Frontostriatal Structural Connectivity and Striatal Glutamatergic Levels in Treatment-Resistant Schizophrenia: An Integrative Analysis of DTI and 1H-MRS

Abstract Given that approximately one-third of patients with schizophrenia do not respond to antipsychotics, different neurobiological bases may underlie treatment resistance in schizophrenia. Previous studies showed that treatment response is associated with both frontostriatal connectivity and glutamatergic neurometabolite levels in the caudate in patients with schizophrenia, which leads to the hypothesis that the relationship between them may be altered, specifically in patients with treatment-resistant schizophrenia (TRS). Employing analyses of covariance and subsequent partial correlation analyses, we compared the relationship between glutamate+glutamine (Glx) levels in the caudate and fractional anisotropy (FA) values in the tract between the dorsolateral prefrontal cortex and caudate in 19 patients with TRS, 20 patients responsive to first-line antipsychotics (FL-Resp), and 19 healthy controls (HCs). TRS was defined by severe positive symptomatology despite first-line antipsychotic treatment. Patients with TRS had lower FA values in the bilateral frontostriatal tracts than patients with FL-Resp and HCs (P < .001), while no group differences were found in caudate Glx levels. There was a significant frontostriatal FA value-by-group interaction on caudate Glx levels (F = 7.37, P = .009). Frontostriatal FA values positively correlated with caudate Glx levels in HCs (r = −.55, P = .028), while they were negatively associated with caudate Glx levels in the TRS group (r = .53, P = .043). Furthermore, in the FL-Resp group, frontostriatal FA values did not significantly correlated with caudate Glx levels. The altered relationship between white matter integrity and the glutamate system in the frontostriatal circuit in the TRS group may reflect the pathophysiology underlying treatment response/resistance in schizophrenia.

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Interaction of Cannabis Use Disorder and Striatal Connectivity in Antipsychotic Treatment Response

Schizophrenia Bulletin Open ◽

10.1093/schizbullopen/sgaa014 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Melanie Blair Thies ◽

Pamela DeRosse ◽

Deepak K Sarpal ◽

Miklos Argyelan ◽

Christina L Fales ◽

...

Keyword(s):

Treatment Response ◽

Reward Processing ◽

Cannabis Use ◽

First Episode ◽

Antipsychotic Treatment ◽

Cannabis Use Disorder ◽

Schizophrenia Spectrum Disorders ◽

Double Blind ◽

History Of ◽

The Relationship

Abstract Antipsychotic (AP) medications are the mainstay for the treatment of schizophrenia spectrum disorders (SSD), but their efficacy is unpredictable and widely variable. Substantial efforts have been made to identify prognostic biomarkers that can be used to guide optimal prescription strategies for individual patients. Striatal regions involved in salience and reward processing are disrupted as a result of both SSD and cannabis use, and research demonstrates that striatal circuitry may be integral to response to AP drugs. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the relationship between a history of cannabis use disorder (CUD) and a striatal connectivity index (SCI), a previously developed neural biomarker for AP treatment response in SSD. Patients were part of a 12-week randomized, double-blind controlled treatment study of AP drugs. A sample of 48 first-episode SSD patients with no more than 2 weeks of lifetime exposure to AP medications, underwent a resting-state fMRI scan pretreatment. Treatment response was defined a priori as a binary (response/nonresponse) variable, and a SCI was calculated in each patient. We examined whether there was an interaction between lifetime CUD history and the SCI in relation to treatment response. We found that CUD history moderated the relationship between SCI and treatment response, such that it had little predictive value in SSD patients with a CUD history. In sum, our findings highlight that biomarker development can be critically impacted by patient behaviors that influence neurobiology, such as a history of CUD.

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

Psychological Medicine ◽

10.1017/s0033291717000435 ◽

2017 ◽

Vol 47 (11) ◽

pp. 1981-1989 ◽

Cited By ~ 78

Author(s):

A. Demjaha ◽

J. M. Lappin ◽

D. Stahl ◽

M. X. Patel ◽

J. H. MacCabe ◽

...

Keyword(s):

Negative Symptoms ◽

Age At Onset ◽

Treatment Resistance ◽

First Episode Psychosis ◽

First Episode ◽

Antipsychotic Treatment ◽

Treatment Resistant ◽

Illness Onset ◽

Episode Psychosis

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

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Increased prevalence of toxoplasma gondii seropositivity in patients with treatment-resistant schizophrenia

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.1640 ◽

2017 ◽

Vol 41 (S1) ◽

pp. s834-s834

Author(s):

M. Sagud ◽

S. Vlatkovic ◽

D. Svob Strac ◽

M. Sviben ◽

M. Zivkovic ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Suicide Attempts ◽

Disease Onset ◽

Depression Scale ◽

Time History ◽

Treatment Resistance ◽

Life Time ◽

Treatment Resistant ◽

Cross Sectional ◽

The Relationship

IntroductionPrevious studies suggested that patients with schizophrenia had an increased prevalence of antibodies against toxoplasma gondii (TG) and that those seropositive patients had higher symptom severity. However, there is no data on the relationship between treatment-resistant schizophrenia (TRS) and TG seroprevalence.ObjectivesTo determine the association between TRS and TG seropositivity, and to further investigate the relationship between TG seropositivity and different clinical features of schizophrenia.MethodsIn this cross-sectional study, we included 210 male inpatients with schizophrenia. TG seropositivity was determined by ELFA assay. Treatment-resistance was defined as a failure of at least 2 adequate anti-psychotic trials. Data were analyzed using χ2 test or Mann–Whitney test.ResultsThe rate of TG seropositivity in the entire sample was 52.3%, whereas 47.6% of patients met the definition for treatment-resistance. Seropositive patients had twice the rate of treatment–resistance compared to seronegative patients (63.6% vs. 30.0%, P < 0.0001). Moreover, in the seropositive group, the patients were older (47.6 ± 12.2 vs. 39.81 ± 12.01 years, P < 0.0001), had higher number of previous hospitalizations (13.9 ± 11.7 vs. 9.6 ± 8.5, P = 0.0073), and increased Calgary depression scale for schizophrenia (CDSS) total score (7.8 ± 4.5 vs. 6.3 ± 3.8, P = 0.012). There were no differences between the groups in the age of disease onset, smoking, positive and negative syndrome scale (PANSS) total, positive and negative scores, and the life-time history of suicide attempts.ConclusionsOur results support the hypothesis that TG seropositivity might contribute to treatment-resistance in schizophrenia, at least in male patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Treatment response and resistance in schizophrenia: principles and definitions

10.1093/med/9780198828761.003.0002 ◽

2018 ◽

Cited By ~ 1

Author(s):

Robert McCutcheon ◽

Christoph U. Correll ◽

Oliver Howes ◽

John Kane

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Treatment Response ◽

Working Group ◽

Treatment Resistance ◽

Consensus Guidelines ◽

Treatment Resistant

Clear, accepted definitions of treatment resistance and response are needed so that clinical trials of treatments can be compared, and evidence can be meaningfully interpreted to inform clinical practice. In this chapter, we review the definitions of treatment response and resistance used in clinical trials, highlighting the variability in definitions used across studies, as well as a number of problems with the definitions used, including mixing treatment-intolerant patients with treatment-resistant patients and limited evaluation of the adequacy of treatment in many cases. The chapter then summarizes the work undertaken by the Treatment Response and Resistance in Psychosis working group to produce consensus guidelines and benchmarks to address these issues. Also reviewed are the principles underlying the concept of resistance developed by the working group. Finally, the chapter discusses the implications of these findings for clinical practice.

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Predictors of antipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreniform disorders

The British Journal of Psychiatry ◽

10.1192/bjp.185.1.18 ◽

2004 ◽

Vol 185 (1) ◽

pp. 18-24 ◽

Cited By ~ 102

Author(s):

Diana O. Perkins ◽

Jeffrey A. Lieberman ◽

Hongbin Gu ◽

Mauricio Tohen ◽

Joseph McEvoy ◽

...

Keyword(s):

Clinical Response ◽

Treatment Response ◽

Negative Symptoms ◽

Positive Symptom ◽

First Episode ◽

Antipsychotic Treatment ◽

Duration Of Untreated Psychosis ◽

First Episode Schizophrenia ◽

Relationship Of ◽

The Relationship

BackgroundDuration of untreated psychosis (DUP) may contribute to the observed heterogeneity of the treatment response in first-episode schizophrenia.AimsTo examine the relationship of DUP and premorbid function with clinical outcomes following up to 2 years of antipsychotic treatment.MethodFor a subsample (n = 191) of subjects participating in a clinical trial, DUP and premorbid function were prospectively compared with clinical response to olanzapine or haloperidol.ResultsShorter DUP and good premorbid function each independently are associated with better clinical response, including improvement in overall psychopathology and negative symptoms. Premorbid function also is associated with positive symptom, social and vocational outcomes.ConclusionsEarlier antipsychotic treatment is associated with better outcomes in first-episode schizophrenia. Poor premorbid function could indicate an illness subtype less likely to respond to antipsychotic treatment regardless of when it is instituted.

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S62. COGNITIVE DEFICITS IN TREATMENT RESISTANT SCHIZOPHRENIA

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.128 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S56-S57

Author(s):

Edward Millgate ◽

Eugenia Kravariti ◽

James MacCabe ◽

Olga Hide

Keyword(s):

Executive Function ◽

Cognitive Deficits ◽

Verbal Memory ◽

Antipsychotic Drugs ◽

Treatment Resistance ◽

Antipsychotic Treatment ◽

Verbal Intelligence ◽

Treatment Resistant ◽

Domain Specific ◽

Visual Spatial

Abstract Background Schizophrenia (Sz) and other psychoses are complex mental disorders, characterised by sensory, cognitive and emotional symptoms, but mainly distinguished by positive and negative symptoms. Cognitive impairment is a core feature of schizophrenia, with research into cognitive deficits indicating that cognitive impairment precedes clinical disease onset and is still evident after positive symptoms are no longer present. The current mainstream treatment for Sz are first and second-generation antipsychotics, such as chlorpromazine and aripiprazole respectively. However, about a third of patients treated with antipsychotic drugs have no change in their symptoms despite adequate trials of several antipsychotic drugs. Treatment-resistant schizophrenia (TRS) refers to individuals with a F20-F29 diagnosis who have had at least two courses of antipsychotic treatment with little to no symptomatic relief. Emerging evidence into the factors associated with antipsychotic treatment response has investigated genetic, demographic and clinical factors and their relation to treatment response, with emerging evidence from cognitive data inferring a domain specific deficit in TRS populations for verbal, general cognition (IQ) and executive function tasks. Methods Publications were selected from a systematic search from four databases: PsycINFO, Ovid MEDLINE(R), Scopus and Web of Science. Following inclusion/exclusion criteria, cognitive test outcomes were extracted for each responder group (TRS/NTRS; treatment responders), as well as variables such as age of psychotic illness onset, average chlorpromazine equivalents and duration of illness. Neuropsychological tasks and subtests identified across publications were then grouped into one of seven exclusive cognitive domains (e.g. executive function) prior to analysis based on recommendations from existing literature. Following this, a random-effects model was adopted to test the differences between responder groups in each cognitive domain across publications. Results From the 17 publications identified, sample sizes ranged from 817 to 36, with the majority of publications using a sample size of ~65 TRS/NTRS cases, and a total sample size of N = 1,943 across studies. The random-effects model indicates that cases reaching treatment resistance criteria demonstrated marked neuropsychological performance generally across all domains (d = 0.372, 95CIs 0.29; 0.46], p< .001), with this being most marked in tasks of verbal memory and learning (d = 0.49, 95CIs [0.28; 0.70], p<. 001), verbal intelligence and processing (d = 0.38, 95CIs [0.17; 0.58], p< .001), IQ/general cognitive functioning (d = 0.46, 95CIs [0.17; 0.75], p = 0.002), attention, Working memory and Visual-motor/processing speed (d = 0.38, 95CIs [0.24; 0.51], p< 0.001) and executive function (d = 0.41, 95CIs [0.13; 0.68], p = 0.003), with these all demonstrating a close to medium effect size. There was no significant differences between responder groups in test performance for visual-spatial memory and learning (d = .16, 95CIs [-0.16; 0.48], p = 0.334) and visual-spatial intelligence and processing (d = .50, 95CIs [-0.05; 01.04], p = 0.074) tasks. Discussion In line with existing literature, treatment resistant schizophrenia appears to demonstrate domain specific marked performance on tasks relating to verbal memory, verbal intelligence, as well as tasks relating to executive function, attention and working memory in relation to responders. When considering the clinical importance of identification of treatment resistance in the early disease stages (i.e. at first episode) the use of domain specific cognitive testing could help improve prediction of future antipsychotic response/non-response.

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S67. TREATMENT-RESISTANCE AFFECTS LONG-TERM COGNITIVE TRAJECTORIES IN SCHIZOPHRENIA: A LONGITUDINAL STUDY

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.133 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S59-S59

Author(s):

Marco Spangaro ◽

Marta Bosia ◽

Margherita Bechi ◽

Mariachiara Buonocore ◽

Francesca Martini ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Cognitive Functioning ◽

Effect Size ◽

Treatment Resistance ◽

Cognitive Outcome ◽

Treatment Resistant ◽

First Line ◽

Index Effect

Abstract Background Schizophrenia is a highly heterogeneous disorder, and despite extensive research progress approximately 30% of patients with schizophrenia show poor response to first-line antipsychotics, denoted as treatment-resistant schizophrenia (TRS). Meta-analytic evidence showed that clozapine is the most effective antipsychotic for TRS, although 40% of TRS patients do not respond even to clozapine (ultra-treatment-resistant schizophrenia -UTR). Recent studies indicated that TRS is neurobiologically and categorically distinct from treatment-responsive schizophrenia, being associated with elevated glutamate levels in the anterior cingulate cortex and unaltered striatal dopamine synthesis. Moreover, the striking majority of TRS patients do not respond to first-line antipsychotic therapy since disease onset and present more severe cognitive deficits since first episode of psychosis, further suggesting the presence of a distinct and more disrupted neurobiological substrate. It is widely known that cognitive impairment is a core feature of schizophrenia and determines a significant detrimental impact on long-term functional outcome, which represents the ultimate treatment goal. However, despite the central role of cognition in schizophrenia, to date no study has investigated longitudinal cognitive outcome among TRS patients. Based on these evidences, the aim of this study is to evaluate longitudinal cognitive trajectories in a sample of clinically stabilized patients with schizophrenia, stratified according to antipsychotic response. We hypothesized that treatment-resistance is associated with a more severe long-term cognitive decline. Methods We enrolled 93 patients with schizophrenia (DSM-V), stratified as follows: 32 first-line responders (FLR), 42 TRS and 19 UTR. Cognition was longitudinally assessed at baseline and at least after 6 years of follow-up (mean: 9.3±2.8 years) using the Brief Assessment of Cognition in Schizophrenia (BACS). From BACS subscores we calculated for each patient a Cognitive Index, as a measure of overall cognitive functioning. In order to quantify global cognitive functioning changes during the course of illness, we estimated effect size score for Cognitive Index using Cohen’s d. Finally, General linear Models (GLM) were performed with overall cognitive index effect size as dependent variable, treatment (FLR/TRS/UTR) as categorical variable and age, duration of illness and education as covariates. Results The first GLM (FLR vs TRS+UTR) showed a significant main effect of treatment (F=7.34, p=0.01), with worse cognitive outcome between resistant patients. Consistently, the second GLM (FLR/TRS/UTR) resulted significant as well (F=17.90, p<0.001), with UTR group showing worse cognitive trajectory (Fisher’s post-hoc: p<0.001, UTR Cognitive Index effect size = -0.7). Discussion This is the first study to longitudinally evaluate cognitive trajectories of patients with schizophrenia according to their antipsychotic response. We showed that treatment resistance is associated with a more severe cognitive decline, with worse outcome among UTR patients. These data suggest that greater severity of treatment resistance in schizophrenia is associated with greater cognitive impairment, possibly due to the presence of a distinct and more disrupted neurobiological substrate that affects both cognition and antipsychotic response. These findings further highlight the necessity of early individuation and tailored pharmacological treatment for TRS patients, in order to improve long-term clinical, cognitive and functional outcome.

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MMPI Indicators of Treatment Response to Spinal Epidural Stimulation in Patients with Chronic Pain and Patients with Movement Disorders

Psychological Reports ◽

10.2466/pr0.1982.51.3f.1059 ◽

1982 ◽

Vol 51 (3_suppl) ◽

pp. 1059-1064 ◽

Cited By ~ 20

Author(s):

Marvin A. Brandwin ◽

Donald G. Kewman

Keyword(s):

Chronic Pain ◽

Treatment Response ◽

Movement Disorders ◽

Minnesota Multiphasic Personality Inventory ◽

Treatment Resistance ◽

Subjective Ratings ◽

Treatment Resistant ◽

Psychological Variables ◽

Epidural Stimulation ◽

Spinal Epidural

The usefulness of the Minnesota Multiphasic Personality Inventory (MMPI) for predicting treatment response to electrical spinal epidural stimulation was examined in 11 patients with chronic pain and 11 patients with movement disorders. The movement-disordered group had generally lower MMPI scores than the group with chronic pain and higher subjective ratings of improvement. However, physicians' ratings for the group as a whole showed that scores on Hs and Hy, while elevated, tended to be relatively lower for patients who were treatment resistant than for those rated as successes. Higher elevations on D were associated with treatment failure. The “conversion V” profile as an indicator of treatment resistance did not hold for this sample. The psychological implications of these findings are discussed. The results suggest that the MMPI has predictive value but the need for refinement of outcome measures and further clarification of psychological variables is evident.

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Functional connectivity as a means to delineate differences between treatment-resistant and treatment-responsive schizophrenia

Journal of Neurophysiology ◽

10.1152/jn.01127.2015 ◽

2016 ◽

Vol 116 (2) ◽

pp. 229-231 ◽

Cited By ~ 4

Author(s):

Sara Paul ◽

Nathan Sharfman

Keyword(s):

Functional Connectivity ◽

Treatment Response ◽

Brain Regions ◽

Antipsychotic Treatment ◽

Treatment Resistant

It has been estimated that one-third of schizophrenia patients are treatment resistant (TRS). Recent studies have shown that functional connectivity (FC) can be used for measuring connections between brain regions in diseased states. White, Wigton, Joyce, Collier, Fornito, and Shergill ( Neuropsychopharmacology. First published September 9, 2015; doi:10.1038/npp.2015.277) used FC to identify differences between schizophrenia patients responding to antipsychotic treatment and TRS patients. Their results support the idea that the groups differ not only in treatment response but also neurophysiologically through differences in FC.

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T137. THE RELATIONSHIP BETWEEN CORTICOSTRIATAL CONNECTIVITY AND STRIATAL DOPAMINE FUNCTION IN SCHIZOPHRENIA: AN 18F-DOPA PET AND DIFFUSION TENSOR IMAGING STUDY

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.697 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S282-S283

Author(s):

Sangho Shin ◽

Euitae Kim

Keyword(s):

Prefrontal Cortex ◽

Dorsolateral Prefrontal Cortex ◽

Striatal Dopamine ◽

Dopamine Synthesis ◽

Treatment Resistant ◽

Control Subjects ◽

Dorsolateral Prefrontal ◽

Healthy Control ◽

The Relationship ◽

And Diffusion

Abstract Background Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia pathophysiology, which underlies in majority of treatment-responsive patients. Although supported by findings that prefrontal cortical lesions lead to striatal dopamine dysregulation and that recently, prefrontal structural volume is negatively correlated with striatal dopamine synthesis, the relationship between corticostriatal connectivity and striatal dopamine synthesis has not been tested in patients with schizophrenia. We therefore investigated the relationship between corticostriatal connectivity and striatal dopamine synthesis capacity in treatment-responsive patients with schizophrenia, and compared them to treatment-resistant patients and healthy control subjects. Methods Twenty-four patients with schizophrenia and twelve matched healthy control subjects underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer), structural and diffusion 3T MRI. Connectivity(indexed as Fractional anisotropy, FA) were assessed in 3 major corticostriatal tracts (dorsolateral prefrontal cortex-associative striatum, ventromedial prefrontal cortex-limbic striatum, and pre/primary motor cortex-sensorimotor striatum). Furthermore, these measures were tested whether they were correlated with a measure of Wisconsin Card Sorting Test (WCST). Results Treatment responsive patients showed a negative correlation between connectivity of dorsolateral prefrontal cortex-associative striatum and striatal dopamine synthesis capacity of associative striatum, but this was not evident in treatment-resistant patients. Furthermore, WCST negatively correlated with Kicer in associative striatum and positively correlated with FA in dorsolateral prefrontal cortex-associative striatum in whole subjects and treatment responsive patients but not in treatment-resistant patients. Discussion These findings demonstrate that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia and especially, connectivity of dorsolateral prefrontal cortex-associative striatum is a core part for the different pathophysiology.

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