Yash Joshi

Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia

Aberrant gamma-band (30–80 Hz) oscillations may underlie cognitive deficits in schizophrenia (SZ). Gamma oscillations and their regulation by NMDA receptors can be studied via their evoked power (γEP) and phase locking (γPL) in response to auditory steady-state stimulation; these auditory steady-state responses (ASSRs) may be biomarkers for target engagement and early therapeutic effects. We previously reported that memantine, an NMDA receptor antagonist, enhanced two biomarkers of early auditory information processing: prepulse inhibition and mismatch negativity (MMN) in SZ patients and healthy subjects (HS). Here, we describe memantine effects on γEP and γPL in those subjects. SZ patients (n=18) and HS (n=14) received memantine 20 mg (p.o.) and placebo over 2 test days in a double-blind, randomized, counterbalanced, cross-over design. The ASSR paradigm (1 ms, 85 dB clicks in 250–0.5 s trains at a frequency of 40 Hz; 0.5 s inter-train interval) was used to assess γEP and γPL. SZ patients had reduced γEP and γPL; memantine enhanced γEP and γPL (p<0.025 and 0.002, respectively) in both SZ and HS. In patients, significant correlations between age and memantine effects were detected for γEP and γPL: greater memantine sensitivity on γEP and γPL were present in younger SZ patients, similar to our reported findings with MMN. Memantine acutely normalized cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Ongoing studies will clarify whether these acute changes predict beneficial clinical, neurocognitive and functional outcomes. These data support the use of gamma-band ASSR as a translational end point in pro-cognitive drug discovery and early-phase clinical trials.

Mismatch negativity impairment is associated with deficits in identifying real-world environmental sounds in schizophrenia

BACKGROUND Patients with schizophrenia (SZ) have impairments in processing auditory information that have been linked to deficits in cognitive and psychosocial functioning. Dysfunction in auditory sensory processing in SZ has been indexed by mismatch negativity (MMN), an event-related potential evoked by a rare, deviant stimulus embedded within a sequence of identical standard stimuli. Although MMN deficits in SZ have been studied extensively, relatively little is known about how these deficits relate to accurately identifying real-world, ecologically-salient sounds. METHODS MMN was assessed in SZ patients (n=21) and non-psychiatric comparison subjects (NCS; n=16). Participants were also assessed in their ability to identify common environmental sounds using a subset of 80 sound clips from the International Affective Digitized Sounds 2nd Ed collection. RESULTS SZ patients made significantly more errors in environmental sound identification (p<0.001, d=0.86) and showed significantly reduced MMN amplitude deficits in MMN compared to NCS (p<0.01, d=0.97). In SZ patients, MMN deficits were associated with significantly greater environmental sound identification errors (r=0.61, p<0.01). CONCLUSIONS Impairments in early auditory information processing in schizophrenia account for significant proportions of variance in the ability to identify real-world, functionally relevant environmental sounds. This study supports the view that interventions targeting deficits in low-level auditory sensory processing may also impact more complex cognitive brain processes relevant to psychosocial disability.

Dissociative Intoxication and Prolonged Withdrawal Associated With Phenibut: A Case Report

To the EditorsNootropic agents, or psychoactive substances intended to augment or enhance cognitive functioning, are becoming increasingly available through the internet. Phenibut (4-amino-3-phenylbutyric acid), an analog of γ-aminobutyric acid (GABA), is licensed in several countries for a variety

Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care

Computerized targeted cognitive training (TCT) of auditory processing has been shown to improve verbal learning in several clinical trials of schizophrenia outpatients. Less is known, however, about the effectiveness of this promising intervention in more chronic, treatment-refractory patients who are treated in non-academic settings. This study aimed to determine whether TCT improves auditory processing, verbal learning, and clinical symptoms in SZ patients mandated to receive care at a locked residential rehabilitation center. Secondarily, potential factors that moderate TCTs effectiveness including age, symptom severity, antipsychotic medication load, and duration of illness were examined. Schizophrenia patients were randomized to treatment as usual (TAU; n = 22) or TAU augmented with TCT (TAU + TCT; n = 24). Outcomes included a measure of auditory perception (Word-In-Noise test, WIN), verbal learning domain scores from the MATRICS Consensus Cognitive Battery (MCCB), and clinical symptoms (Scale for the Assessment of Positive Symptoms, SAPS; Scale for the Assessment of Negative Symptoms, SANS). TCT produced significant improvements in auditory perception (d = 0.67) and verbal learning (d = 0.65); exploratory analyses revealed a statistically significant reduction in auditory hallucinations (d = -0.64). TCTs effects were only weakly, and mostly non-significantly, moderated by age, clinical symptoms, medication, and illness duration. These findings indicate that even highly symptomatic, functionally disabled patients with chronic illness benefit from this emerging treatment. Ongoing studies will examine the predictive utility of neurophysiological biomarkers and other characteristics assessed at baseline.