Joshua Kantrowitz - Academia.edu (original) (raw)

Papers by Joshua Kantrowitz

Biological Psychiatry, 2021

Biological Psychiatry, 2017

Psychiatry research, Mar 23, 2016

There has been recent interest in understanding the role that sleep disturbance plays in patients... more There has been recent interest in understanding the role that sleep disturbance plays in patients at Clinical High Risk for psychosis (CHR). We assessed sleep disturbance in 194 CHR patients and 66 healthy control subjects and their relationship to symptoms (positive, negative and general functioning). Patients experienced significantly more sleep disturbance than healthy control subjects and their sleep disturbance was related to greater positive and negative symptoms and worse overall functioning. Targeting sleep disturbance in CHR individuals may provide alternative means of treating the CHR syndrome.

Current Psychiatry, Sep 1, 2013

Handbook of Neurochemistry and Molecular Neurobiology, 2009

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 4, 2015

Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key comp... more Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key component of social cognitive impairment. AER deficits are tied behaviorally to impaired ability to interpret tonal ("prosodic") features of speech that normally convey emotion, such as modulations in base pitch (F0M) and pitch variability (F0SD). These modulations can be recreated using synthetic frequency modulated (FM) tones that mimic the prosodic contours of specific emotional stimuli. The present study investigates neural mechanisms underlying impaired AER using a combined event-related potential/resting-state functional connectivity (rsfMRI) approach in 84 schizophrenia/schizoaffective disorder patients and 66 healthy comparison subjects. Mismatch negativity (MMN) to FM tones was assessed in 43 patients/36 controls. rsfMRI between auditory cortex and medial temporal (insula) regions was assessed in 55 patients/51 controls. The relationship between AER, MMN to FM tones, and r...

Are Schizophrenia Patients Amusical? : The Role of Pitch and Rhythm in Auditory Emotion Recogniti... more Are Schizophrenia Patients Amusical? : The Role of Pitch and Rhythm in Auditory Emotion Recognition Impairments in Schizophrenia

Schizophrenia Research, 2014

The last fifteen years have seen a great increase in our understanding of the role of glutamate i... more The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy (1 H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ. 1 H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of 1 H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.

Schizophrenia Research, 2010

Psychological Medicine, 2013

BackgroundIntact sarcasm perception is a crucial component of social cognition and mentalizing (t... more BackgroundIntact sarcasm perception is a crucial component of social cognition and mentalizing (the ability to understand the mental state of oneself and others). In sarcasm, tone of voice is used to negate the literal meaning of an utterance. In particular, changes in pitch are used to distinguish between sincere and sarcastic utterances. Schizophrenia patients show well-replicated deficits in auditory function and functional connectivity (FC) within and between auditory cortical regions. In this study we investigated the contributions of auditory deficits to sarcasm perception in schizophrenia.MethodAuditory measures including pitch processing, auditory emotion recognition (AER) and sarcasm detection were obtained from 76 patients with schizophrenia/schizo-affective disorder and 72 controls. Resting-state FC (rsFC) was obtained from a subsample and was analyzed using seeds placed in both auditory cortex and meta-analysis-defined core-mentalizing regions relative to auditory perfor...

Expert Opinion on Drug Safety, 2008

Olanzapine is a second-generation antipsychotic approved for the treatment of schizophrenia, bipo... more Olanzapine is a second-generation antipsychotic approved for the treatment of schizophrenia, bipolar mania and associated agitation. To assess the safety profile of olanzapine, including its propensity to be associated with weight gain, diabetes mellitus and dyslipidemias. Review of English-language reports located through PubMed and information available on regulatory agency websites. The use of olanzapine can pose a therapeutic dilemma in that on one hand, a number of large scale studies have found effectiveness advantages for olanzapine in comparison to other first-line second-generation medications. On the other hand, olanzapine is associated with substantial weight gain and the development of dyslipidemia. Regarding other important safety concerns, olanzapine has a favorable profile in terms of extra-pyramidal side effects and is also relatively prolactin-sparing. The effectiveness benefits may outweigh the risks, particularly in patients with low baseline risk for metabolic syndrome but monitoring for untoward metabolic effects crucial. Switch-or-stay and other intervention decisions need to be made early before substantial weight gain has occurred.

American Journal of Psychiatry, 2007

LETTERS TO THE EDITOR ajp.psychiatryonline.org total cholesterol level was 408 mg/dl, and his tot... more LETTERS TO THE EDITOR ajp.psychiatryonline.org total cholesterol level was 408 mg/dl, and his total triglyceride level was 2,796 mg/dl. Unfortunately, he developed depression and akathisia with the switch to aripiprazole. The aripiprazole dose was tapered to 15 mg, and a regimen, including enteric-coated valproic acid (1500 mg every night), sertraline (100 mg every morning), clonazepam (0.5 mg bid), and zolpidem (10 mg every night), appeared to be effective. One month later, the patient's total cholesterol level was 310 mg/dl and total triglyceride level was 1,313 mg/dl. After another month, the total cholesterol decreased to 260 mg/dl and the total triglycerides decreased to 400 mg/dl, respectively; high-density lipoprotein was 32 mg/dl, low-density lipoprotein was 48 mg/dl, and glucose was153 mg/dl. After another month, the patient's total cholesterol level was 263 mg/dl, and his total triglyceride level increased to 527 mg/dl. He reported difficulty sleeping and receiving quetiapine at night (100-300 mg). After observing the lipid increase, the patient agreed to discontinue quetiapine. One month later, his total cholesterol level was 207 mg/dl and total triglyceride level was 300 mg/dl.

Journal of clinical psychopharmacology, 2017

Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive d... more Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia and are associated with impaired generation of event-related potential measures including auditory mismatch negativity. Parallel studies of the NMDAR agonist D-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport. This study investigates effects of bitopertin on NMDAR-related event-related potential deficits in schizophrenia. Patients with schizophrenia/schizoaffective disorder were treated with bitopertin (10 mg, n = 29), in a double-blind, parallel group investigation. Auditory mismatch negativity served as primary outcome measures. Secondary measures included clinical symptoms and neurocognitive performance. No significant changes were seen with bitopertin for neurophysiological, clinical, or neurocognitive assessme...

Core Evidence, Jul 31, 2008

Paliperidone, the 9-hydroxy metabolite of risperidone, is a second-generation antipsychotic that ... more Paliperidone, the 9-hydroxy metabolite of risperidone, is a second-generation antipsychotic that was recently approved for the treatment of schizophrenia. It is marketed as an improvement over risperidone, but is likely to be considerably more costly when risperidone is no longer protected by patent. To review the evidence for the clinical impact of paliperidone in the treatment of patients with schizophrenia, particularly in contrast to risperidone. Paliperidone is primarily metabolized and excreted renally, and thus may be of particular utility for patients with hepatic impairment. There is clear evidence that paliperidone is more efficacious than placebo in reducing the positive and negative symptoms of schizophrenia. In patients with schizophrenia, paliperidone has been shown to stabilize acute psychotic symptoms. There is some evidence that it can prevent relapse in stabilized patients. Studies on the cost effectiveness of paliperidone are needed. Most importantly, there are no...

Neuropsychopharmacology

Serotonin type-3 receptor (5-HT 3 R) antagonists show potential as a treatment for cognitive defi... more Serotonin type-3 receptor (5-HT 3 R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT 3 R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT 3 R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT 3 R, and support the potential utility of CVN058 in correcting the excitatory/ inhibitory imbalance in schizophrenia.

CNS Drugs

The specific efficacy of antipsychotics on negative symptoms is questionable, suggesting an urgen... more The specific efficacy of antipsychotics on negative symptoms is questionable, suggesting an urgent need for specific treatments for negative symptoms. This review includes studies published since 2014 with a primary or secondary focus on treating negative symptoms in schizophrenia. Special emphasis is given to recently published meta-analyses. Topics include novel pharmacological approaches, including glutamatergic-based and nicotinic-acetylcholinergic treatments, treatments approved for other indications by the US FDA (or other regulatory bodies) (antipsychotics, antidepressants, and mood stabilizers), brain stimulation, and behavioral- and activity-based approaches, including physical exercise. Potential complications regarding the design of current negative symptom trials are discussed and include inconsistent placebo effects, lack of reliable biomarkers, negative symptom scale and inclusion criteria variability, attempts to distinguish between primary and secondary negative symptoms, lack of focus on early psychosis, and the potential iatrogenic bias of clinical trials.

The Journal of Clinical Psychiatry, 2015

Letter to the Editor Single-Dose Ketamine Followed by Daily d-Cycloserine in Treatment-Resistant ... more Letter to the Editor Single-Dose Ketamine Followed by Daily d-Cycloserine in Treatment-Resistant Bipolar Depression Figure 1. Sustained Response/Remission After Acute Ketamine Followed by Daily d-Cycloserine in Treatment-Resistant Bipolar Depression a a Change in Hamilton Depression Rating Scale (HDRS) (A) and Beck Depression Inventory (BDI) (B) mixed-model analysis results are noted on figures, with *P < .05 and **P < .01 on a last-observationcarried-forward paired t test (gray bar represents remission cutoff). The relationship between acute improvement after ketamine (day 1) vs improvement after 8 weeks of d-cycloserine treatment (C) is shown in a scatter plot across the HDRS (circle) and the BDI (triangle). study, with 3 successfully obtaining insurance coverage, further suggesting tolerability by the patients taking d-cycloserine. Discussion. These findings provide proof-of-concept for further study of combined treatment with NMDAR antagonists and FDA-approved medications for bipolar depression. Although d-cycloserine is generally well tolerated by psychiatric populations, 7 See commentary by Iosifescu p738 To the Editor: Bipolar depression is a leading cause of disability in the United States. Recently, N-methyl-d-asparate glutamatereceptor (NMDAR) antagonists, such as ketamine, have been shown to induce remission in bipolar depression. 1,2 Nevertheless, ketamine use is limited by transient effects and psychogenic potential during repeated administration. 3 d-Cycloserine is a US Food and Drug Administration (FDA)-approved antituberculosis drug that acts as an NMDAR antagonist when used at high doses (> 750 mg). d-Cycloserine targets the glycine coreceptor of the NMDAR and may have improved safety relative to ketamine (analogous to use of benzodiazepines vs barbiturates at γ-aminobutyric acid-A receptors). Antidepressant effects of d-cycloserine were first noted in the 1950s. 4-6 However, double-blind, placebo-controlled studies at high doses were not conducted until recently. 7 A large, betweengroup, large effect-size (d = 0.91, P = .005) difference was seen in unipolar depression, corresponding to a mean 48% reduction in symptoms. We report the first study of acute ketamine followed by daily d-cycloserine in bipolar depression (ClinicalTrials.gov identifier NCT01833897). This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher's Terms & Conditions.

The Lancet Psychiatry, 2015

Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely... more Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals. We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620. We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2). This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia. National Institutes of Health.

Protocols, 1996

Dementia is the most common degenerative neuropsychiatric disorder, affecting up to 50% of commun... more Dementia is the most common degenerative neuropsychiatric disorder, affecting up to 50% of community-dwelling elders over the age of 85 (Sink 2005). Dementia is a syndrome of concurrent impairments in cognition and level of functioning (APA 2000). Behavioural and ...

Schizophrenia Research, 2006

Three cases of risperidone-induced enuresis Dear Editors, Antipsychotic-induced enuresis is a rar... more Three cases of risperidone-induced enuresis Dear Editors, Antipsychotic-induced enuresis is a rare, but a potentially treatment-limiting side effect (Agarwal, 2000). The reported rates of this adverse event (Physicians' Desk Reference, 2005; Shaikh, 1978), listed in Table 1, are generally less than 1%, although there is evidence that Clozapine has higher rates (Lin et al., 1999). Moreover, an open study (Vokas et al., 1997) found that risperidone doubled the rate of enuresis in a clinic population. Risperidone-induced enuresis is most commonly reported in children treated with risperidone in combination with serotonergic antidepressants (Took and Buck, 1996) or in combination with mood stabilizers (Physicians' Desk Reference, 2005), but we found only two adult case-reports (Agarwal, 2000). We report three cases of probable risperidone-induced enuresis in three psychiatrically stable African-American women treated for chronic psychotic disorders. Patient initials have been changed to protect confidentiality.