asked to remain as still as possible during the scan.

Manufacturer’s software from the PET-MR device (e7tool; Siemens Healthcare) was used for the reconstruction of the PET data. The PET images were reconstructed using the ordered-subset expectation maximization algorithm with 24 subsets and 5 iterations. Images were filtered with a 4-mm full-width at half-maximum Gaussian filter at the center of the field of view (image matrix, 256 × 256; 127 sections; voxel size, 1.4 × 1.4 × 2.0 mm). Segmentation-based attenuation correction was conducted with a 3-tissue segmentation map acquired by an ultrashort echo time (TE) sequence (repetition time [TR], 11.9 milliseconds; TE 1, 0.07 milliseconds; TE 2, 2.46 milliseconds; flip angle, 10°; 192 × 192 matrix). A high-resolution structural T1 image (TE, 2.2 milliseconds; TR, 2400 milliseconds; flip angle, 8°; 0.85-mm section thickness) was also collected for each participant at the same time to rule out structural lesions in the brain and to provide an anatomical reference for the [ 18 F]THK5351 analysis.

All preprocessing was conducted using Statistical Parametric Mapping (SPM 12; Welcome Department of Imaging Neuroscience). The analysis flowchart and selected cerebellar lobules are presented in eFigure 1 in Supplement 1 .

For semiquantitative PET analysis, standardized uptake value ratios (SUVrs) were calculated in reference to the inferior cerebellar parcels of the cerebellar cortex. To delineate the inferior cerebellar ROI, the SUIT (spatially unbiased infratentorial template) toolbox, 35 which contains a high-resolution atlas template of the cerebellum and brainstem and individual T1 images, was used. The cerebellar structure was isolated from the cerebral structure and segmented into tissue types using the Dartel algorithm. Using the deformation field obtained during the Dartel procedure, the SUIT template was transferred to an individual PET space. The lobular ROIs that corresponded to the inferior cerebellar gray matter (bilateral Crus II, VIIb, VIIIa, VIIIb, and IX) were used to extract radioactivity from the PET image. After frame-by-frame motion correction of the PET image, the T1 images were coregistered to the mean images of 27 realigned PET frames.

The bilateral ACC and hippocampus, as primary ROIs, and other limbic regions (bilateral PCC, parahippocampal gyri, amygdala, insula, and nucleus accumbens), as secondary ROIs, were predefined using the Wake Forest University PickAtlas toolbox in SPM 12. 36 The predefined ROIs were transformed into PET standard space using the deformation matrix calculated from PET-coregistered T1 images, and SUVs were extracted for all PET frames to assess the time activity curve in each ROI. Finally, based on previous studies that tested the optimal time windows to estimate [ 18 F]THK5351 quantification, 37 the SUVr was calculated as the sum of 45- to 65-minute postinjection frames using the mean radioactivity of the inferior cerebellar ROI obtained by the SUIT procedure as a reference.

Data were collected from October 1, 2021, to January 31, 2023. Demographic and clinical characteristics were compared between patients with schizophrenia and healthy controls using an independent t test or a Welch t test if the variance was not equal and a χ 2 test or a Fisher exact test for categorical data. Group differences in the SUVr in the bilateral ACC and hippocampus (ie, primary ROIs) were tested using analysis of covariance, with age and sex as covariates. Pearson correlation analysis was performed to investigate the association between altered SUVrs in primary ROIs and PANSS positive symptom scores in patients with schizophrenia. To rule out the possible effect of the duration of illness or olanzapine-equivalent dose of antipsychotics prescribed at the time of study participation on the SUVrs of the primary ROIs, Pearson correlation analysis was performed. To account for multiple comparisons, a false discovery rate (FDR) correction was performed. Group differences in SUVrs in other limbic ROIs were assessed using repeated-measures analysis of variance (ANOVA), with brain regions (ie, bilateral PCC, parahippocampal gyri, amygdala, insula, and nucleus accumbens) as the within-participants factor and age and sex as covariates. All statistical analyses were performed in SPSS, version 25.0 for Windows (IBM Corporation), and the level of statistical significance was set at 2-sided P  < .05.

A total of 68 participants (mean [SD] age, 32.0 [7.0] years; 41 men [60.3%] and 27 women 39.7%]) included 33 patients with schizophrenia (mean [SD] age, 32.3 [6.3] years; 22 men [66.7%] and 11 women [33.3%]) and 35 healthy controls (mean [SD] age, 31.8 [7.6] years; 19 men [54.3%] and 16 women [45.7%]). Table 1 summarizes the demographic and clinical characteristics of the participants. There were no significant group differences in age or sex, while mean (SD) IQ (107.2 [12.5] vs 116.7 [11.0]; P  = .001) and modified Global Assessment of Functioning scores (54.1 [11.9] vs 87.3 [4.8]; P  < .001) were lower in patients with schizophrenia than in healthy controls. There were no significant group differences in the amount of [ 18 F]THK5351 injected.

According to the group comparison of primary ROIs, patients with schizophrenia had significantly greater SUVrs in the bilateral ACC (left, F = 5.767 [FDR-corrected  P = .04]; right, F = 5.977 [FDR-corrected  P = .04]) and left hippocampus ( F = 4.834 [FDR-corrected  P = .04]) than healthy controls ( Table 2 and Figure 1 ). There were positive correlations between the SUVrs in the bilateral ACC and the PANSS positive symptom scores (left, r  = 0.423 [FDR-corrected  P = .03]; right, r  = 0.406 [FDR-corrected  P = .03]) in patients with schizophrenia ( Figure 2 and eTable 1 in Supplement 1 ). Repeated-measures ANOVA revealed trend-level group differences in the SUVrs in the secondary ROIs (eg, right parahippocampal gyrus, F = 3.387 [ P  = .07]) (eFigure 2 and eTable 2 in Supplement 1 ). There was no correlation between the duration of illness or olanzapine-equivalent dose of antipsychotics prescribed at the time of study participation and the SUVrs of the primary ROIs (eTable 3 in Supplement 1 ).

In this study, we investigated in vivo reactive astrocyte imaging using MAO-B–binding [ 18 F]THK5351 PET to reveal the role of reactive astrocytes, which are involved in both glutamate imbalance and neuroinflammation, in schizophrenia pathophysiology. Patients with schizophrenia had elevated SUVrs in the bilateral ACC and left hippocampus compared with healthy controls. In addition, positive correlations between the SUVrs in the bilateral ACC and the PANSS-positive symptom scores were found in patients with schizophrenia. There were trend-level group differences in the SUVrs in other limbic regions investigated as secondary ROIs. The results of this study not only provide in vivo neuroimaging evidence of the role of reactive astrocytes in schizophrenia pathophysiology but also highlight the region-specific association between reactive astrocytes in the ACC and positive symptoms in patients with schizophrenia.

Our findings of elevated MAO-B–binding [ 18 F]THK5351 uptake in patients with schizophrenia suggest a role for reactive astrocytes in the neurodevelopmental abnormalities of these patients. Astrocytes are known to be important in neurodevelopment and to play a critical role in synapse formation and function as well as neuronal survival and migration; thus, abnormal astrocytes can increase the vulnerability of the brain to neurodevelopmental disorders such as schizophrenia. 38 , 39 Windrem et al 40 showed that mice chimerized with induced pluripotent stem cells derived from patients with childhood-onset schizophrenia exhibited problems with glial cells, including astrocytes, suggesting that genetic abnormalities in schizophrenia produce abnormalities in astrocytes, which are critical for brain development and schizophrenia pathophysiology. Thus, the results of the present study support the vulnerability and neurodevelopmental model of schizophrenia and suggest the role of reactive astrocytes in schizophrenia pathophysiology by providing in vivo neuroimaging evidence of reactive astrocytes in patients with schizophrenia.

Furthermore, the results of this study provide integrative supporting evidence for the glutamate and immune hypotheses in schizophrenia pathophysiology. Previous studies aimed at measuring glutamate and/or glutamine levels in patients with schizophrenia 11 , 13 have produced inconsistent results, which may be due to the lack of consideration of interacting systems other than glutamate. Microglial imaging studies using translocator protein PET to show neuroinflammation in patients with schizophrenia 16 , 18 have also provided insufficient evidence that may be caused by subtle changes in microglial activity. Astrocytes not only play important roles in glutamate cycling and synaptic transmission but also undergo astrogliosis in reaction to neuroinflammation, as shown in neuroinflammatory diseases such as Wilson disease and multiple sclerosis. 2 , 6 , 25 , 41 Therefore, the results of the present study support that both the glutamate and immune hypotheses can provide a more comprehensive understanding of the interaction between glutamate and the immune system in the pathophysiology of schizophrenia by revealing reactive astrocytes in vivo in patients with schizophrenia.

In the present study, elevated [ 18 F]THK5351 uptake was detected in the bilateral ACC and left hippocampus of patients with schizophrenia compared with healthy controls. These findings are consistent with previous studies 23 , 42 reporting that elevated astrocyte-, glutamate-, and immune-related genes and gene products were found in the postmortem brains of patients with schizophrenia. Previous neuroimaging studies targeting the glutamate system or neuroinflammation 13 , 14 , 16 , 28 , 43 have also reported alterations in the ACC and hippocampus, which are known to be important brain regions involved in schizophrenia. In addition, an elevated SUVr of MAO-B–binding [ 18 F]THK5351 in the bilateral ACC was positively correlated with positive symptom severity, as measured by the PANSS, in patients with schizophrenia. The ACC is one of the limbic cortices, and its role in fundamental cognitive processes, such as motivation, decision-making, and social cognition, which are impaired in patients with schizophrenia in relation to psychotic symptoms, has been highlighted. 44 , 45 A previous study from Kim et al, 46 which revealed that thalamocortical dysrhythmia represented by elevated resting-state theta phase–gamma amplitude coupling in the ACC of patients with schizophrenia spectrum disorder was positively correlated with symptom severity, also supported the association of reactive astrocytes in the ACC with positive symptoms. 2

This study has several limitations. First, the current study participants were patients with schizophrenia who had more than 5 years of antipsychotic treatment, although there have been suggestions of an association between prolonged exposure to antipsychotics and increased MAO-B expression in animal studies. 47 , 48 However, there have been no reports regarding the association between chronic antipsychotic exposure and MAO-B elevation in patients with schizophrenia, and a recent study 49 suggested that MAO-B detected by PET imaging is a target for novel drug development in patients with schizophrenia. 23 , 50 In addition, we did not find any correlation between the duration of illness or olanzapine-equivalent dose of antipsychotics prescribed at the time of study participation and the SUVrs of the primary ROIs. The current study results should be interpreted with caution because we did not perform this study in patients who were drug naive or with first-episode psychosis who may experience a minimal effect of antipsychotics on MAO-B expression. Second, because of the limitations of the MAO-B–detecting PET method, this study could only provide indirect evidence of reactive astrocytes in schizophrenia pathophysiology, as in previous animal, postmortem brain, and neuroimaging studies. 13 , 21 , 23 , 40 Further studies with direct methods to investigate astrocytes in patients with schizophrenia are warranted to confirm the role of reactive astrocytes in the pathophysiology of schizophrenia. Third, the results of the present study are exploratory findings that need further validation in other studies due to the small effect size associated with the small sample size and other limitations mentioned above.

This case-control study provides novel in vivo imaging evidence of reactive astrocyte involvement in the pathophysiology of schizophrenia. Considering the role of astrocytes in brain development, neurotransmission, and immune reactions, reactive astrocytes can be a strong biomarker for schizophrenia treatment. In particular, reactive astrocytes in the ACC may be a future target of neuromodulation therapeutics for the positive symptoms of schizophrenia. To support the findings of the present study, a more direct investigation of astrocytes generated by the reverse differentiation of induced pluripotent stem cells derived from patients with schizophrenia is needed.

Accepted for Publication: March 3, 2024.

Published: May 9, 2024. doi:10.1001/jamanetworkopen.2024.10684

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Kim M et al. JAMA Network Open .

Corresponding Author: Jun Soo Kwon, MD, PhD, Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-no, Chongno-gu, Seoul 03080, Republic of Korea ( [email protected] ).

Author Contributions: Drs M. Kim and Kwon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: M. Kim, Song, Lho, Kwon.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: M. Kim, Cho.

Critical review of the manuscript for important intellectual content: M. Kim, W. Choi, S. Choi, Oh, J. Kim, J. Lee, An, Hwang, Y.-S. Lee, Song, Moon, Lho, Kwon.

Statistical analysis: M. Kim, W. Choi, S. Choi, Cho.

Obtained funding: M. Kim, Kwon.

Administrative, technical, or material support: M. Kim, J. Lee, Y.-S. Lee, Song, Moon, Lho, Cho, Kwon.

Supervision: M. Kim, Song, Cho, Kwon.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was supported by the Basic Science Research Program, the Brain Pool Program, and the Brain Science Convergence Research Program through the National Research Foundation of Korea and the Basic Research Program of the Korea Brain Research Institute, funded by grants 2020M3E5D9079910, 2020H1D3A2A02085669, RS-2023-00266120, and 21-BR-03-01 from the Ministry of Science and Information and Communication Technology.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2 .

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• Open access
• Published: 24 February 2022

Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics

• Christoph U. Correll   ORCID: orcid.org/0000-0002-7254-5646 1 , 2 , 3 ,
• Amber Martin 4 ,
• Charmi Patel 5 ,
• Carmela Benson 5 ,
• Rebecca Goulding 6 ,
• Jennifer Kern-Sliwa 5 ,
• Kruti Joshi 5 ,
• Emma Schiller 4 &
• Edward Kim   ORCID: orcid.org/0000-0001-8247-6675 7  

Schizophrenia volume  8 , Article number:  5 ( 2022 ) Cite this article

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• Schizophrenia

Clinical practice guidelines (CPGs) translate evidence into recommendations to improve patient care and outcomes. To provide an overview of schizophrenia CPGs, we conducted a systematic literature review of English-language CPGs and synthesized current recommendations for the acute and maintenance management with antipsychotics. Searches for schizophrenia CPGs were conducted in MEDLINE/Embase from 1/1/2004–12/19/2019 and in guideline websites until 06/01/2020. Of 19 CPGs, 17 (89.5%) commented on first-episode schizophrenia (FES), with all recommending antipsychotic monotherapy, but without agreement on preferred antipsychotic. Of 18 CPGs commenting on maintenance therapy, 10 (55.6%) made no recommendations on the appropriate maximum duration of maintenance therapy, noting instead individualization of care. Eighteen (94.7%) CPGs commented on long-acting injectable antipsychotics (LAIs), mainly in cases of nonadherence (77.8%), maintenance care (72.2%), or patient preference (66.7%), with 5 (27.8%) CPGs recommending LAIs for FES. For treatment-resistant schizophrenia, 15/15 CPGs recommended clozapine. Only 7/19 (38.8%) CPGs included a treatment algorithm.

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Introduction.

Schizophrenia is an often debilitating, chronic, and relapsing mental disorder with complex symptomology that manifests as a combination of positive, negative, and/or cognitive features 1 , 2 , 3 . Standard management of schizophrenia includes the use of antipsychotic medications to help control acute psychotic episodes 4 and prevent relapses 5 , 6 , whereas maintenance therapy is used in the long term after patients have been stabilized 7 , 8 , 9 . Two main classes of drugs—first- and second-generation antipsychotics (FGA and SGA)—are used to treat schizophrenia 10 . SGAs are favored due to the lower rates of adverse effects, such as extrapyramidal effects, tardive dyskinesia, and relapse 11 . However, pharmacologic treatment for schizophrenia is complicated because nonadherence is prevalent, and is a major risk factor for relapse 9 and poor overall outcomes 12 . The use of long-acting injectable (LAI) versions of antipsychotics aims to limit nonadherence-related relapses and poor outcomes 13 .

Patient treatment pathways and treatment choices are determined based on illness acuity/severity, past treatment response and tolerability, as well as balancing medication efficacy and adverse effect profiles in the context of patient preferences and adherence patterns 14 , 15 . Clinical practice guidelines (CPG) serve to inform clinicians with recommendations that reflect current evidence from meta-analyses of randomized controlled trials (RCTs), individual RCTs and, less so, epidemiologic studies, as well as clinical experience, with the goal of providing a framework and road-map for treatment decisions that will improve quality of care and achieve better patients outcomes. The use of clinical algorithms or other decision trees in CPGs may improve the ease of implementation of the evidence in clinical practice 16 . While CPGs are an important tool for mental health professionals, they have not been updated on a regular basis like they have been in other areas of medicine, such as in oncology. In the absence of current information, other governing bodies, healthcare systems, and hospitals have developed their own CPGs regarding the treatment of schizophrenia, and many of these have been recently updated 17 , 18 , 19 . As such, it is important to assess the latest guidelines to be aware of the changes resulting from consideration of updated evidence that informed the treatment recommendations. Since CPGs are comprehensive and include the diagnosis as well as the pharmacological and non-pharmacological management of individuals with schizophrenia, a detailed comparative review of all aspects of CPGs for schizophrenia would have been too broad a review topic. Further, despite ongoing efforts to broaden the pharmacologic tools for the treatment of schizophrenia 20 , antipsychotics remain the cornerstone of schizophrenia management 8 , 21 . Therefore, a focused review of guideline recommendations for the management of schizophrenia with antipsychotics would serve to provide clinicians with relevant information for treatment decisions.

To provide an updated overview of United States (US) national and English language international guidelines for the management of schizophrenia, we conducted a systematic literature review (SLR) to identify CPGs and synthesize current recommendations for pharmacological management with antipsychotics in the acute and maintenance phases of schizophrenia.

Systematic searches for the SLR yielded 1253 hits from the electronic literature databases. After removal of duplicate references, 1127 individual articles were screened at the title and abstract level. Of these, 58 publications were deemed eligible for screening at the full-text level, from which 19 were ultimately included in the SLR. Website searches of relevant organizations yielded 10 additional records, and an additional three records were identified by the state-by-state searches. Altogether, this process resulted in 32 records identified for inclusion in the SLR. Of the 32 sources, 19 primary CPGs, published/issued between 2004 and 2020, were selected for extraction, as illustrated in the PRISMA diagram (Fig. 1 ). While the most recent APA guideline was identified and available for download in 2020, the reference to cite in the document indicates a publication date of 2021.

SLR systematic literature review.

Of the 19 included CPGs (Table 1 ), three had an international focus (from the following organizations: International College of Neuropsychopharmacology [CINP] 22 , United Nations High Commissioner for Refugees [UNHCR] 23 , and World Federation of Societies of Biological Psychiatry [WFSBP] 24 , 25 , 26 ); seven originated from the US; 17 , 18 , 19 , 27 , 28 , 29 , 30 , 31 , 32 three were from the United Kingdom (British Association for Psychopharmacology [BAP] 33 , the National Institute for Health and Care Excellence [NICE] 34 , and the Scottish Intercollegiate Guidelines Network [SIGN] 35 ); and one guideline each was from Singapore 36 , the Polish Psychiatric Association (PPA) 37 , 38 , the Canadian Psychiatric Association (CPA) 14 , the Royal Australia/New Zealand College of Psychiatrists (RANZCP) 39 , the Association Française de Psychiatrie Biologique et de Neuropsychopharmacologie (AFPBN) from France 40 , and Italy 41 . Fourteen CPGs (74%) recommended treatment with specific antipsychotics and 18 (95%) included recommendations for the use of LAIs, while just seven included a treatment algorithm Table 2 ). The AGREE II assessment resulted in the highest score across the CPGs domains for NICE 34 followed by the American Psychiatric Association (APA) guidelines 17 . The CPA 14 , BAP 33 , and SIGN 35 CPGs also scored well across domains.

Acute therapy

Seventeen CPGs (89.5%) provided treatment recommendations for patients experiencing a first schizophrenia episode 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 40 , 41 , but the depth and focus of the information varied greatly (Supplementary Table 1 ). In some CPGs, information on treatment of a first schizophrenia episode was limited or grouped with information on treating any acute episode, such as in the CPGs from CINP 22 , AFPBN 40 , New Jersey Division of Mental Health Services (NJDMHS) 32 , the APA 17 , and the PPA 37 , 38 , while the others provided more detailed information specific to patients experiencing a first schizophrenia episode 14 , 18 , 19 , 23 , 24 , 28 , 33 , 34 , 35 , 36 , 39 , 41 . The American Association of Community Psychiatrists (AACP) Clinical Tips did not provide any information on the treatment of schizophrenia patients with a first episode 29 .

There was little agreement among CPGs regarding the preferred antipsychotic for a first schizophrenia episode. However, there was strong consensus on antipsychotic monotherapy and that lower doses are generally recommended due to better treatment response and greater adverse effect sensitivity. Some guidelines recommended SGAs over FGAs when treating a first-episode schizophrenia patient (RANZCP 39 , Texas Medication Algorithm Project [TMAP] 28 , Oregon Health Authority 19 ), one recommended starting patients on an FGA (UNHCR 23 ), and others stated specifically that there was no evidence of any difference in efficacy between FGAs and SGAs (WFSBP 24 , CPA 14 , SIGN 35 , APA 17 , Singapore guidelines 36 ), or did not make any recommendation (CINP 22 , Italian guidelines 41 , NICE 34 , NJDMHS 32 , Schizophrenia Patient Outcomes Research Team [PORT] 30 , 31 ). The BAP 33 and WFBSP 24 noted that while there was probably no difference between FGAs and SGAs in efficacy, some SGAs (olanzapine, amisulpride, and risperidone) may perform better than some FGAs. The Schizophrenia PORT recommendations noted that while there seemed to be no differences between SGAs and FGAs in short-term studies (≤12 weeks), longer studies (one to two years) suggested that SGAs may provide benefits in terms of longer times to relapse and discontinuation rates 30 , 31 . The AFPBN guidelines 40 and Florida Medicaid Program guidelines 18 , which both focus on use of LAI antipsychotics, both recommended an SGA-LAI for patients experiencing a first schizophrenia episode. A caveat in most CPGs was that physicians and their patients should discuss decisions about the choice of antipsychotic and that the choice should consider individual patient factors/preferences, risk of adverse and metabolic effects, and symptom patterns 17 , 18 , 19 , 22 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 41 .

Most CPGs recommended switching to a different monotherapy if the initial antipsychotic was not effective or not well tolerated after an adequate antipsychotic trial at an appropriate dose 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 32 , 33 , 35 , 36 , 39 . For patients initially treated with an FGA, the UNHCR recommended switching to an SGA (olanzapine or risperidone) 23 . Guidance on response to treatment varied in the measures used but typically required at least a 20% improvement in symptoms (i.e. reduction in Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale scores) from pre-treatment levels.

Several CPGs contained recommendations on the duration of antipsychotic therapy after a first schizophrenia episode. The NJDMHS guidelines 32 recommended nine to 12 months; CINP 22 recommended at least one year; CPA 14 recommended at least 18 months; WFSBP 25 , the Italian guidelines 41 , and NICE 34 recommended 1 to 2 years; and the RANZCP 39 , BAP 33 , and SIGN 35 recommended at least 2 years. The APA 17 and TMAP 28 recommended continuing antipsychotic treatment after resolution of first-episode symptoms but did not recommend a specific length of therapy.

Twelve guidelines 14 , 18 , 22 , 24 , 28 , 30 , 31 , 33 , 34 , 35 , 36 , 39 , 40 (63.2%) discussed the treatment of subsequent/multiple episodes of schizophrenia (i.e., following relapse). These CPGs noted that the considerations guiding the choice of antipsychotic for subsequent/multiple episodes were similar to those for a first episode, factoring in prior patient treatment response, adverse effect patterns and adherence. The CPGs also noted that response to treatment may be lower and require higher doses to achieve a response than for first-episode schizophrenia, that a different antipsychotic than used to treat the first episode may be needed, and that a switch to an LAI is an option.

Several CPGs provided recommendations for patients with specific clinical features (Supplementary Table 1 ). The most frequently discussed group of clinical features was negative symptoms, with recommendations provided in the CINP 22 , UNHCR 23 , WFSBP 24 , AFPBN 40 , SIGN 35 , BAP 33 , APA 17 , and NJDMHS guidelines; 32 negative symptoms were the sole focus of the guidelines from the PPA 37 , 38 . The guidelines noted that due to limited evidence in patients with predominantly negative symptoms, there was no clear benefit for any strategy, but that options included SGAs (especially amisulpride) rather than FGAs (WFSBP 24 , CINP 22 , AFPBN 40 , SIGN 35 , NJDMHS 32 , PPA 37 , 38 ), and addition of an antidepressant (WFSBP 24 , UNHCR 23 , SIGN 35 , NJDMHS 32 ) or lamotrigine (SIGN 35 ), or switching to another SGA (NJDMHS 32 ) or clozapine (NJDMHS 32 ). The PPA guidelines 37 , 38 stated that the use of clozapine or adding an antidepressant or other medication class was not supported by evidence, but recommended the SGA cariprazine for patients with predominant and persistent negative symptoms, and other SGAs for those with full-spectrum negative symptoms. However, the BAP 33 stated that no recommendations can be made for any of these strategies because of the quality and paucity of the available evidence.

Some of the CPGs also discussed treatment of other clinical features to a limited degree, including depressive symptoms (CINP 22 , UNHCR 23 , CPA 14 , APA 17 , and NJDMHS 32 ), cognitive dysfunction (CINP 22 , UNHCR 23 , WFSBP 24 , AFPBN 40 , SIGN 35 , BAP 33 , and NJDMHS 32 ), persistent aggression (CINP 22 , WFSBP 24 , CPA 14 , AFPBN 40 , NICE 34 , SIGN 35 , BAP 33 , and NJDMHS 32 ), and comorbid psychiatric diagnoses (CINP 22 , RANZCP 39 , BAP 33 , APA 17 , and NJDMHS 32 ).

Fifteen CPGs (78.9%) discussed treatment-resistant schizophrenia (TRS); all defined it as persistent, predominantly positive symptoms after two adequate antipsychotic trials; clozapine was the unanimous first choice 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 . However, the UNHCR guidelines 23 , which included recommendations for treatment of refugees, noted that clozapine is only a reasonable choice in regions where white blood cell monitoring and specialist supervision are available, otherwise, risperidone or olanzapine are alternatives if they had not been used in the previous treatment regimen.

There were few options for patients who are resistant to clozapine therapy, and evidence supporting these options was limited. The CPA guidelines 14 therefore stated that no recommendation can be given due to inadequate evidence. Other CPGs discussed options (but noted there was limited supporting evidence), such as switching to olanzapine or risperidone (WFSBP 24 , TMAP 28 ), adding a second antipsychotic to clozapine (CINP 22 , NICE 34 , TMAP 28 , BAP 33 , Florida Medicaid Program 18 , Oregon Health Authority 19 , RANZCP 39 ), adding lamotrigine or topiramate to clozapine (CINP 22 , Florida Medicaid Program 18 ), combination therapy with two non-clozapine antipsychotics (Florida Medicaid Program 18 , NJDMHS 32 ), and high-dose non-clozapine antipsychotic therapy (BAP 33 , SIGN 35 ). Electroconvulsive therapy was noted as a last resort for patients who did not respond to any pharmacologic therapy, including clozapine, by 10 CPGs 17 , 18 , 19 , 22 , 24 , 28 , 32 , 35 , 36 , 39 .

Maintenance therapy

Fifteen CPGs (78.9%) discussed maintenance therapy to various degrees via dedicated sections or statements, while three others referred only to maintenance doses by antipsychotic agent 18 , 23 , 29 without accompanying recommendations (Supplementary Table 2 ). Only the Italian guideline provided no reference or comments on maintenance treatment. The CINP 22 , WFSBP 25 , RANZCP 39 , and Schizophrenia PORT 30 , 31 recommended keeping patients on the same antipsychotic and at the same dose on which they had achieved remission. Several CPGs recommended maintenance therapy at the lowest effective dose (NJDMHS 32 , APA 17 , Singapore guidelines 36 , and TMAP 28 ). The CPA 14 and SIGN 35 defined the lower dose as 300–400 mg chlorpromazine equivalents or 4–6 mg risperidone equivalents, and the Singapore guidelines 36 stated that the lower dose should not be less than half the original dose. TMAP 28 stated that given the relapsing nature of schizophrenia, the maintenance dose should often be close to the original dose. While SIGN 35 recommended that patients remain on the same antipsychotic that provided remission, these guidelines also stated that maintenance with amisulpride, olanzapine, or risperidone was preferred, and that chlorpromazine and other low-potency FGAs were also suitable. The BAP 33 recommended that the current regimen be optimized before any dose reduction or switch to another antipsychotic occurs. Several CPGs recommended LAIs as an option for maintenance therapy (see next section).

Altogether, 10/18 (55.5%) CPGs made no recommendations on the appropriate duration of maintenance therapy, noting instead that each patient should be considered individually. Other CPGs made specific recommendations: Both the Both BAP 33 and SIGN 35 guidelines suggested a minimum of 2 years, the NJDMHS guidelines 32 recommended 2–3 years; the WFSBP 25 recommended 2–5 years for patients who have had one relapse and more than 5 years for those who have had multiple relapses; the RANZCP 39 and the CPA 14 recommended 2–5 years; and the CINP 22 recommended that maintenance therapy last at least 6 years for patients who have had multiple episodes. The TMAP was the only CPG to recommend that maintenance therapy be continued indefinitely 28 .

Recommendations on the use of LAIs

All CPGs except the one from Italy (94.7%) discussed the use of LAIs for patients with schizophrenia to some extent. As shown in Table 3 , among the 18 CPGs, LAIs were primarily recommended in 14 CPGs (77.8%) for patients who are non-adherent to other antipsychotic administration routes (CINP 22 , UNHCR 23 , RANZCP 39 , PPA 37 , 38 , Singapore guidelines 36 , NICE 34 , SIGN 35 , BAP 33 , APA 17 , TMAP 28 , NJDMHS 32 , AACP 29 , Oregon Health Authority 19 , Florida Medicaid Program 18 ). Twelve CPGs (66.7%) also noted that LAIs should be prescribed based on patient preference (RANZCP 39 , CPA 14 , AFPBN 40 , Singapore guidelines 36 , NICE 34 , SIGN 35 , BAP 33 , APA 17 , Schizophrenia PORT 30 , 31 , AACP 29 , Oregon Health Authority 19 , Florida Medicaid Program 18 ).

Thirteen CPGs (72.2%) recommended LAIs as maintenance therapy 18 , 19 , 24 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 40 . While five CPGs (27.8%), i.e., AFPBN 40 , RANZCP 39 , TMAP 28 , NJDMHS 32 , and the Florida Medicaid Program 18 recommended LAIs specifically for patients experiencing a first episode. While the CPA 14 did not make any recommendations regarding when LAIs should be used, they discussed recent evidence supporting their use earlier in treatment. Five guidelines (27.8%, i.e., Singapore 36 , NICE 34 , SIGN 35 , BAP 33 , and Schizophrenia PORT 30 , 31 ) noted that evidence around LAIs was not sufficient to support recommending their use for first-episode patients. The AFPBN guidelines 40 also stated that LAIs (SGAs as first-line and FGAs as second-line treatment) should be more frequently considered for maintenance treatment of schizophrenia. Four CPGs (22.2%, i.e., CINP 22 , UNHCR 23 , Italian guidelines 41 , PPA guidelines 37 , 38 ) did not specify when LAIs should be used. The AACP guidelines 29 , which evaluated only LAIs, recommended expanding their use beyond treatment for nonadherence, suggesting that LAIs may offer a more convenient mode of administration or potentially address other clinical and social challenges, as well as provide more consistent plasma levels.

Treatment algorithms

Only Seven CPGs (36.8%) included an algorithm as part of the treatment recommendations. These included decision trees or flow diagrams that map out initial therapy, durations for assessing response, and treatment options in cases of non-response. However, none of these guidelines defined how to measure response, a theme that also extended to guidelines that did not include treatment algorithms. Four of the seven guidelines with algorithms recommended specific antipsychotic agents, while the remaining three referred only to the antipsychotic class.

LAIs were not consistently incorporated in treatment algorithms and in six CPGs were treated as a separate category of medicine reserved for patients with adherence issues or a preference for the route of administration. The only exception was the Florida Medicaid Program 18 , which recommended offering LAIs after oral antipsychotic stabilization even to patients who are at that point adherent to oral antipsychotics.

Benefits and harms

The need to balance the efficacy and safety of antipsychotics was mentioned by all CPGs as a basic treatment paradigm.

Ten CPGs provided conclusions on benefits of antipsychotic therapy. The APA 17 and the BAP 33 guidelines stated that antipsychotic treatment can improve the positive and negative symptoms of psychosis and leads to remission of symptoms. These CPGs 17 , 33 as well as those from NICE 34 and CPA 14 stated that these treatment effects can also lead to improvements in quality of life (including quality-adjusted life years), improved functioning, and reduction in disability. The CPA 14 and APA 17 guidelines noted decreases in hospitalizations with antipsychotic therapy, and the APA guidelines 17 stated that long-term antipsychotic treatment can also reduce mortality. The UNHCR 23 and the Italian 41 guidelines noted that early intervention increased positive outcomes. The WFSBP 24 , AFPBN 40 , CPA 14 , BAP 33 , APA 17 , and NJDMHS 32 affirmed that relapse prevention is a benefit of continued/maintenance treatment.

Some CPGs (WFSBP 24 , Italian 41 , CPA 14 , and SIGN 35 ) noted that reduced risk for extrapyramidal adverse effects and treatment discontinuation were potential benefits of SGAs vs. FGAs.

The risk of adverse effects (e.g., extrapyramidal, metabolic, cardiovascular, and hormonal adverse effects, sedation, and neuroleptic malignant syndrome) was noted by all CPGs as the major potential harm of antipsychotic therapy 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 29 , 30 , 31 , 32 , 34 , 35 , 36 , 37 , 39 , 40 , 41 , 42 . These adverse effects are known to limit long-term treatment and adherence 24 .

This SLR of CPGs for the treatment of schizophrenia yielded 19 most updated versions of individual CPGs, published/issued between 2004 and 2020. Structuring our comparative review according to illness phase, antipsychotic type and formulation, response to antipsychotic treatment as well as benefits and harms, several areas of consistent recommendations emerged from this review (e.g., balancing risk and benefits of antipsychotics, preferring antipsychotic monotherapy; using clozapine for treatment-resistant schizophrenia). On the other hand, other recommendations regarding other areas of antipsychotic treatment were mostly consistent (e.g., maintenance antipsychotic treatment for some time), somewhat inconsistent (e.g., differences in the management of first- vs multi-episode patients, type of antipsychotic, dose of antipsychotic maintenance treatment), or even contradictory (e.g., role of LAIs in first-episode schizophrenia patients).

Consistent with RCT evidence 43 , 44 , antipsychotic monotherapy was the treatment of choice for patients with first-episode schizophrenia in all CPGs, and all guidelines stated that a different single antipsychotic should be tried if the first is ineffective or intolerable. Recommendations were similar for multi-episode patients, but factored in prior patient treatment response, adverse effect patterns, and adherence. There was also broad consensus that the side-effect profile of antipsychotics is the most important consideration when making a decision on pharmacologic treatment, also reflecting meta-analytic evidence 4 , 5 , 10 . The risk of extrapyramidal symptoms (especially with FGAs) and metabolic effects (especially with SGAs) were noted as key considerations, which are also reflected in the literature as relevant concerns 4 , 45 , 46 , including for quality of life and treatment nonadherence 47 , 48 , 49 , 50 .

Largely consistent with the comparative meta-analytic evidence regarding the acute 4 , 51 , 52 and maintenance antipsychotic treatment 5 effects of schizophrenia, the majority of CPGs stated there was no difference in efficacy between SGAs and FGAs (WFSBP 24 , CPA 14 , SIGN 35 , APA 17 , and Singapore guidelines 36 ), or did not make any recommendations (CINP 22 , Italian guidelines 41 , NICE 34 , NJDMHS 32 , and Schizophrenia PORT 30 , 31 ); three CPGs (BAP 33 , WFBSP 24 , and Schizophrenia PORT 30 , 31 ) noted that SGAs may perform better than FGAs over the long term, consistent with a meta-analysis on this topic 53 .

The 12 CPGs that discussed treatment of subsequent/multiple episodes generally agreed on the factors guiding the choices of an antipsychotic, including that the decision may be more complicated and response may be lower than with a first episode, as described before 7 , 54 , 55 , 56 .

There was little consensus regarding maintenance therapy. Some CPGs recommended the same antipsychotic and dose that achieved remission (CINP 22 , WFSBP 25 , RANZCP 39 , and Schizophrenia PORT 30 , 31 ) and others recommended the lowest effective dose (NJDMHS 32 , APA 17 , Singapore guidelines 36 , TMAP 28 , CPA 14 , and SIGN 35 ). This inconsistency is likely based on insufficient data as well as conflicting results in existing meta-analyses on this topic 57 , 58 , 59 .

The 15 CPGs that discussed TRS all used the same definition for this condition, consistent with recent commendations 60 , and agreed that clozapine is the primary evidence-based treatment choice 14 , 17 , 18 , 19 , 22 , 23 , 24 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , reflecting the evidence base 61 , 62 , 63 . These CPGs also agreed that there are few options well supported by evidence for patients who do not respond to clozapine, with a recent meta-analysis of RCTs showing that electroconvulsive therapy augmentation may be the most evidence-based treatment option 64 .

One key gap in the treatment recommendations was how long patients should remain on antipsychotic therapy after a first episode or during maintenance therapy. While nine of the 17 CPGs discussing treatment of a first episode provided a recommended timeframe (varying from 1 to 2 years) 14 , 22 , 24 , 32 , 33 , 34 , 35 , 39 , 41 , the APA 17 and TMAP 28 recommended continuing antipsychotic treatment after resolution of first-episode symptoms but did not recommend a specific length of therapy. Similarly, six of the 18 CPGs discussing maintenance treatment recommended a specific duration of therapy (ranging from two to six years) 14 , 22 , 25 , 32 , 39 , while as many as 10 CPGs did not point to a firm end of the maintenance treatment, instead recommending individualized decisions. The CPGs not stating a definite endpoint or period of maintenance treatment after repeated schizophrenia episodes or even after a first episode of schizophrenia, reflects the different evidence types on which the recommendation is based. The RCT evidence ends after several years of maintenance treatment vs. discontinuation supporting ongoing antipsychotic treatment; however, naturalistic database studies do not indicate any time period after which one can safely discontinue maintenance antipsychotic care, even after a first schizophrenia episode 8 , 65 . In fact, stopping antipsychotics is associated not only with a substantially increased risk of hospitalization but also mortality 65 , 66 , 67 . In this sense, not stating an endpoint for antipsychotic maintenance therapy should not be taken as an implicit statement that antipsychotics should be discontinued at any time; data suggest the contrary.

A further gap exists regarding the most appropriate treatment of negative symptoms, such as anhedonia, amotivation, asociality, affective flattening, and alogia 1 , a long-standing challenge in the management of patients with schizophrenia. Negative symptoms often persist in patients after positive symptoms have resolved, or are the presenting feature in a substantial minority of patients 22 , 35 . Negative symptoms can also be secondary to pharmacotherapy 22 , 68 . Antipsychotics have been most successful in treating positive symptoms, and while eight of the CPGs provided some information on treatment of negative symptoms, the recommendations were generally limited 17 , 22 , 23 , 24 , 32 , 33 , 35 , 40 . Negative symptom management was a focus of the PPA guidelines, but the guidelines acknowledged that supporting evidence was limited, often due to the low number of patients with predominantly negative symptoms in clinical trials 37 , 38 . The Polish guidelines are also one of the more recently developed and included the newer antipsychotic cariprazine as a first-line option, which although being a point of differentiation from the other guidelines, this recommendation was based on RCT data 69 .

Another area in which more direction is needed is on the use of LAIs. While all but one of the 19 CPGs discussed this topic, the extent of information and recommendations for LAI use varied considerably. All CPGs categorized LAIs as an option to improve adherence to therapy or based on patient preference. However, 5/18 CPGs (27.8%) recommended the use of LAI early in treatment (at first episode: AFPBN 40 , RANZCP 39 , TMAP 28 , NJDMHS 32 , and Florida Medicaid Program 18 ) or across the entire illness course, while five others stated there was not sufficient evidence to recommend LAIs for these patients (Singapore 36 , NICE 34 , SIGN 35 , BAP 33 , and Schizophrenia PORT 30 , 31 ). The role of LAIs in first-episode schizophrenia was the only point where opposing recommendations were found across CPGs. This contradictory stance was not due to the incorporation of newer data suggesting benefits of LAIs in first episode and early-phase patients with schizophrenia 70 , 71 , 72 , 73 , 74 in the CPGs recommending LAI use in first-episode patients, as CPGs recommending LAI use were published between 2005 and 2020, while those opposing LAI use were published between 2011 and 2020. Only the Florida Medicaid CPG recommended LAIs as a first step equivalent to oral antipsychotics (OAP) after initial OAP response and tolerability, independent of nonadherence or other clinical variables. This guideline was also the only CPG to fully integrate LAI use in their clinical algorithm. The remaining six CPGs that included decision tress or treatment algorithms regarded LAIs as a separate paradigm of treatment reserved for nonadherence or patients preference rather than a routine treatment option to consider. While some CPGs provided fairly detailed information on the use of LAIs (AFPBN 40 , AACP 29 , Oregon Health Authority 19 , and Florida Medicaid Program 18 ), others mentioned them only in the context of adherence issues or patient preference. Notably, definitions of and means to determine nonadherence were not reported. One reason for this wide range of recommendations regarding the placement of LAIs in the treatment algorithm and clinical situations that prompt LAI use might be due to the fact that CPGs generally favor RCT evidence over evidence from other study designs. In the case of LAIs, there was a notable dissociation between consistent meta-analytic evidence of statistically significant superiority of LAIs vs OAPs in mirror-image 75 and cohort study designs 76 and non-significant advantages in RCTs 77 . Although patients in RCTs comparing LAIs vs OAPs were less severely ill and more adherent to OAPs 77 than in clinical care and although mirror-image and cohort studies arguably have greater external validity than RCTs 78 , CPGs generally disregard evidence from other study designs when RCT evidence exits. This narrow focus can lead to disregarding important additional data. Nevertheless, a most updated meta-analysis of all 3 study designs comparing LAIs with OAPs demonstrated consistent superiority of LAIs vs OAPs for hospitalization or relapse across all 3 designs 79 , which should lead to more uniform recommendations across CPGs in the future.

Only seven CPGs included treatment algorithms or flow charts to guide LAI treatment selection for patients with schizophrenia 17 , 18 , 19 , 24 , 29 , 35 , 40 . However, there was little commonality across algorithms beyond the guidance on LAIs mentioned above, as some listed specific treatments and conditions for antipsychotic switches, while others indicated that medication choice should be based on a patient’s preferences and responses, side effects, and in some cases, cost effectiveness. Since algorithms and flow charts facilitate the reception, adoption and implementation of guidelines, future CPGs should include them as dissemination tools, but they need to reflect the data and detailed text and be sufficiently specific to be actionable.

The systematic nature in the identification, summarization, and assessment of the CPGs is a strength of this review. This process removed any potential bias associated with subjective selection of evidence, which is not reproducible. However, only CPGs published in English were included and regardless of their quality and differing timeframes of development and publication, complicating a direct comparison of consensus and disagreement. Finally, based on the focus of this SLR, we only reviewed pharmacologic management with antipsychotics. Clearly, the assessment, other pharmacologic and, especially, psychosocial interventions are important in the management of individuals with schizophrenia, but these topics that were covered to varying degrees by the evaluated CPGs were outside of the scope of this review.

Numerous guidelines have recently updated their recommendations on the pharmacological treatment of patients with schizophrenia, which we have summarized in this review. Consistent recommendations were observed across CPGs in the areas of balancing risk and benefits of antipsychotics when selecting treatment, a preference for antipsychotic monotherapy, especially for patients with a first episode of schizophrenia, and the use of clozapine for treatment-resistant schizophrenia. By contrast, there were inconsistencies with regards to recommendations on maintenance antipsychotic treatment, with differences existing on type and dose of antipsychotic, as well as the duration of therapy. However, LAIs were consistently recommended, but mainly suggested in cases of nonadherence or patient preference, despite their established efficacy in broader patient populations and clinical scenarios in clinical trials. Guidelines were sometimes contradictory, with some recommending LAI use earlier in the disease course (e.g., first episode) and others suggesting they only be reserved for later in the disease. This inconsistency was not due to lack of evidence on the efficacy of LAIs in first-episode schizophrenia or the timing of the CPG, so that other reasons might be responsible, including possibly bias and stigma associated with this route of treatment administration. Lastly, gaps existed in the guidelines for recommendations on the duration of maintenance treatment, treatment of negative symptoms, and the development/use of treatment algorithms whenever evidence is sufficient to provide a simplified summary of the data and indicate their relevance for clinical decision making, all of which should be considered in future guideline development/revisions.

The SLR followed established best methods used in systematic review research to identify and assess the available CPGs for pharmacologic treatment of schizophrenia with antipsychotics in the acute and maintenance phases 80 , 81 . The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including use of a prespecified protocol to outline methods for conducting the review. The protocol for this review was approved by all authors prior to implementation but was not submitted to an external registry.

Data sources and search algorithms

Searches were conducted by two independent investigators in the MEDLINE and Embase databases via OvidSP to identify CPGs published in English. Articles were identified using search algorithms that paired terms for schizophrenia with keywords for CPGs. Articles indexed as case reports, reviews, letters, or news were excluded from the searches. The database search was limited to CPGs published from January 1, 2004, through December 19, 2019, without limit to geographic location. In addition to the database sources, guideline body websites and state-level health departments from the US were also searched for relevant CPGs published through June 2020. A manual check of the references of recent (i.e., published in the past three years), relevant SLRs and relevant practice CPGs was conducted to supplement the above searches and ensure and the most complete CPG retrieval.

This study did not involve human subjects as only published evidence was included in the review; ethical approval from an institution was therefore not required.

Selection of CPGs for inclusion

Each title and abstract identified from the database searches was screened and selected for inclusion or exclusion in the SLR by two independent investigators based on the populations, interventions/comparators, outcomes, study design, time period, language, and geographic criteria shown in Table 4 . During both rounds of the screening process, discrepancies between the two independent reviewers were resolved through discussion, and a third investigator resolved any disagreement. Articles/documents identified by the manual search of organizational websites were screened using the same criteria. All accepted studies were required to meet all inclusion criteria and none of the exclusion criteria. Only the most recent version of organizational CPGs was included for data extraction.

Data extraction and synthesis

Information on the recommendations regarding the antipsychotic management in the acute and maintenance phases of schizophrenia and related benefits and harms was captured from the included CPGs. Each guideline was reviewed and extracted by a single researcher and the data were validated by a senior team member to ensure accuracy and completeness. Additionally, each included CPG was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Following extraction and validation, results were qualitatively summarized across CPGs.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

The data that support the findings of the SLR are available from the corresponding author upon request.

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C.C., A.M., R.G., C.P., C.B., K.J., J.K.S., E.S. and E.K. contributed to the conception and the design of the study. A.M., R.G. and E.S. conducted the literature review, including screening, and extraction of the included guidelines. All authors contributed to the interpretations of the results for the review; A.M. and C.C. drafted the manuscript and all authors revised it critically for intellectual content. All authors gave their final approval of the completed manuscript.

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C.C. has received personal fees from Alkermes plc, Allergan plc, Angelini Pharma, Gedeon Richter, Gerson Lehrman Group, Intra-Cellular Therapies, Inc, Janssen Pharmaceutica/Johnson & Johnson, LB Pharma International BV, H Lundbeck A/S, MedAvante-ProPhase, Medscape, Neurocrine Biosciences, Noven Pharmaceuticals, Inc, Otsuka Pharmaceutical Co, Inc, Pfizer, Inc, Recordati, Rovi, Sumitomo Dainippon Pharma, Sunovion Pharmaceuticals, Inc, Supernus Pharmaceuticals, Inc, Takeda Pharmaceutical Company Limited, Teva Pharmaceuticals, Acadia Pharmaceuticals, Inc, Axsome Therapeutics, Inc, Indivior, Merck & Co, Mylan NV, MedInCell, and Karuna Therapeutics and grants from Janssen Pharmaceutica, Takeda Pharmaceutical Company Limited, Berlin Institute of Health, the National Institute of Mental Health, Patient Centered Outcomes Research Institute, and the Thrasher Foundation outside the submitted work; receiving royalties from UpToDate; and holding stock options in LB Pharma. A.M., R.G., and E.S. were all employees of Evidera at the time the study was conducted on which the manuscript was based. C.P., C.B., K.J., J.K.S., and E.K. were all employees of Janssen Scientific Affairs, who hold stock/shares, at the time the study was conducted.

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Correll, C.U., Martin, A., Patel, C. et al. Systematic literature review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics. Schizophr 8 , 5 (2022). https://doi.org/10.1038/s41537-021-00192-x

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Treatment outcomes in schizophrenia: qualitative study of the views of family carers

• Joanne Lloyd 1 ,
• Helen Lloyd 2 ,
• Ray Fitzpatrick 3 &
• Michele Peters 3  

BMC Psychiatry volume  17 , Article number:  266 ( 2017 ) Cite this article

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Schizophrenia is a complex, heterogeneous disorder, with highly variable treatment outcomes, and relatively little is known about what is important to patients. The aim of the study was to understand treatment outcomes informal carers perceive to be important to people with schizophrenia.

Qualitative interview study with 34 individuals and 8 couples who care for a person with schizophrenia/schizoaffective disorder. Interviews were transcribed verbatim and analysed by a thematic framework based approach.

Carers described well-recognised outcomes of importance, alongside more novel outcomes relating to: Safety (of the patient/others); insight (e.g. into non-reality of psychotic phenomena); respite from fear, distress or pain; socially acceptable behaviour; getting out of the house; attainment of life milestones; changes in personality and/or temperament; reduction of vulnerability to stress; and several aspects of physical health.

Conclusions

These findings have the potential to inform the development of patient- or carer- focused outcome measures that take into account the full range of domains that carers feel are important for patients.

Peer Review reports

Improving treatment outcomes and quality of life for people with long-term mental health conditions are key aims of health care policy [ 1 , 2 ]. Schizophrenia is a particularly important target, being associated with poor quality of life [ 3 ] and individual and societal impacts [ 4 , 5 , 6 ], and requiring long-term treatment [ 7 ]. Antipsychotic medications can ameliorate some symptoms and improve quality of life [ 3 , 8 , 9 ], but individual responses vary [ 10 , 11 ], and many discontinue medication due to poor efficacy or debilitating side effects [ 12 , 13 ]. Treatment outcomes are often assessed by clinician ratings, and/or symptom scales [ 14 ], but patients and carers may prioritise different outcomes to clinicians [ 15 , 16 , 17 ], and controlling symptoms is not the only outcome of importance [ 14 ]. The recovery literature draws attention to the importance of recognising a broad array of outcome domains in schizophrenia treatment, highlighting the relevance of improved social and domestic functioning, alongside subjective wellbeing, optimism and empowerment (e.g. [ 18 , 19 ]). Patients and relatives, in particular, refer to subjective wellbeing when defining ‘remission’, in contrast to traditional clinical definitions focused around reduced symptom scores [ 17 ]. People with schizophrenia value outcomes such as achieving life milestones, feeling safe, improved physical activity, employment, a positive sense of self and psychosocial outcomes [ 20 ]. Understanding the full range of treatment outcomes important to people with schizophrenia and their carers is key for ensuring that clinical practice, research and assessment are aligned with patient and carer priorities [ 4 , 21 ].

While people with schizophrenia can give valid and reliable accounts of outcomes [ 22 , 23 , 24 ], symptoms can make it difficult to participate in research [ 25 ], and carers represent a valuable additional resource [ 15 , 21 , 26 ]. Furthermore, carers have the potential to influence treatment decisions [ 26 ], and experience, indirectly, the impact of outcomes. This study sought to explore the treatment outcomes that carers feel are important for people with schizophrenia. It used a framework informed by a thematic review of the existing literature on treatment outcomes of importance to patients and carers, and a consensus conference with professionals, carers and patients, and aimed to identify whether carers report any outcome domains that have not been emphasised in the current literature.

Design of the study

A qualitative study using in-depth semi-structured interviews was conducted with self-identified ‘carers’ of a family member with a diagnosis of schizophrenia made at least 2 years previously. Ethical approval was obtained from NHS East of Scotland Research Ethics Service (EoSRES) REC 1 by proportionate review (Application Number 13/ES/0143). All participants gave written informed consent.

Participants and recruitment

A total of 34 individuals and 8 couples were interviewed (i.e. 50 people in 42 interviews). While qualitative methodology papers tend to avoid prescribing hard guidelines for sample sizes for qualitative studies, 25–30 participants have been deemed an acceptable minimum by Dworkin [ 27 ] and this number is usually sufficient for reaching data saturation. An email circulated by charity ‘Rethink Mental Illness’ was responded to by 102 people who were screened via telephone to confirm that they were the carer of someone with a ≥ 2-year diagnosis of schizophrenia or schizoaffective disorder. Within this self-selecting convenience sample, participants were then recruited purposively to generate a relatively heterogeneous final sample, consisting of 38 females and 12 males, aged from 20s–80s (48% in their 60s, 26% in their 50s, and the remainder in their 20s, 40s, 70s or 80s), and coming from urban (e.g. Greater London) and rural (e.g. Wiltshire) locations. Thirty-seven were the mother of a person with schizophrenia, 10 were the father or stepfather, one the husband, one the wife, and one the sibling. Duration of illness of the patients discussed ranged from 2 to 20+ years, with a modal duration of 11–15 years (42%). The majority ( n  = 44) cared for someone with schizophrenia, and six cared for someone with schizoaffective disorder.

Most participants chose to be interviewed at home, but approximately 20% chose to come to the University. At the beginning of the interviews, carers re-confirmed that the patient had received a formal diagnosis of schizophrenia or schizoaffective disorder from a GP or psychiatrist, at least two years prior to the interview. Carers were then asked what they felt were important outcomes of treatment for the patient who they cared for: at present; at a time when the patient was particularly ill or unwell; at a time when they were more stable; and at a time when they were doing particularly well. Prompts were designed to encourage participants to discuss both directly-experienced outcomes, and important/desired but unattained outcomes. In addition, a series of prompts relating to key outcomes were compiled based on the conceptual review of the literature and feedback from a consensus conference, but were not in fact utilised in any of the interviews, as participants spontaneously discussed a broad array of outcomes of importance in response to the preliminary, general questions. After the initial 6 interviews, when it became apparent that participants identified multiple outcomes in response to the primary questions, without need for prompts, the researchers agreed that all future interviews in the study would proceed without prompts. Carers were encouraged to expand upon ideas that they themselves raised in relation to outcomes, rather than directed towards any specific topic. It was felt that this strengthened the data, as it reduced the potential for investigator bias. The topic guide, which was reviewed for tone and content prior to use by two carers and one person with schizophrenia, can be found in online Additional file 1 . Interview duration ranged from 40 to 125 min (average, approx. 60 min).

Interviews were transcribed verbatim by a professional transcriber, and anonymised. Transcripts were analysed in NVivo 8 by JL, using a thematic, framework based approach [ 28 ]. This involved the creation of a preliminary framework based on a literature review and consensus conference. Transcripts were then analysed, with themes being coded into appropriate categories within that framework, wherever appropriate categories existed. Where themes did not fit well into an existing category, novel categories were created. Interviews were continued until no further novel categories emerged, by which point all categories had been spontaneously mentioned by several participants, and saturation was deemed to have been reached. Once all interviews had been coded, the categories were reviewed by the research team, to ensure that they were representative of all the statements coded within them. Where categories were ambiguous, e.g. contained material that could potentially be better conceptualised within different domains, or could be better represented by different titles, they were revised, and the material coded within them was re-coded in order to ensure that it was coded within the most appropriate category. A final framework that encompassed the original and the novel categories was then agreed amongst the researchers. All of the interviews were then re-coded, using the final framework. In this second iteration, the majority of the material was coded into the same categories as during the initial coding. However, this process was important to ensure that any statements that had originally been coded into categories within the preliminary framework, but in retrospect better-reflected a novel category that had been added to the final framework, were coded appropriately. RF and MP independently cross-checked the final categorisation by coding a random selection of 6 transcripts, and no disagreements emerged. Categorized data were summarized and synthesized, and the resultant categories (and associations between them) were interpreted in relation to the categories already identified within the literature and consensus conference. After the final coding, the number of interviews in which each category occurred was calculated.

Outcomes of importance in schizophrenia reported by the carers included symptom related outcomes, quality of life, functional outcomes, personal recovery, physical health and lifestyle, and satisfaction with treatment. Table 1 lists these outcomes, and their sub-categories, and the proportion of interviews in which they occurred (using the conventions: ‘few’ for 2–10% ( n  = 1–4), ‘some’ for 12–24% ( n  = 5–10), ‘many’ for 25–50% ( n  = 11–21), and ‘most’ for >50% ( n  = 22–42)). It was not necessary for a participant to overtly state that an outcome had been experienced by the person they care for, in order to code their statement as an endorsement of that domain. While ‘endorsement’ of an outcome domain did, in some cases, take this form, any statement that either explicitly or implicitly indicated that a domain was relevant or important to that carer, was also coded within that domain. For example, where a carer identified that the person they cared for experienced ongoing difficulties with engaging in physical activity, or that they wished the person they cared for could have the energy to engage in physical activity, this was interpreted as the carer indicating that being able to engage in physical activity was an important outcome, and hence it was coded within the ‘physical activity’ category.

The categories in Table 1 were first identified through a literature review and consensus conference and subsequently adapted to include the newly identified and/or expanded categories from the interview data reported here. Standard font indicates categories which were pre-identified from the literature review (and replicated in the current study), and italic font indicates novel/ modified categories which emerged from the current study (which are illustrated by quotations in Tables 3 and 4 , and discussed below). All categories in Table 1 were identified as relevant by at least some of the carers interviewed, and the majority were mentioned in >50% of the interviews.

Symptom-related outcomes (Table 2 )

Safety was mentioned in most interviews, and encompassed safety from dangerous behaviours prompted by psychosis (such as absconding/ putting oneself or others into risky situations); from health risks linked to negative symptoms (e.g. not eating, living in squalor); and from potential for deliberate self-harm related to affective symptoms.

‘It's great for it to be diagnosed, to be put on your medication and you're safe’ [C41]

The importance of reduction of, or relief from fear, distress and emotional (or even physical) pain was raised in most interviews, often closely related to positive symptoms, but at the level of their physical and emotional consequences.

‘He was absolutely intimidated by his environment… he felt frightened and threatened’ [C25]

Insight was also mentioned in most interviews, encompassing both recognition that current/prior psychotic phenomena are not real, and understanding that one has a long-term illness. It was described as a gatekeeper to many other treatment benefits, partly through its impact upon treatment adherence, and was important in helping people deal with residual psychotic phenomena.

‘He can rationalise…although he hears the voices he has a sense of reality.’ [C40]

Side-effects are not described in detail here as they are well reported within existing literature (e.g. [ 29 ]), but they were identified as important in the majority of interviews, and in addition to commonly-reported side effects (e.g. weight gain and fatigue), a few participants mentioned negative impact of medication on imagination and/or creativity, and concerns over toxicity of medication during pregnancy and breastfeeding.

Quality of life (Table 2 )

The concept of ‘social acceptability’ was raised in most interviews, i.e. behaving in a socially appropriate way and avoiding bizarre/unconventional behaviour. Many discussed the importance of treatment in helping patients avoid illegal behaviour (sometimes precipitated by symptoms).

‘[When] he's not taking his medication, he occasionally offends people in the street’ [C25]

Functional outcomes (Table 3 )

The domain of ‘life milestones’ was added to encompass many carers’ reports of the importance of reaching key life/developmental milestones, such as attaining qualifications, learning to drive, moving out of the caregiver’s home, or having a family.

‘I think he missed out all his twenties and thirties so maybe catching up in some ways.’ [C03]

Simply ‘getting out’ of the house was mentioned in most interviews, and was consequently added as a sub-category of ‘leisure pursuits’. This encompassed the importance of being well enough to leave the house, which was something many patients needed to achieve before the more ambitious step of engaging in structured leisure activities or even activities of daily living.

‘The worst time that we've had was… when he was so unwell he didn’t go out the house for a year’ [C24]

A novel sub-category of ‘pets’ was added within the ‘role functioning and productivity’ category, because the importance of being able to care for a pet was raised in some interviews.

Personal recovery (Table 3 )

The importance of ‘personality/temperament’ was raised in most interviews, and was often particularly valued by carers themselves. This encompassed emergence of aspects of the patient’s character, such as sense of humour, consideration, and thoughtfulness, and of a generally calmer temperament, more ‘like oneself’.

‘He reverted to his old self. You could reason with him, you could have a laugh with him’ [C46]

The vast majority of carers also mentioned ‘vulnerability/sensitivity’ to all kinds of stress, in most cases as a residual difficulty that treatment failed to resolve, rather than a positive, attained outcome.

‘Although he seems fairly even I don’t think it would take a huge amount to kick him over the edge.’ [C06]

Physical health and lifestyle (Table 4 )

Exercise/physical activity and diet/weight were raised by the majority of carers, who sometimes described how treatment facilitated physical activity and healthy diet (by improving symptoms that create barriers), but also described how side-effects (such as alteration in appetite/metabolism, and fatigue) could act as barriers.

‘On such a high dose… of a sedating medication. Motivation is just not there’. [C46]

Many described the importance of outcomes related to drugs/alcohol/smoking, such as decreased reliance upon substances previously used to self-medicate positive or affective symptoms, or compensate for lack of social/functional activities.

‘She was drinking herself to sleep, I think, mostly because she had recurrent nightmares, and day time nightmares’ [C50]

Daily routine was mentioned in many interviews, in relation to sleep and waking, eating and self-care, and was described both as a factor that contributed to improving other outcomes, and as an outcome in itself.

Principle findings

All the schizophrenia treatment outcomes identified in the literature review and consensus conference preceding the study (i.e. symptom-related outcomes; functional outcomes; personal recovery; quality of life; and satisfaction with treatment) were confirmed in these qualitative interviews, along with several novel sub-categories within existing domains and a novel category of physical health and lifestyle, thus giving a deeper understanding of outcomes in this condition. While a large proportion of the sample endorsed most of the themes, it should be noted that frequency information are indicative of the frequency of these domains within our sample, and cannot be extrapolated from to estimate the prevalence of these concerns in carers of persons with schizophrenia.

While the importance of physical activity for persons with schizophrenia is recognised within the literature [ 30 ], and low levels of physical activity have been demonstrated empirically to be associated with poorer outcomes in schizophrenia [ 31 ], its importance as a treatment outcome is not expressed in existing outcome measures. This highlights the need to consider physical activity as a potentially relevant outcome domain in its own right. Designing interventions for schizophrenia that include attention to physical health and lifestyle, could help improve outcomes for many patients.

Safety of the patient (and those around them), and reduction of their fear, distress or pain, were considered important by most carers, and it is easy to see why they would value these outcomes, relating to resolution of negative practical and emotional consequences of symptoms. While the importance of these outcomes may be intuitive, they are not explicitly represented in current outcome measures, and this study is novel in highlighting their particular salience. These outcomes could be described as ‘secondary’, in the sense that they could be logically expected to follow on from the more ‘primary’ outcome of amelioration of (particularly, positive) symptoms. However, it could also be argued that there are other means of reducing patients’ fear, distress, or pain, aside from by symptom resolution, and thus outcome measures could benefit from assessing the extent to which treatments help to reduce a patient’s experience of these negative states. This could help professionals to gain a fuller understanding of how a given treatment programme is impacting on the individual’s level of fear and distress.

Most carers also valued insight which they often reported to be associated with improved communication with the person with schizophrenia, and a return of their personality and/or of a more favourable, ‘normal’ temperament. This is consistent with findings that insight in schizophrenia is associated with social cognition [ 32 ], and lower scores on an aggression scale [ 33 ]. Carers also described insight’s importance for enabling patients to apply cognitive strategies to counter paranoid thoughts, delusions or hallucinations, consistent with the finding that insight can be predictive of prognosis [ 34 ]. Monitoring level of insight may be beneficial in order to inform decisions about when cognitive interventions may be more effective. Exploring the value of educating carers in ways to cope with poor insight in the person for whom they care, could be another important target for future work.

Within functional outcomes, many carers talked of ‘getting out’ (i.e. leaving the house), similar to the existing domain of engaging in leisure pursuits, but at a more preliminary level. Caring for pets, similarly, could be conceptualised as a specific form of role functioning/productivity. Where residual difficulties are considerable and/or recovery is particularly limited, less ‘ambitious’ functional outcomes such as these may be particularly relevant. This is consistent with the observation that traditional social functioning measures may not be relevant to people with severe disabilities related to schizophrenia [ 35 ], and with carers’ comments about reduced potential and lowering of expectations. From carers’ references to a range of key developmental/life events such as moving out of the family home, getting a job, learning to drive, and having a romantic relationship, we identified ‘reaching life milestones’ as an important and novel outcome. Because schizophrenia onset is typically during adolescence or early adulthood [ 36 ], before traditional milestones have been reached, it is logical that the reaching of milestones would for many be the goal, rather than the resumption of familial, domestic, occupational or educational roles and responsibilities. This highlights the fact that functional outcome measures in schizophrenia may need to take subtle levels of attainment into account, in order to accurately capture small gains.

Within the realm of ‘personal recovery’ many carers highlighted the importance of changes in personality and temperament, and several described the return of the person they used to know as the most important outcome; understandably so, considering that these are good outward indicators of wellness and ‘personal recovery’ and directly impact upon the patient-carer relationship. Indeed, temperament has been linked with functional outcomes and psychological health [ 37 ]. Also relating to personal recovery, many carers discussed patients’ vulnerability (to stress, and in general) and sensitivity, consistent with empirical findings of increased biological reactivity to stress in schizophrenia [ 38 ]. These were typically described as residual unresolved difficulties, and several carers reported that they limited patients’ attainment of functional outcomes and acted as precipitants of relapse, requiring careful monitoring. This could indicate a potential benefit to be found in involving carers, where appropriate, in helping patients to monitor level of stress, and react quickly to try and reduce its impact.

In the sub-category of ‘leading a normal life’, a number of carers spoke of the importance of treatment for helping patients to avoid socially unacceptable/antisocial/illegal behaviours, (often precipitated by positive symptoms), in order to reduce risk of arrest or sectioning, facilitate social interactions and minimise stigma – consistent with findings that socially unacceptable behaviour is strongly associated with stigma in schizophrenia [ 39 ].

Consistent with other studies, many carers expressed desire for greater monitoring of physical health [ 40 ]. Exercise/physical activity, diet, and weight were all salient concerns; again consistent with findings of elevated obesity [ 41 ] and low activity [ 42 ] in schizophrenia/severe mental illness. A wide range of contributing factors were cited by the carers, including medication side effects, positive, negative and affective symptoms, and eating replacing less attainable leisure pursuits. Several also described patients who used alcohol or drugs to self-medicate and/or compensate for a lack of alternative leisure outlets; consistent with reported motivations for substance use in schizophrenia [ 43 ]. Some carers did describe physical health benefits of treatment, e.g. where it reduced use of drugs or alcohol for self-medication, or reduced symptoms enough to allow patients to exercise or shop for healthy food. In relation to lifestyle more generally, several carers emphasised the importance of routine, as a desirable outcome and useful intervention for facilitating the attainment of other outcomes (consistent with a study where people with schizophrenia rated organization of time as a useful coping strategy [ 44 ]). The discovery that physical health is an important concern in schizophrenia is not novel, but this study does support the growing body of work emphasising the importance of incorporating physical health interventions into schizophrenia treatment programmes (e.g. [ 45 ]).

Strengths and limitations

This study confirms the key treatment outcome categories found in the current literature, and contributes evidence of additional outcomes that carers feel are important for patients but are not apparently captured in current thinking about, and measurement of, schizophrenia outcomes. However, there are some possible biases in the sample. The majority of carers interviewed were parents of a person with schizophrenia, with a gender bias in the sample, such that around three quarters of participants were female. However, this is in line with the gender balance found in other convenience samples of carers of persons with schizophrenia [ 46 ], and reflects the fact that mothers are most frequently the primary carer in schizophrenia [ 47 ]. It is possible that spouses, siblings, or children (or those of a younger age in general) may have different perceptions of what the important outcomes are. Most participants were recruited via Rethink Mental Illness, which may have meant they were particularly well-informed about features of schizophrenia and issues around treatment. Finally, the patients discussed were typically quite advanced in chronicity (in most cases >10 years post-diagnosis). While carers were asked to discuss outcomes that they felt were important at different phases of illness, it is nevertheless possible that carers of patients more immediately post-diagnosis would report different outcomes. Future studies could benefit from exploring outcomes with younger carers with different relationships to the patient, from a range of backgrounds, and those caring for people more early post-diagnosis.

The outcomes carers identified as being important for patients may not be identical to the outcomes that patients themselves would identify. However, there is generally good agreement between the two [ 21 ], and as agents who potentially influence patients’ treatment decisions [ 16 ], and experience the consequences of the illness [ 48 ], carers’ views are important in their own right. Furthermore, we were able to gain insight into outcomes that might not otherwise have been represented, as most of the carers interviewed reported that the patients they were speaking about would have been unwilling/unable to participate (e.g. ‘he hates talking about it when he was really ill… he said, “It makes me feel so ill again” [C41]).

The findings from this study contribute to our understanding of the full range of treatment outcomes that carers feel are important to people with schizophrenia, and could contribute to ensuring research, treatment planning and assessment are aligned with the needs and priorities of patients [ 4 ]. The breadth of information gleaned from these interviews with family carers indicates what an important resource this population represents. Furthermore, it is clear that informal carers typically bear a high burden of care in schizophrenia [ 49 ]. Working with carers to gain insights and coordinate interventions, where appropriate, could be a valuable way for professionals to develop person-centred approaches in schizophrenia. Outcomes of treatment should ideally be assessed with measures that both complement existing clinical scales and incorporate patient and carer priorities. The domains and more specific experience emphasised here should inform the further development of such patient- or carer- focused outcome measures in order to ensure more appropriate and complete evaluation of interventions.

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Acknowledgments

The authors would like to acknowledge the support of Rethink Mental Illness in advertising the study, and the input of all the carers who took part.

This work was supported by EUFAMI, the European Federation of Associations of Families with Mental Illness.

Dr. Joanne Lloyd was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care Oxford whilst working on drafts of this article. Dr. Helen Lloyd was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula whilst commenting on drafts of this paper. Throughout this project, Prof Ray Fitzpatrick and Dr. Michele Peters were supported by the Department of Health funded Policy Research Unit on Quality and Outcomes of Person Centred Care (QORU), a collaboration between the London School of Economics and Political Science (LSE) and the Universities of Kent and Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

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MP and RF conceived the study and raised the funding. JL and HL conducted the interviews and led the data analysis. MP and RF contributed to the analysis. All authors were involved in writing the publication. All authors read and approved the final manuscript.

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Lloyd, J., Lloyd, H., Fitzpatrick, R. et al. Treatment outcomes in schizophrenia: qualitative study of the views of family carers. BMC Psychiatry 17 , 266 (2017). https://doi.org/10.1186/s12888-017-1418-8

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DOI : https://doi.org/10.1186/s12888-017-1418-8

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• Schizophrenia

BMC Psychiatry

ISSN: 1471-244X

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• General enquiries: [email protected]

Case study: treatment-resistant schizophrenia

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Learning objectives

After reading this article, individuals should be able to:

• Describe the management of schizophrenia;
• Understand pharmaceutical issues that occur during treatment with antipsychotics, especially clozapine ;
• Explain how the Mental Health Act 1983 impacts on care;
• Understand the importance of multidisciplinary and patient-centred care in managing psychosis.

Around 0.5–0.7% of the UK population is living with schizophrenia. Of these individuals, up to one-third are classified as treatment-resistant. This is defined as schizophrenia that has not responded to two different antipsychotics ​[1,2]​ .

Clozapine is the most effective treatment for such patients ​[3]​ . It is recommended by the National Institute for Health and Care Excellence (NICE)[4], and is the only licensed medicine for this patient group ​[4,5]​ . For treatment-responsive patients, there should be a collaborative approach when choosing a treatment ​[4]​ . More information on the recognition and management of schizophrenia can be found in a previous article here , and in accompanying case studies  here . 

This case study aims to explore a patient’s journey in mental health services during a relapse of schizophrenia. It also aims to highlight good practice for communicating with patients with severe mental illness in all settings, and in explaining the role of clozapine. 

Case presentation

Mr AT is a male, aged 26 years, who has been diagnosed with paranoid schizophrenia. He moved to the UK with his family from overseas five years ago. He lives with his parents in a small flat in London. His mother calls the police after he goes missing, finding his past two months’ medication untouched. 

He is found at an airport, attempting to go through security without a ticket. He is confused and paranoid about the police asking him to come with them. 

He is taken to A&E and is medically cleared (see Box 1) ​[6]​ . 

Box 1: Common differentials for psychotic symptoms

Medical conditions can present as psychosis. These include:

• Intoxication/effects of drugs (cannabis, stimulants, opioids, corticosteroids);
• Cerebrovascular disease;
• Temporal lobe epilepsy.

Mr AT’s history is taken by a psychiatrist, and his crisis plan sought (as per NICE recommendations) but he does not have one ​[7]​ .

He has been under the care of mental health services for two years and disputes his diagnosis of paranoid schizophrenia. He was admitted to a psychiatric hospital 18 months ago where he was prescribed the antipsychotic amisulpride at 600mg daily. 

He is teetotal, smokes ten cigarettes a day and smokes cannabis every day. His BMI is 26 and he has hypercholesterolaemia (total cholesterol = 6.1mmol/L, reference range <5mmol/L) but all other tests are normal. 

He has no allergies. His only medication is amisulpride 600mg each morning, which he does not take. 

Medicines reconciliation

Mr AT is transferred to a psychiatric ward and placed under Section 2 of the Mental Health Act , allowing detention for up to 28 days for assessment and treatment (see Box 2).

Box 2: The Mental Health Act 1983

This legislation allows for the detention and treatment of patients with serious mental illness, where urgent care is required. This is often referred to as “sectioning”.

It includes regulations about treatment against a patient’s consent to safeguard patients’ liberty, which become more stringent with longer detentions.

Patients may only be given medication to treat their mental illness without their consent and may refuse physical health treatment. 

He denies any mental illness and tells the team they are conspiring with MI6. He is visibly experiencing auditory hallucinations: seen by him talking to himself and looking to empty corners of the room. Amisulpride is re-prescribed at 300mg, which he declines to take. 

A pharmacy technician completes a medicines reconciliation and contacts the care coordinator. The technician provides information about Mr AT’s treatment and feels he is still unwell as he has continued to express paranoid beliefs about his neighbours and MI6.

The ward pharmacist speaks to the patient. As per NICE guidance on medicines adherence , they adopt a non-judgemental attitude ​[8]​ . Mr AT is provided with information on the benefits and side effects of the medication and is asked open questions regarding his reluctance to take it. For more information on non-adherence to medicines and mental illness, see Box 3 ​[9]​ .

Box 3: Medicines adherence and mental health

Adherence to medication is similar for both physical and mental health medicines: only about 50% of patients are adherent. 

Side effects and lack of involvement in decision making often lead to poor adherence. 

In mental illness, other factors are: 

• Denial of illness (poor ‘insight’); 
• Lack of contact by services;
• Cultural factors, such as family, religious or personal beliefs around mental illness or medication.

Mr AT reports gynaecomastia and impotence, and says that he will not take any antipsychotics as they are “poison designed by MI6”, although is unable to concentrate on the discussion owing to hearing voices. 

He is prescribed clonazepam 1mg twice daily owing to his distress, which is to be reduced as treatment controls his psychosis. He is offered nicotine replacement therapy but decides to use an e-cigarette on the ward. 

He is unable to weigh up information to make decisions owing to his chaotic thinking and is felt to not have capacity to make decisions on his treatment. The team debates what treatment to offer.

Patient preference

Mr AT refuses all options presented to him. A decision is made to administer against his will and aripiprazole is chosen as it is less likely to cause hyperprolactinaemia and sexual dysfunction. He then agrees to take tablets “if it will get me out of hospital”. 

After eight weeks of treatment with orodispersible aripiprazole 15mg, Mr AT is able have a more coherent conversation, but is hallucinating and distressed. He is clearly under treated. The pharmacist attempts to complete a side-effect rating scale ( Glasgow Antipsychotic Side-effect Scale [GASS] ) but he declines. He is pacing around the ward in circles: it is felt he may be experiencing akathisia (restlessness) — a common side effect of antipsychotics (see  Table 1 ). 

Treatment review

The team feels clozapine is the best option owing to the treatment failure of two antipsychotics.  

The team suggests this to Mr AT. He refuses, stating the ward is experimenting on him with new medication and he refuses to take another antipsychotics. 

The pharmacist meets the patient with an occupational therapist to discuss what his goals are. Mr AT states he wants to go to college to become a carpenter. They discuss routes to achieve this, which all involve the first step of leaving hospital and the conclusion that clozapine is the best way to achieve this. The pharmacist clarifies the patient’s aripiprazole will not continue once clozapine is established. They leave information about clozapine with the patient and offer to return to discuss it further. 

Mr AT agrees to take clozapine a week later (see Box 4) ​[10–14]​ . Aripiprazole is tapered and stopped.

Box 4: Clozapine characteristics

Clozapine significantly prolongs life and improves quality of life ​[10]​ . Delaying clozapine is associated with poorer outcomes for patients ​[11]​ . 

Clozapine is under-prescribed owing to healthcare professionals’ anxiety and unfamiliarity around its use ​[12–14]​ .

It causes neutropenia in up to 3% of patients so regular monitoring is required . Twice-weekly monitoring is needed if neutrophils are <2 x10 9 /L. Most patients should stop clozapine if neutrophils are <1.5×10 9 /L. These ranges can differ from some laboratory definitions of neutropenia. 

Other side effects include sedation, hypersalivation and weight gain. See  Table 2  for red flags for serious side effects. 

Clozapine is titrated up slowly to avoid cardiovascular complications. A treatment break of >48 hours warrants specialist advice for a retitration plan. 

The pharmacist meets with Mr AT to discuss clozapine. He is told that this is likely to be a long-term treatment. The pharmacist acknowledges that the patient disagrees with his diagnosis, but this treatment is likely to prevent him from returning to hospital. 

He is started on clozapine at 12.5mg at night, which is slowly increased. Pre- and post-dose monitoring of his vital signs is completed. 

On day nine of the titration, his pulse is 115bpm. He otherwise feels well and blood tests show no signs of myocarditis (see   Table 2), so the titration is continued but slowed.

After 3 weeks he is taking 150mg twice daily of clozapine and his symptoms have significantly improved: he is regularly bathing, not visibly hallucinating and engaging with staff.

The pharmacy technician completes a GASS form. Mr AT reports constipation, hypersalivation and sedation. 

A pharmacist meets the patient to reiterate important counselling points, and discuss questions he may have about his treatment and how to manage side effects. Medication changes are made with the patients’ input: 

• His constipation is monitored with a stool chart and he is started on senna 15mg at night;
• He is started on hyoscine hydrobromide 300 micrograms at night for salivation;
• He is switched to clozapine 300mg once daily at night to simplify his regime and reduce daytime sedation. His clonazepam is reduced and stopped.

Smoking is discussed owing to tobacco’s role as an enzyme inducer (more information on tobacco smoking and its potential drug interactions can be found in a previous article here ). Mr AT states he will continue to use an e-cigarette for now. He is informed that if he starts smoking again, his clozapine may become less effective and he should immediately inform his team. 

He is discharged a few weeks later via a home treatment team and attends a clinic once weekly. On each attendance, he has a full blood count taken and analysed on site. He is assessed by a pharmacy technician and nurse for side effects and adherence to treatment, and his smoking status is clarified. 

The technician asks what he thinks the clozapine has done for him. Mr AT states he is still unsure about having a mental illness, but recognises that clozapine has helped him out of hospital and intends to continue taking it. 

Good practice in the pharmaceutical care of psychosis involves:

• Active patient involvement in discussions on treatment decisions;
• Regular review of treatment: discussing efficacy, side effects and the patient’s view and understanding of treatment; 
• Multidisciplinary approaches to helping patients choose treatment;
• For patients who dispute their diagnosis and the need for treatment, open dialogue is important. Such discussions should involve the patient’s goals, which are likely to be shared by the team (rapid discharge, preventing admissions, reducing distress); 
• Information about treatment should be provided regularly in both written and verbal form;
• Where appropriate, involve carers/next of kin in decision making and information sharing. 

Important points

• Schizophrenia affects 1 in 200 people, meaning such patients will present regularly in all settings;
• Patients with acute psychosis, who are in recovery, may be managed by specialist teams, who are the best source of information for a patient’s care;
• Collaborating with the patient on a viable long-term treatment plan improves adherence;
• Clozapine is recommended where two antipsychotics have failed;
• Clozapine is a high-risk medicine, but the risks are manageable;
• Hydrocarbons produced by smoking (but not nicotine replacement therapy, e-cigarettes or chewing tobacco) induce the enzyme CYP1A2, which reduces clozapine levels markedly (up to 20–60%). Starting or stopping smoking could precipitate relapse or induce toxicity, respectively.
• 1 Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biological Psychiatry. 2001; 50 :898–911. doi: 10.1016/s0006-3223(01)01271-9
• 2 Gillespie AL, Samanaite R, Mill J, et al. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review. BMC Psychiatry. 2017; 17 . doi: 10.1186/s12888-016-1177-y
• 3 Taylor DM. Clozapine for Treatment-Resistant Schizophrenia: Still the Gold Standard? CNS Drugs. 2017; 31 :177–80. doi: 10.1007/s40263-017-0411-6
• 4 Psychosis and schizophrenia in adults: prevention and management. NICE. 2014. https://www.nice.org.uk/guidance/cg178/ (accessed Jan 2022).
• 5 Clozaril 25 mg tablets. Electronic medicines compendium. 2020. https://www.medicines.org.uk/emc/product/4411/smpc (accessed Jan 2022).
• 6 Psychosis and schizophrenia: what else might it be? NICE. 2020. https://cks.nice.org.uk/topics/psychosis-schizophrenia/diagnosis/differential-diagnosis/ (accessed Jan 2022).
• 7 Service user experience in adult mental health: improving the experience of care for people using adult NHS mental health services. NICE. 2011. https://www.nice.org.uk/guidance/cg136/ (accessed Jan 2022).
• 8 Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence . NICE. 2009. https://www.nice.org.uk/guidance/cg76/ (accessed Jan 2022).
• 9 Taylor D, Barnes T, Young A. The Maudsley Prescribing Guidelines in Psychiatry . 13th ed. Hoboken, New Jersey: : Wiley 2018.
• 10 Meltzer HY, Burnett S, Bastani B, et al. Effects of Six Months of Clozapine Treatment on the Quality of Life of Chronic Schizophrenic Patients. PS. 1990; 41 :892–7. doi: 10.1176/ps.41.8.892
• 11 Üçok A, Çikrikçili U, Karabulut S, et al. Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. International Clinical Psychopharmacology. 2015; 30 :290–5. doi: 10.1097/yic.0000000000000086
• 12 Whiskey E, Barnard A, Oloyede E, et al. An Evaluation of the Variation and Underuse of Clozapine in the United Kingdom. SSRN Journal. 2020. doi: 10.2139/ssrn.3716864
• 13 Nielsen J, Dahm M, Lublin H, et al. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol. 2009; 24 :965–71. doi: 10.1177/0269881108100320
• 14 Verdoux H, Quiles C, Bachmann CJ, et al. Prescriber and institutional barriers and facilitators of clozapine use: A systematic review. Schizophrenia Research. 2018; 201 :10–9. doi: 10.1016/j.schres.2018.05.046
• This article was corrected on 31 January 2022 to clarify that tobacco is an enzyme inducer, not an enzyme inhibitor

Useful structured introduction to the subject for clinical purposes

Thank you Amrit for your feedback, we are pleased that you found this article useful.

Michael Dowdall, Executive Editor, Research & Learning

Please note that smoking causes enzyme INDUCTION not INHIBITION as stated. (Via aromatic polyhydrocarbons, not nicotine)

Hi James. Thank you for bringing this to our attention. This has now been corrected. Hannah Krol, Deputy Chief Subeditor

Only with Herbal formula I was able to cure my schizophrenia Illness with the product I purchase from Dr Sims Gomez Herbs A Clinic in South Africa

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Psychosis, a condition marked by a loss of touch with reality, is distressing for those who experience it and their loved ones. If left untreated, psychosis can have serious impacts on people's lives. But the good news is there's hope. In this episode, we talk with Dr. Robert Heinssen, a leader in the development and adoption of coordinated specialty care for treating psychosis. We learn about the signs and symptoms of psychosis, discuss coordinated specialty care, and explore how NIMH research in psychosis and schizophrenia fundamentally changed the health care landscape.

Dr. Heinssen : People may start not so much by hearing voices, but they might hear sounds or their name being called, and they can look around and check and see, "Well, I don't know where that came from." They may become a little bit anxious and attentive of what's going on in their environment, and maybe they start being a little afraid and suspicious that people around them might be observing them or monitoring them in some way. So changes in all of those areas would be some of the early signs that something is amiss.

Dr. Gordon : Psychosis, a condition marked by a loss of touch with reality, is distressing for both those who experience it and their loved ones. If left untreated, psychosis can have serious impacts on people's lives. But the good news is there's hope. Hello, and welcome to Mental Health Matters, a National Institute of Mental Health podcast. I'm Dr. Joshua Gordon, Director of NIMH, and today we'll be talking with Dr. Robert Heinssen, a leader in the development and adoption of coordinated specialty care for treating psychosis. In this episode, we'll learn about the signs and symptoms of psychosis, talk about coordinated specialty care, and discuss how NIMH research in psychosis and schizophrenia fundamentally changed the healthcare landscape. Welcome to Dr. Robert Heinssen of the National Institute of Mental Health. Bob, it's a pleasure to have you here today.

Dr. Heinssen : Dr. Gordon, thank you for this opportunity, and I am equally pleased to be here with you.

Dr. Gordon : Today we're going to talk about psychosis, which is a serious mental condition, of course. Can you talk about what that is exactly?

Dr. Heinssen : Sure. So, psychosis is a condition that affects an individual's perception of reality, their thinking, and their functioning. So to unpack that a little bit, people who are experiencing psychosis may see or hear things that aren't apparent to other individuals. They may have difficulties in their thinking in terms of memory or concentration. Those difficulties may impede their ability to converse with somebody in a fluent way, which has some impact on the person's social relationships, interpersonal relationships. And that can get to be a problem in situations like school and work.

Dr. Gordon : It sounds like it's a real challenge and a burden for those who have it. What causes psychosis?

Dr. Heinssen : Well, there are a variety of pathways to psychosis. You could have a medical condition or an acute infection, a fever that would, in some cases, cause some of these symptoms. Sometimes abuse of substances or alcohol can cause psychotic symptoms. And there are some conditions that are independent of those causes that are mental disorders that start usually in late adolescence and, if untreated, can progress into the person's young adult and adult life.

Dr. Gordon : One of the mental illnesses we often think of as associated with psychosis is schizophrenia. Can you talk about the relationship between psychosis in general and schizophrenia specifically?

Dr. Heinssen : Sure. So, schizophrenia is a very disabling condition, but it includes among the symptoms of that condition, psychosis is a central feature. To make a diagnosis of schizophrenia, professionals require a period of time where psychotic symptoms are present before they'll make the determination that it's clearly schizophrenia. So, for a young person, some of those cognitive problems and perceptual problems might become a barrier to them functioning effectively in a school situation. The anxiety and distress that they feel may cause them to withdraw from other people around them, their friends, other students, even their family members. And that would create the social difficulty and isolation that is often seen later in schizophrenia. And again, without intervention, this can spiral into a set of symptoms and then functional problems that really impede the person's ability to achieve expected developmental milestones of education, relationships, work, and so forth.

Dr. Gordon : So psychosis, and in particular the psychosis that accompanies schizophrenia can be devastating. It can really prevent people from being able to lead normal lives.

Dr. Heinssen : I think devastating is the right word. It's devastating for the individual who is experiencing these symptoms. It's devastating to family members who observe changes and often are unsure of what is driving those changes.

Dr. Gordon : What's one thing you'd want people to understand about psychosis?

Dr. Heinssen : One thing I'd want people to understand is that behind the symptoms are human beings that have hopes and dreams and aspirations just like the rest of us. The symptoms sometimes create a barrier between the person with psychosis and others. If you look behind those symptoms, you see the promise of a human being, of an individual who wants the same things that you want out of life and has the same aspirations, the same type of goals, and the same type of prospects. So if we look beyond the symptoms to the human being, we'll perhaps have more compassion to offer this kind of assistance that help people get to the kind of futures that we all want.

Dr. Gordon : Can people recover from a psychotic episode? Can people get better?

Dr. Heinssen : So, Josh, a little bit of history here. If you asked me that question in 1990, I, like most mental health professionals, would say, "Well, people will get better with treatment. Their chances for full recovery are probably slight." And that was the message that healthcare professionals delivered in the late 1980s, early 1990s. But through research that has identified a critical period for intervention in the early stages of psychosis, we now have a very different story, a much more optimistic story that early intervention can really help people gain control of these symptoms, to get back on track with things like school and relationships and work. And with enduring care, over time, they can expect to lead productive, fulfilling, and meaningful life. So yes. Short answer, yes, recovery is possible.

Dr. Gordon : Tell me about ways that we might be able to help people recognize that something is wrong.

Dr. Heinssen : It's not always clear that something that it's a start of an illness or a disorder, it could just be people might say the child is going through a phase or having a rough spot, but educating the individuals who are experiencing the condition, the parents or caregivers who were surrounding them, the health care providers that would be the first professionals to come in contact and then mobilizing our healthcare system so that there are open doors when individuals present for a consultation and potential care that they have rapid access to those services, that the services can rapidly perform an evaluation and then, when indicated, can rapidly start the treatment. All of those things reduce the interval between the onset of symptoms and the initiation of treatment. And we know from NIMH-supported research that intervals, often called the duration of untreated psychosis, is an important factor in determining how well people will respond to treatment and to what extent they will recover in the long term.

Dr. Gordon : So it's important to detect risk for psychosis early because getting people into treatment early means that they can have better outcomes.

Dr. Heinssen : Yes, time is our enemy. The faster we can identify and intervene, the much more potent are our existing interventions.

Dr. Gordon : Let's say someone does have psychosis. They have schizophrenia, so not necessarily the first episode. What's the role of medication and other forms of treatment for individuals with psychosis?

Dr. Heinssen : We do have individual treatments that do help with components of the experience of psychosis. So antipsychotic medications are an effective strategy for dealing with some of the perceptual problems, the hallucinations that people might be seeing or hearing things that others don't see. They are all also affected with some of the distortions and thinking, some of these ideas that others are monitoring them, there are suspiciousness or worries in that regard. Antipsychotic medications can help with that component of psychosis. Psychotherapies, particularly cognitive and behavioral psychotherapies, are a very effective way of dealing with the distress that people feel and for managing the disruption that has occurred in their lives.

The cognitive and behavioral therapies can help the person, one, come to terms with the experience that they're having. It can reinstill an optimism that recovery is possible and it can help them map out a treatment plan that will set out a roadmap and goals for resuming their normal activities. In addition to that, we know that family education and support is very crucial in helping the family be a support to the individual and help them as they negotiate or navigate their recovery from these episodes.

Dr. Gordon : An important effort in understanding how best to care for these young people who are experiencing their first episode of psychosis was funded by NIMH. The recovery after an initial schizophrenia episode or RAISE Study. What were the main findings? What was involved in getting that off the ground?

Dr. Heinssen : So, a little historical context. By the late 1990s, researchers throughout the world were actually recognizing this idea that early intervention in this critical window could make a real difference. It could help people recover from their initial episode of psychosis and could put them onto a path of more normal functioning. So there were a number of research studies that were exploring how this could be done, and in those, they were testing various models that had these multiple components to address the various symptoms of psychosis. So a number of us at NIMH were looking at these results and thinking, if this could work in the United States, this really could be a very big advance for young people with psychosis and their families.

So three research aims, feasibility, effectiveness, and scalability, were at the heart of the recovery after an initial schizophrenia episode initiative. And NIMH launched that in 2008 and we ended up funding two studies. One of them was a comparative effectiveness study. This took place in 34 community clinics throughout the United States. And 17 of these clinic programs were assigned to that type of coordinated treatment. And then the remaining 17 clinics provided treatment as usual. That study addressed the questions of feasibility and effectiveness. And then a second study, an implementation study, explored what would be potential barriers to implementing such a coordinated approach in public health settings across the U.S.

And that study identified barriers, but more importantly, they developed approaches to be able to surmount those barriers and make it possible that this intervention would be able to be delivered with fidelity and to be done on a broad scale. We had stunning success in both studies. Coordinated treatment was more effective than treatment as usual in terms of improving quality of life and reducing distressing symptoms, and helping individuals return to school and work. These programs led to the adoption of coordinated specialty care by the states of New York and Maryland immediately after the research was concluded. So those two studies set a foundation for a broad implementation of this new approach across the United States.

Dr. Gordon : Can you talk about what effect the RAISE Study has had on mental health care, in particular for health care for first-episode psychosis in the U.S.?

Dr. Heinssen : Sure. I'll start this by saying that NIMH science has been a very critical element in this success story. But it's one element and one thing that I learned is as terrific as our science is, if we don't have partnerships with key stakeholders, it's not a given that science will actually make its way into the healthcare system. So in this case, we did this study in the context of growing awareness among federal partners, among advocacy groups, among private foundations, that early intervention was really a new concept that should be exploited.

And we worked very hard with all of those stakeholders to be able to translate the science into new clinical practice. And hats off to our partners at the Substance Abuse and Mental Health Services Administration who embraced this new scientific approach and partnered with us in disseminating the new approaches, in training people in being able to implement them, and then providing the resources or channeling the resources that Congress provided through their community mental health block grant to fund these new programs, these coordinated specialty care programs via a set aside to their block grant program.

So all of this came together, the science, the partnerships, and the coordinated effort to move the science into practice. And today, it's a much different world. In 2008, we know that there were only two states that had committed to early intervention as a state policy in mental health care. And we estimate that there were only about a dozen high-quality specialty care programs in the United States at that time. A dozen years later, there are over 350 of these programs in all 50 states, and they today serve tens of thousands of young people each year.

Dr. Gordon : Can you compare what treatment and prognosis is like for individuals experiencing their first episode of psychosis before and after RAISE?

Dr. Heinssen : So if we look back in the United States in the late 1990s and early 2000s, in academic circles, there was recognition that early intervention was the way to go, and people were studying ways to do that, but that message had not gone to the broader community. So if you were somebody experienced a first episode psychosis, in all likelihood, your symptoms would really not be recognized until some sort of crisis occurred that required either an emergency department visit or an unplanned inpatient treatment, or in some cases, contact with the police that might result in arrest and involuntary commitment to one of these treatment facilities.

Once you got into treatment, the chances were that you were going to be evaluated and treated by somebody who didn't have a wealth of experience in early psychosis. So your care would likely be fragmented. It may not have been up to the guidelines that existed for medication treatment at that point, and it would not have been continuous. You would have been discharged from an inpatient facility and left on your own, perhaps with the help of your family, to try to navigate outpatient services. Now, today, the best-case scenario is very different. In these programs that have established referral networks in the community, very often, a person can be referred to a first-episode psychosis program before an initial hospitalization. So the differences are really kind of night and day, and the outcomes are also night and day.

Dr. Gordon : Early intervention is key. Before RAISE, before these clinics, did people have to wait a long time for care in order to get it?

Dr. Heinssen : Yeah. In the United States, believe it or not, a person could be psychotic for anywhere between one and three years.

Dr. Gordon : Years?

Dr. Heinssen : Years.

Dr. Gordon : Wow.

Dr. Heinssen : In the RAISE program, the average amount of time a person waited was 18 months. And think about that. Psychotic symptoms, they're very dramatic, and they're very disabling, and they are associated with a lot of distress and pain. And for people experiencing those symptoms for that period of time, it's just astounding that was the state of care.

Dr. Gordon : So RAISE showed us that we can reduce the time to treat psychosis, and we can get people better and keep them better if we get them into a coordinated specialty care treatment and ensure continuity of care. What has NIMH been up to try to solidify that success of RAISE, to make sure that we're doing the best we can to treat individuals in their first episode of psychosis?

Dr. Heinssen : So the results of the RAISE study, the principal results started to become available around 2014, 2015. I think at that point there were maybe somewhere around 50 or 60 of these programs nationwide. So we started thinking there's 50 or 60 of these programs, and it would be great if we had 50 excellent programs in the United States. But imagine what would happen if you linked those programs together so that they could talk to one another, they could share data, they could share learning. So that became the beginning of an idea that we imagined, an Early Psychosis Intervention Network, or EPINET. And the idea started in 2015. And then we took some lessons learned from the RAISE program in developing that idea. We started funding regional networks in 2019.

So this would be a network of like-minded programs that offered services within a defined area. And then we have linked those regional networks through a national data coordinating center. And so together, this enterprise embraces 8 regional networks, 101 community clinics throughout the United States, well, in 17 states. And we're anticipating that somewhere between 3,000 and 4,000 young people with first-episode psychosis will be enrolled in these programs.

Dr. Gordon : Wow. So 100 clinics, thousands of individuals, all participating in an effort to really understand how best to take care of people with first-episode psychosis, what are they learning?

Dr. Heinssen : I like to think of this. If you're a person with cancer and you go to a cancer clinic that's affiliated with a research program, you go in there and you know that information about your care is going to be utilized by that clinic to help them improve the quality of the care that they offer and then also to offer you opportunities to participate in research that may benefit others by generating increased knowledge about cancer and its treatment. We're building that same kind of culture within the EPINET clinics that people come in there and they're first struck with this idea that this is a different experience. The person who's entering this program will know that I'm in a program that looks at its procedures continuously with an eye towards improvement. That's the kind of system that a person will be entering in.

Dr. Gordon : So these learning health care systems, these clinics, they're not just providing care, they're asking the questions that will help them provide better care in the future. Bob, what's it like for a patient who's in one of these first episode psychosis clinics, from their point of view, what are they getting?

Dr. Heinssen : So they're getting access to a treatment team. So it all starts with conversations about what's happened and what's been disrupted for you. What would you like to return to or what would you like to get out of treatment? And then here are some of the tools that we have that we can make available to you. And then that conversation with the treatment team leads to an individualized treatment plan that usually is a combination of the medication, the psychotherapy, the family intervention, and these rehabilitation or supported employment and education activities. Then the interesting thing, what I hear from people who run these programs, young people are interested in getting back on track with their lives. And they embrace this as their job. Their job is to get better and get back on track.

Dr. Gordon : So how long will a person stay in one of these first-episode psychosis clinics? How long will they be in a program like that?

Dr. Heinssen : I would say between one and three years is probably typical. Most programs organize themselves around two years. Important to note that the treatment plans are individualized. So this is not like you're going through a program and that you have the same program over the course of a year or two years. You have an individualized treatment plan, and that plan adjusts continuously based on your recovery, your emerging needs, and so forth.

Dr. Gordon : What inspires you as a scientist?

Dr. Heinssen : So before I came to NIMH, I worked in a psychiatric hospital that was the center of a community treatment program for serious mental illness, for schizophrenia. And I ran a treatment program for adults with serious mental illness, several hundred adults. And these programs, I thought they were quite good in embracing a lot of the science-based treatments that were available at that time. I was very proud of the fact that we were able to move people out of hospital settings into the community and to help them lead independent lives in the community. One day, I was giving a talk about this treatment program and what was available to people with serious mental illness, and I gave the talk. I was very proud to talk about our programs, about how they were science-based, the outcomes we had achieved. And I was feeling very good about this meeting. There was a long line of people who wanted to speak with me afterwards.

The last person was somebody who looked very familiar to me. The woman introduced herself and she said, " Dr. Heinssen , you might remember me. My son so-and-so was in your program." I immediately remembered who she was talking about, and I was thinking, "Boy, this is going to be great. He did so well." He was a young man who had had schizophrenia for several years by the time he came into our program. But we had helped him to achieve his goal of returning to college. He was going to community college. He was taking a course. He was living in an assisted living facility, but he was living in the community. And he was also working part-time in a grocery store. And I thought this was a great...this is a great outcome. And I was waiting for this feedback, boy, what a great outcome. And the woman started crying and she said, "I know I should be grateful, he's doing so much better than he was but we had hoped for so much more."

And that really arrested me thinking that on the one hand, we did the best that we could do given the current state of knowledge, but hubris was not called for in this situation. Humility was called for. I had the opportunity to come to NIMH very shortly after that, and when I had the opportunity to jump on to this early intervention research, that mother's story was in the back of my mind. Her voice was ringing in my ears that we had hoped for so much more. And I thought, "There's so much more that we need to do." That was the initial impetus and that's been the thing that has kept me in the race for as long as I have been, that it is only through research and then through the hard work of implementing the research that we can hope for better outcomes. That really has been the motivation for me over these 22 years. So to that woman, if you hear this podcast, thank you very much. You changed the whole trajectory of my career.

Dr. Gordon : This concludes this episode of Mental Health Matters. I'd like to thank our guest, Dr. Robert Heinssen, for joining us today. And I'd like to thank you for listening. If you enjoyed this podcast, please subscribe and tell a friend to tune in. If you'd like to know more about psychosis or coordinated specialty care, please visit nimh.gov. We hope you'll join us for the next podcast.

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Understanding Schizophrenia: A Case Study

Schizophrenia is characterized mainly, by the gross distortion of reality, withdrawal from social interaction, disorganization and fragmentation of perception, thoughts and emotions. Insight is an important concept in clinical psychiatry, a lack of insight is particularly common in schizophrenia patient. Previous studies reported that between 50-80% of patients with schizophrenia do not believe, they have a disorder. By the help of psychological assessment, we can come to know an individual's problems especially in cases, where patient is hesitant or has less insight into illness. Assessment is also important for the psychological management of the illness. Knowing the strengths and weaknesses of that particular individual with psychological analysis tools can help to make better plan for the treatment. The present study was designed to assess the cognitive functioning, to elicit severity of psychopathology, understanding diagnostic indicators, personality traits that make the individual vulnerable to the disorder and interpersonal relationship in order to plan effective management. Schizophrenia is a chronic disorder, characterized mainly by the gross distortion of reality, withdrawal from social interaction, and disorganization and fragmentation of perception, thought and emotion. Approximately, 1% world population suffering with the problem of Schizophrenia. Both male and female are almost equally affected with slight male predominance. Schizophrenia is socioeconomic burden with suicidal rate of 10% and expense of 0.02-1.65% of GDP spent on treatment. Other co-morbid factors associated with Schizophrenia are diabetes, Obesity, HIV infection many metabolic disorders etc. Clinically, schizophrenia is a syndrome of variables symptoms, but profoundly disruptive, psychopathology that involves cognition, emotion, perception, and other aspects of behavior. The expression of these manifestations varies across patients and over the time, but the effect of the illness is always severe and is usually long-lasting. Patients with schizophrenia usually get relapse after treatment. The most common cause for the relapse is non-adherent with the medication. The relapse rate of schizophrenia increases later time on from 53.7% at 2 years to

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Schizophrenia is a chronic psychiatric illness with high rate of relapse which is commonly associated with noncompliance of medicine, as well as stress and high expressed emotions. The objective of the study was to determine the factors of relapse among the schizophrenic patients attending in outpatient departments of three tertiary level psychiatric facilities in Bangladesh. This was a cross sectional study conducted from July, 2001 to June, 2002. Two hundred patients including both relapse and nonrelapse cases of schizophrenia and their key relatives were included by purposive sampling. The results showed no statistically significant difference in terms of relapse with age, sex, religion, residence, occupation and level of education (p&gt;0.05), but statistically significant difference was found with marital status and economic status (p&lt;0.01). The proportion of non-compliance was found to be 80% and 14%, of high expressed emotion was 17% and 2% and of the occurrence of stressf...

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A Sometimes Overlooked Schizophrenia and Psychosis Symptom

For some, emotions can feel iced..

Updated May 5, 2024 | Reviewed by Abigail Fagan

• What Is Psychosis?
• Find counselling to treat psychosis
• Changes to emotional experience such as emotional blunting is common in schizophrenia.
• A systematic review suggests that art and body-focused therapies may help with emotional blunting.
• New and emerging medications have also shown to be promising in addressing this symptom.

In her Ted Talk, "My Journey Through Schizophrenia and Homelessness" (2006), Bethany Yeiser describes her experience of schizophrenia. She courageously details how her thinking changed and became clouded by beliefs that she would be a prophet and menacing voices. After a battle involving hospitalizations and times of being unhoused, she made a remarkable recovery and now advocates for others while sharing her own story.

Early in her talk, she says, "My heart was like ice." This experience of emotional flatness or blunted affect is common in schizophrenia. On the outside, it can look like a still face, on the inside it can feel like a disconnection. This is one of several schizophrenia symptoms known as negative symptoms, things like loss of motivation , social withdrawal, and flatness.

While not as well-known as the hallmark symptoms of hallucinations and delusions in schizophrenia, research shows that this set of symptoms might better predict a person's functioning (Milev et al., 2005). These symptoms can affect a person's relationships and joy in life. Yet perhaps because these symptoms are sometimes less apparent than others, they often go untreated.

Psychotherapy Approaches

That said, psychotherapy techniques involving focus on the body and the use of art in therapy are effective in treating negative symptoms including emotional blunting in schizophrenia (Isabelina et al., 2023). Research on the use of time and negative symptoms has also uncovered that less productive use of time is often linked with increased negative symptoms (D’Anna et al., 2023). While it is difficult to draw the arrow of causation here, behavior activation might also be a target in treating negative symptoms.

A study of Recovery-Oriented Cognitive Therapy (CT-R) for individuals living with a schizophrenia spectrum disorder with a high level of negative symptoms found a decrease in negative symptoms after the six-month treatment (Grant et al., 2017). This is particularly interesting as CT-R has taken a non-traditional focus in treating serious mental illness. By focusing on cultivating what is called the 'adaptive mode,' or a mindset bent toward how the person is at their best while also invigorating aspirations, the treatment takes a recovery-oriented approach.

New Medications

While the majority of medications currently in use to treat schizophrenia, with the possible exception of clozapine, have not been found effective in treating negative symptoms, newer and investigational medications are showing more positive results. These newer medications appear to have somewhat different mechanisms of action than most antipsychotics .

The medication lumateperone, for example, appears to target glutamate, a neurotransmitter that has been considered in its role of negative symptoms (Gruber et al., 2014) in addition to dopamine and serotonin. This medication has shown some positive effects on negative symptoms of schizophrenia (Tarzian et al., 2023).

Other investigational medications with entirely novel mechanisms of action including KarTX, which is expected to be released later this year are also showing promising effects on negative symptoms like emotion blunting (Horan et al, 2023).

The recent research focus on the long-neglected challenge of negative symptoms in schizophrenia is encouraging. With innovative interventions, more individuals facing this blunting may have an opportunity for an increased quality of life and a sense of connection.

D’Anna, G., Zarbo, C., Cardamone, G., Zamparini, M., Calza, S., Rota, M., ... & de Girolamo, G. (2023). Interplay between negative symptoms, time spent doing nothing, and negative emotions in patients with schizophrenia spectrum disorders: results from a 37-site study. Schizophrenia , 9 (1), 63.

Grant, P. M., Bredemeier, K., & Beck, A. T. (2017). Six-month follow-up of recovery-oriented cognitive therapy for low-functioning individuals with schizophrenia. Psychiatric Services , 68 (10), 997-1002.

Gruber, O., Chadha Santuccione, A., & Aach, H. (2014). Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system. Frontiers in psychiatry , 5 , 32.

Horan, William P., et al. "Potential impact of KarXT on negative symptoms in acute schizophrenia: An analysis of pooled data from 3 trials." CNS Summit (2023).

Milev, P., Ho, B. C., Arndt, S., & Andreasen, N. C. (2005). Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry , 162 (3), 495-506.

Tarzian, M., Ndrio, M., Chique, B., Serai, J., Thalackal, B., Lau, J., ... & Serai, J. K. (2023). Illuminating Hope for Mental Health: A Drug Review on Lumateperone. Cureus , 15 (9).

Yeiser, B. (2016). My Journey Through Schizophrenia and Homelessness. Ted Talk. My journey through schizophrenia and homelessness | Bethany Yeiser | TEDxCincinnati (youtube.com)

Jennifer Gerlach, LCSW, is a psychotherapist based in Southern Illinois who specializes in psychosis, mood disorders, and young adult mental health.

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