Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

Comparison of Delivery of Care Before and During COVID-19 Within an Academic Outpatient Psychiatry Practice.

Introduction: The COVID-19 pandemic has challenged outpatient mental health clinics. This article compares care delivery and patient characteristics before and during the COVID-19 pandemic in outpatient mental health clinics within an academic health system. Methods: A retrospective cohort study was conducted in patients who received outpatient psychiatric services at two clinics (A and B). The investigators compared care delivery with patients with mental health conditions prepandemic (January 1-December 31, 2019) and midpandemic (January 1-December 31, 2020) periods. Care delivery was defined as the number and type of new and return visits (telehealth and face-to-face visits), patients with recorded measurement-based care (MBC) outcomes, and communication capability between patients and providers. Results: During the prepandemic period, 6,984 patients were seen in Clinics A and B, resulting in 57,629 visits. In the midpandemic period, 7,110 patients were served, resulting in 61,766 total visits. Medication management visits increased from 2019 to 2020; number of visits with documented outcome measures increased by 90% in Clinic A and 15% in Clinic B. The number of MyChart messages per patient increased more than twofold during the midpandemic period. The number of new visits with primary diagnosis of anxiety disorders increased in CY2020 and the number of visits with primary diagnosis of major depressive/mood disorders decreased in CY2020. Payor mix did not vary between the two periods although there was variability between payor mix at the two primary clinic locations. Discussion: The study suggests that there was no detrimental impact on access to care between the prepandemic and midpandemic periods within the health system. Mental health visits while pivoting to telehealth increased during the midpandemic period. Transition to telepsychiatry improved the ability to administer and document MBC.

Auditory discrimination and frequency modulation learning in schizophrenia patients: amphetamine within-subject dose response and time course.

BACKGROUND: Auditory frequency modulation learning ('auditory learning') is a key component of targeted cognitive training (TCT) for schizophrenia. TCT can be effective in enhancing neurocognition and function in schizophrenia, but such gains require significant time and effort and elude many patients. METHODS: As a strategy to increase and/or accelerate TCT-induced clinical gains, we tested the dose- and time-course effects of the pro-attentional drug, amphetamine (AMPH; placebo, 2.5, 5 or 10 mg po; within-subject double-blind, order balanced) on auditory learning in schizophrenia patients [n = 32; M:F = 19:13; age 42.0 years (24-55)]. To understand predictors and/or mechanisms of AMPH-enhanced TCT, we also measured auditory fidelity (words-in-noise (WIN), quick speech-in-noise (QuickSIN)) and neurocognition (MATRICS comprehensive cognitive battery (MCCB)). Some measures were also acquired from age-matched healthy subjects (drug free; n = 10; M:F = 5:5). RESULTS: Patients exhibited expected deficits in neurocognition. WIN and QuickSIN performance at low signal intensities was impaired in patients with low v. high MCCB attention/vigilance (A/V) scores; these deficits were corrected by AMPH, maximally at 2.5-5 mg (d's = 0.79-1.29). AMPH also enhanced auditory learning, with maximal effects at 5 mg (d = 0.93), and comparable effects 60 and 210 min post pill. 'Pro-learning' effects of AMPH and AMPH-induced gains in auditory fidelity were most evident in patients with low MCCB A/V scores. CONCLUSIONS: These findings advance our understanding of the impact of pro-attentional interventions on auditory information processing and suggest dose- and time-course parameters for studies that assess the ability of AMPH to enhance the clinical benefits of TCT in schizophrenia patients.

Amphetamine alters an EEG marker of reward processing in humans and mice.

The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine. Motivated by human electroencephalographic (EEG) findings, we recently reported that frontal midline delta-band power is an electrophysiological biomarker of reward surprise in humans and in mice. In the current series of experiments, we determined the impact of parametric doses of d-amphetamine on this reward-related EEG response from humans (n = 23) and mice (n = 28) performing a probabilistic learning task. In humans, d-amphetamine (placebo, 10 mg, 20 mg) boosted the Reward Positivity event-related potential (ERP) component as well as the spectral delta-band representations of this signal. In mice, d-amphetamine (placebo, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) boosted both reward and punishment ERP features, yet there was no modulation of spectral activities. In sum, the present results confirm the role of dopamine in the generation of the Reward Positivity in humans, and pave the way toward a pharmacologically valid biomarker of reward sensitivity across species.

EEG reveals that dextroamphetamine improves cognitive control through multiple processes in healthy participants.

The poor translatability between preclinical and clinical drug trials has limited pro-cognitive therapeutic development. Future pro-cognitive drug trials should use translatable cross-species cognitive tasks with biomarkers (1) relevant to specific cognitive constructs, and (2) sensitive to drug treatment. Here, we used a difficulty-modulated variant of a cross-species cognitive control task with simultaneous electroencephalography (EEG) to identify neurophysiological biomarkers sensitive to the pro-cognitive effects of dextroamphetamine (d-amp) (10 or 20 mg) in healthy adults (n = 23), in a randomized, placebo-controlled, counterbalanced, double blind, within-subject study, conducted across three test days each separated by one week. D-amp boosted d-prime, sped reaction time, and increased frontal P3a amplitude to non-target correct rejections independent of task difficulty. Task difficulty did however, moderate d-amp effects on EEG during target performance. D-amp suppressed frontal theta power during easy target responses which negatively correlated with drug-induced improvement in hit rate while d-amp-induced changes in P3b amplitude during hard target trials strongly correlated with drug-induced improvement in hit rate. In summary, d-amp affected both behavioral and neurophysiological measures of cognitive control elements. Under low-demand, d-amp diminished cognitive control by suppressing theta, yet under high-demand it boosted control in concert with higher P3b amplitudes. These findings thus appear to reflect a gain-sharpening effect of d-amp: during high-demand processes were boosted while during low-demand processes were neglected. Future studies will use these neurophysiological measures of cognitive control as biomarkers to predict d-amp sensitivity in people with cognitive control deficits, including schizophrenia.

Electrophysiological biomarkers of behavioral dimensions from cross-species paradigms.

There has been a fundamental failure to translate preclinically supported research into clinically efficacious treatments for psychiatric disorders. One of the greatest impediments toward improving this species gap has been the difficulty of identifying translatable neurophysiological signals that are related to specific behavioral constructs. Here, we present evidence from three paradigms that were completed by humans and mice using analogous procedures, with each task eliciting candidate a priori defined electrophysiological signals underlying effortful motivation, reinforcement learning, and cognitive control. The effortful motivation was assessed using a progressive ratio breakpoint task, yielding a similar decrease in alpha-band activity over time in both species. Reinforcement learning was assessed via feedback in a probabilistic learning task with delta power significantly modulated by reward surprise in both species. Additionally, cognitive control was assessed in the five-choice continuous performance task, yielding response-locked theta power seen across species, and modulated by difficulty in humans. Together, these successes, and also the teachings from these failures, provide a roadmap towards the use of electrophysiology as a method for translating findings from the preclinical assays to the clinical settings.

Memantine effects on auditory discrimination and training in schizophrenia patients.

The uncompetitive low-affinity NMDA receptor antagonist, memantine, acutely increases electrophysiological measures of auditory information processing in both healthy subjects (HS) and patients with schizophrenia. Memantine effects on functional measures of auditory discrimination performance and learning are not known; conceivably, beneficial effects on these measures might suggest a role for memantine in augmenting the cognitive and functional impact of auditory targeted cognitive training (TCT). Here, carefully characterized HS (n = 20) and schizophrenia patients (n = 22) were tested in measures of auditory discrimination performance (words-in-noise (WIN), quick speech-in-noise (QuickSIN), gaps-in-noise) and auditory frequency modulation learning (a component of TCT) on 2 days about a week apart, after ingesting either placebo or 20 mg memantine po, in a double-blind, within-subject cross-over random order design. Memantine modestly enhanced functional measures of auditory discrimination in both schizophrenia patients (WIN) and HS (WIN and QuickSIN), as well as auditory frequency modulation learning in schizophrenia patients. These findings converge with a growing literature showing that memantine can enhance a range of metrics of auditory function. These properties could contribute to the apparent benefits of memantine as an adjunctive treatment in schizophrenia, and suggest that memantine might augment learning and potentially clinical gains from auditory-based TCT.

Memantine Effects on Electroencephalographic Measures of Putative Excitatory/Inhibitory Balance in Schizophrenia.

BACKGROUND: Abnormalities in cortical excitation and inhibition (E/I) balance are thought to underlie sensory and information processing deficits in schizophrenia. Deficits in early auditory information processing mediate both neurocognitive and functional impairment and appear to be normalized by acute pharmacologic challenge with the NMDA antagonist memantine (MEM). METHODS: Thirty-six subjects with a diagnosis of schizophrenia and 31 healthy control subjects underwent electroencephalographic recordings. Subjects ingested either placebo or MEM (10 or 20 mg) in a double-blind, within-subject, crossover, randomized design. The aperiodic, 1/f-like scaling property of the neural power spectra, which is thought to index relative E/I balance, was estimated using a robust linear regression algorithm. RESULTS: Patients with schizophrenia had greater aperiodic components compared with healthy control subjects (p < .01, d = 0.64), which was normalized after 20 mg MEM. Analysis revealed a significant dose × diagnosis interaction (p < .0001, d = 0.82). Furthermore, the MEM effect (change in aperiodic component in MEM vs. placebo conditions) was associated with baseline attention and vigilance (r = .54, p < .05) and MEM-induced enhancements in gamma power (r = -.60, p < .01). CONCLUSIONS: Findings confirmed E/I balance abnormalities in schizophrenia that were normalized with acute MEM administration and suggest that neurocognitive profiles may predict treatment response based on E/I sensitivity. These data provide proof-of-concept evidence for the utility of E/I balance indices as metrics of acute pharmacologic sensitivity for central nervous system therapeutics.

Lessons learned by giving amphetamine to antipsychotic-medicated schizophrenia patients.

Experimental Medicine studies in psychiatric populations test specific, mechanistic hypotheses related to the biology of mental illness, by combining well-characterized neurobiological probes and laboratory-based measures of behavioral performance and neurobiology. However, scientific inquiry through the acute administration of psychoactive drugs to patients with serious mental illness raises important ethical issues. These issues arise in studies in which the psychostimulant, amphetamine, is used as an Experimental Medicine probe in patients with schizophrenia. In this study, we summarize relevant aspects of our experience with acute, laboratory-based challenges of amphetamine in schizophrenia patients. Schizophrenia patients participated in one or more Experimental Medicine studies involving limited doses of amphetamine with clinical monitoring, over a 4-year period. Acute (within hours of ingestion; collective n = 53), subacute (three active doses over 4 weeks; n = 28), and long-term (mean = 17 months after ingestion; n = 19) effects of amphetamine ingestion were assessed. In antipsychotic (AP)-medicated schizophrenia patients, amphetamine was associated with no detrimental subjective, autonomic, or functional changes. Symptoms assessed acutely, subacutely, or long term were either unchanged or diminished. No adverse acute, subacute, or long-term consequences from the Experimental Medicine use of amphetamine in antipsychotic-medicated schizophrenia patients were detected. These findings do not address the safety or effectiveness of the use of amphetamine in unmedicated patients, or as an adjunctive treatment for schizophrenia. Indeed, it is important to distinguish evidence-based risks of symptom exacerbation in an Experimental Medicine setting vs. risks associated with long-term, daily clinical use or even misuse of amphetamine.

Room to move: Plasticity in early auditory information processing and auditory learning in schizophrenia revealed by acute pharmacological challenge.

Many patients with chronic psychotic disorders including schizophrenia (SZ) maintain meaningful levels of plasticity (i.e., capacity for change) within neurocognition-relevant brain mechanisms, as evidenced by gains in neurocognition and function after interventions such as targeted cognitive training. However, like many clinical features of these disorders, therapeutic responses in SZ are heterogeneous, and prospectively identifying treatment-sensitive individuals and individualized treatment modalities remains an unmet challenge. We propose that available plasticity in neurocognition-relevant brain mechanisms in individual SZ patients can be detected by gains in laboratory measures of early auditory information processing (EAIP) and auditory learning after a single challenge-dose of a pharmacologic agent; here, we present supportive data for this strategy with the non-competitive NMDA antagonist, memantine, and the psychostimulant, amphetamine. We describe a novel therapeutic model where this "challenge dose" strategy is used to prospectively identify a sensitive cohort of patients, and in these patients, a therapeutic response is elicited by pairing drug-enhanced EAIP and auditory learning with auditory-based targeted cognitive training.

Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic-Medicated Schizophrenia Patients.

Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects. Moderators predicting AMPH sensitivity were assessed, including the rs4680 single-nucleotide polymorphism for catechol-O-methyltransferase (COMT). After placebo, patients exhibited PPI deficits with 60 ms prepulse intervals; these deficits were 'rescued' by amphetamine. The magnitude of amphetamine-enhanced PPI was greater in patients than in HS (p<0.032), and was associated with positive symptoms (p<0.007), antipsychotic load (p<0.015), hedonic effects of AMPH (p<0.003), and with the presence of at least one methionine allele in rs4680 (p<0.008). No significant effects of amphetamine on MCCB performance were detected in either group, though pro-attentional effects of amphetamine in patients were associated with greater amphetamine-enhanced TCT learning. Amphetamine acutely 'normalized' PPI in antipsychotic-medicated schizophrenia patients; no concurrent acute neurocognitive changes were detected by the MCCB. Findings suggest that in the context of appropriate antipsychotic medication, a low dose of amphetamine enhances brain processes associated with higher function in schizophrenia patients, without accompanying changes in MCCB performance.

Tolcapone-Enhanced Neurocognition in Healthy Adults: Neural Basis and Predictors.

Background: Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects. Methods: Healthy men and women (n=27; ages 18-35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design. On each test day, neurocognitive performance was assessed using the MATRICS Consensus Cognitive Battery and an electroencephalogram-based 5 Choice-Continuous Performance Test. Results: Tolcapone enhanced visual learning in low-baseline MATRICS Consensus Cognitive Battery performers (d=0.35) and had an opposite effect in high performers (d=0.5), and enhanced verbal fluency across all subjects (P=.03) but had no effect on overall MATRICS Consensus Cognitive Battery performance. Tolcapone reduced false alarm rate (d=0.8) and enhanced frontal P200 amplitude during correctly identified nontarget trials (d=0.6) in low-baseline 5 Choice-Continuous Performance Test performers and had opposite effects in high performers (d=0.5 and d=0.25, respectively). Tolcapone's effect on frontal P200 amplitude and false alarm rate was correlated (rs=-0.4, P=.05). All neurocognitive effects of tolcapone were independent of rs4680 genotype. Conclusion: Tolcapone enhanced neurocognition and engaged electroencephalogram measures relevant to cognitive processes in specific subgroups of healthy individuals. These findings support an experimental medicine model for identifying procognitive treatments and provide a strong basis for future biomarker-informed procognitive studies in schizophrenia patients.

The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species.

BACKGROUND: Neurodevelopmental disorders including Tourette's syndrome (TS) and attention deficit hyperactivity disorder (ADHD) are characterized by significant impairment in attention and cognitive control. These cognitive deficits persist throughout development, contribute significantly to socio-occupational impairment, and are relatively impervious to available treatment. A critical challenge in pro-cognitive drug discovery is translatability of findings across species, underscoring the need for developing valid and reliable cross-species cognitive tasks. NEW METHOD: Here we describe a cross-species 5 choice continuous performance task that was developed to measure cognitive control processes of attention, vigilance, and response inhibition, enabling the translation of findings for pro-cognitive drug discovery across species and delineate neural mechanisms underlying cognitive control construct. RESULTS: Construct validity of 5C-CPT has been verified by multiple cross-species studies. Several lines of evidence report consistent findings across species including, deficits resulting from 36-h sleep deprivation studies, engagement of parietal cortex in human brain imaging and rodent lesion studies, and vigilance decrements over time. COMPARISON WITH EXISTING METHOD: Unlike the widely used rodent 5 choice serial reaction time task (5CSRTT) and the sustained attention task (SAT), the rodent 5C-CPT includes both target and non-target stimuli that allow measuring of cognitive control elements including response inhibition, an ability to inhibit pre-potent response during non-target trials, detect vigilance decrement and calculate signal detection parameters in rodents analogous to human CPT. CONCLUSION: The cross-species 5C-CPT is a robust translational tool to characterize the neurobiological substrates underlying cognitive control deficits in clinical population including, ADHD and TS and develop targeted pro-cognitive therapeutics.

Amphetamine Enhances Gains in Auditory Discrimination Training in Adult Schizophrenia Patients.

Targeted cognitive training (TCT) of auditory processing enhances higher-order cognition in schizophrenia patients. TCT performance gains can be detected after 1 training session. As a prelude to a potential clinical trial, we assessed a pharmacological augmentation of cognitive therapy (PACT) strategy by testing if the psychostimulant, amphetamine, augments TCT gains in auditory processing speed (APS) in schizophrenia patients and healthy subjects (HS). HS and schizophrenia patients were tested in a screening session (test 1), followed by a double-blind crossover design (tests 2-3), comparing placebo vs amphetamine (10 mg; 7 d between tests). On each test day, 1 hour of Posit Science "Sound Sweeps" training was bracketed by 2- to 4-minute pre- and post-training assessments of APS. Training consisted of a speeded auditory time-order judgment task of successive frequency modulation sweeps. Auditory system "learning" (APS post- vs pre-training) was enhanced by amphetamine (main effect of drug: P < .002; patients: d = 0.56, P < .02; HS: d = 0.39, nonsignificant), and this learning was sustained for at least 1 week. Exploratory analyses assessed potential biomarker predictors of sensitivity to these effects of amphetamine. Amphetamine enhances auditory discrimination learning in schizophrenia patients. We do not know whether gains in APS observed in patients after 1 hour of TCT predict clinical benefits after a full course of TCT. If amphetamine can enhance the therapeutic effects of TCT, this would provide strong support for a "PACT" treatment paradigm for schizophrenia.

Sensorimotor gating in healthy adults tested over a 15 year period.

BACKGROUND: Prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, is used to study normal and pathological brain function. From 2001 to 2016, we screened healthy subjects (HS) to establish their suitability for tests of drug effects on PPI. Because of the size and systematic characterization of this sample across variables of relevance to PPI, we now report these screening results. METHODS: Acoustic startle and PPI were assessed in HS to identify those eligible for studies of drug effects on PPI from 2001 to 2016, yielding 457 "eligible" subjects. RESULTS: Data confirmed the consistency of PPI across this 15-year period, and supported the role of several variables previously reported to moderate either startle or PPI. CONCLUSIONS: Startle and PPI are robust physiological measures that are predictably moderated by specific physiological variables in healthy adults. As such, these measures serve as robust markers of neurobiological processes in healthy and patient populations.

Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy.

RATIONALE: Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug's pro-cognitive effects. OBJECTIVE: This study aims to use an experimental medicine model to test the hypothesis that "target engagement" predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs. METHODS: MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs. 10 or 20 mg p.o.). Measures of prepulse inhibition (PPI) and mismatch negativity previously reported from this cohort substantiated target engagement. Biomarkers predicting MEM neurocognitive sensitivity were assessed. RESULTS: Testing confirmed MCCB deficits associated with CPD diagnosis, age, and anticholinergic exposure. MEM (20 mg p.o.) reduced MCCB performance in HS. To control for significant test order effects, an "order-corrected MEM effect" (OCME) was calculated. In CPD subjects, greater age, positive MEM effects on PPI, and SNP rs1337697 (within the ionotropic NMDA receptor gene, GRIN3A) predicted greater positive OCME with 20 mg MEM. CONCLUSIONS: An experimental medicine model to assess acute pro-cognitive drug effects in CPD subjects is feasible but not without challenges. A single MEM 20 mg dose had a negative impact on neurocognition among HS. In CPD patients, age, MEM effects on PPI, and rs1337697 predicted sensitivity to the neurocognitive effects of MEM. Any potential clinical utility of these predictive markers for pro-cognitive effects of MEM in subgroups of CPD patients cannot be inferred without a validating clinical trial.

The 3rd Schizophrenia International Research Society Conference, 14-18 April 2012, Florence, Italy: summaries of oral sessions.

The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012 and this year had as its emphasis, "The Globalization of Research". Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.

The COMT Met158 allele and violence in schizophrenia: a meta-analysis.

BACKGROUND: The Met158 allele of catechol-O-methyl transferase (COMT) gene is associated with increased levels of catecholamines in the prefrontal cortex and may increase the likelihood of aggressiveness. We conducted a meta-analysis to test the hypothesis that the Met158 allele of the COMT gene is associated with aggressive and violent behavior in schizophrenia. METHODS: MEDLINE search (12/31/11) yielded 14 studies examining the association of the COMT gene polymorphism (rs4680) and aggression in schizophrenia (total n=2219). Three separate analyses were conducted using a random effects model for Met allele carriers vs. Val/Val homozygotes, Met/Met homozygotes vs. Val allele carriers, and Met allele vs. Val allele, respectively. Primary outcome was frequency of patients with aggressive behavior and odds ratio (OR) was the effect size measure. RESULTS: The frequency of violent patients in the sample ranged from 20% to 75%. The pooled effect sizes for the Met homozygotes vs. Val allele carriers, Met allele carriers vs. Val homozygotes and the Met allele vs. Val allele comparisons were 1.74, 1.65 and 1.35, ps<.05, respectively, suggesting that the Met 158 allele of the COMT gene is associated with higher risk for violence in schizophrenia. Results remained significant after examining heterogeneity among samples and potential publication biases. CONCLUSIONS: The Met158 allele of the COMT gene confers a significantly increased risk for aggressive and violent behavior in schizophrenia. These data may provide basis for developing informative strategies for reducing violence in patients with schizophrenia.

Familial vulnerability to an unusual cognitive adverse effect of topiramate: Discussion of mechanisms.

BACKGROUND: Some patients experience cognitive disturbances with topiramate. CASE HISTORIES: A 19-year-old bipolar woman and her 46-year-old mother with paranoid personality disorder both used topiramate (25-50 mg/day) off-label for weight loss. Both women suffer from learning disorders, and both are excessively sensitive to the sedative adverse effects of psychotropic medications. RESULTS: Within days of starting topiramate, the women began to exhibit troublesome word- and phrase-repetition and word substitution, both occurring only in their written expression. The symptoms were associated with mild sedation, persisted during two weeks of topiramate treatment, and remitted days after topiramate was withdrawn. DISCUSSION: The presence of the learning disorders and the sensitivity to the sedative adverse effects of drugs may explain why cognitive adverse effects, known to occur with topiramate, developed at the low dose of 25-50 mg/day. The proclivity of topiramate to affect language functions and a possible familial vulnerability herein may explain why the women explained similar, language-specific symptoms. An investigation of topiramate-induced cognitive impairments in family members with epilepsy may throw light on the subject.