Edward Lauterbach - Academia.edu (original) (raw)

Papers by Edward Lauterbach

Therapeutic Value and Neuroprotection, 2014

Sleep-wake rhythm regulation

The Neurologist, 2007

Dextromethorphan (DM) is a widely-used antitussive. DM's ... more Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism. Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM's protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM's limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed. Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders.

Alzheimer Disease & Associated Disorders, 2012

Psychotropics are widely prescribed in Alzheimer disease (AD) without regard to their pathobiolog... more Psychotropics are widely prescribed in Alzheimer disease (AD) without regard to their pathobiological effects. Results summarize a comprehensive survey of psychotropic effects on messenger ribonucleic acid (mRNA) expression for 52 genes linked to AD. Pending future investigations, current data indicate that atypical antipsychotics, lithium, and fluoxetine reduce AD risk, whereas other drug classes promote risk. Risk may be attenuated by antipsychotics and lithium (down-regulate TNF), atypical antipsychotics (down-regulate TF), risperidone (down-regulates IL1B), olanzapine (up-regulates TFAM, down-regulates PRNP), fluoxetine (up-regulates CLU, SORCS1, NEDD9, GRN, and ECE1), and lithium coadministered with antipsychotics (down-regulates IL1B). Risk may be enhanced by neuroleptics (up-regulate TF), haloperidol (up-regulates IL1B and PION), olanzapine (down-regulates THRA and PRNP, up-regulates IL1A), and chlorpromazine, imipramine, maprotiline, fluvoxamine, and diazepam (up-regulate IL1B). There were no results for dextromethorphan-plus-quinidine. Fluoxetine effects on CLU, NEDD9, and GRN were statistically robust. Drug effects on specific variants, polymorphisms, genotypes, and other genes (CCR2, TF, and PRNP) are detailed. Translational AD risk applications and their limitations related to specific genes, mutations, variants, polymorphisms, genotypes, brain site, sex, clinical population, AD stage, and other factors are discussed. This report provides an initial summary and framework to understand the potential impact of psychotropic drugs on AD-relevant genes.

Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly... more Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly prescribed to treat Huntington's disease (HD). In HD preclinical models, while no psychotropic has convincingly affected huntingtin gene, HD modifying gene, or huntingtin protein expression, psychotropic neuroprotective effects include upregulated huntingtin autophagy (lithium), histone acetylation (lithium, valproate, lamotrigine), miR-222 (lithium-plus-valproate), mitochondrial protection (haloperidol, trifluoperazine, imipramine, desipramine, nortriptyline, maprotiline, trazodone, sertraline, venlafaxine, melatonin), neurogenesis (lithium, valproate, fluoxetine, sertraline), and BDNF (lithium, valproate, sertraline) and downregulated AP-1 DNA binding (lithium), p53 (lithium), huntingtin aggregation (antipsychotics, lithium), and apoptosis (trifluoperazine, loxapine, lithium, desipramine, nortriptyline, maprotiline, cyproheptadine, melatonin). In HD live mouse models, delayed disease onset (nortriptyline, melatonin), striatal preservation (haloperidol, tetrabenazine, lithium, sertraline), memory preservation (imipramine, trazodone, fluoxetine, sertraline, venlafaxine), motor improvement (tetrabenazine, lithium, valproate, imipramine, nortriptyline, trazodone, sertraline, venlafaxine), and extended survival (lithium, valproate, sertraline, melatonin) have been documented. Upregulated CREB binding protein (CBP; valproate, dextromethorphan) and downregulated histone deacetylase (HDAC; valproate) await demonstration in HD models. Most preclinical findings await replication and their limitations are reviewed. The most promising findings involve replicated striatal neuroprotection and phenotypic disease modification in transgenic mice for tetrabenazine and for sertraline. Clinical data consist of an uncontrolled lithium case series (n = 3) suggesting non-progression and a primarily negative double-blind, placebo-controlled clinical trial of lamotrigine.

Evidence-based medicine, 2013

Journal of Neuropsychiatry and Clinical Neurosciences, 2010

... Kerry L. Coburn, Ph.D. Edward C. Lauterbach, MD Nash N. Boutros, MD Kevin J. Black, MD David ... more ... Kerry L. Coburn, Ph.D. Edward C. Lauterbach, MD Nash N. Boutros, MD Kevin J. Black, MD David B. Arciniegas, MD C. Edward Coffey, MD LETTERS E4 http://neuro. psychiatryonline.org J Neuropsychiatry Clin Neurosci 22:1, Winter 2010

Parkinson's Disease, 2012

Neuroprotective treatments in Parkinson&a... more Neuroprotective treatments in Parkinson's disease (PD) have remained elusive. Psychotropics are commonly prescribed in PD without regard to their pathobiological effects. The authors investigated the effects of psychotropics on pathobiological proteins, proteasomal activity, mitochondrial functions, apoptosis, neuroinflammation, trophic factors, stem cells, and neurogenesis. Only findings replicated in at least 2 studies were considered for these actions. Additionally, PD-related gene transcription, animal model, and human neuroprotective clinical trial data were reviewed. Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms) include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R), although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided. The most promising neuroprotective investigative priorities will involve disease-modifying trials of the safest agents alone or in combination to capture salutary effects on H3 histone deacetylase, gene transcription, glycogen synthase kinase-3, α-synuclein, reactive oxygen species (ROS), reactive nitrogen species (RNS), apoptosis, inflammation, and trophic factors including GDNF and BDNF.

Schizophrenia Bulletin, 2001

Of 49 state hospital patients referred for movement disorder consultation for tardive dyskinesia ... more Of 49 state hospital patients referred for movement disorder consultation for tardive dyskinesia (TD), 11 (23.9%) of 46 meeting inclusion criteria had movement disorders other than TD. These other disorders led to a false diagnosis of TD in 6 subjects (12.2%). Between-day dyskinesia variability affected TD ascertainment in only 3.2 percent of subjects. Prevalences of other neurological conditions in the 30 patients identified with definite TD were parkinsonism (90%), dystonia (25%), akathisia (16%), cerebellar signs (40%), dysmetria (23%), cerebellar tremor (17%), tardive dystonia (3.3%), and tardive akathisia (33%). Concurrence rates of parkinsonism with TD varied significantly according to which clinical signs were used to define parkinsonism. Using a rating score threshold of at least mild, rigidity occurred in 793 percent, bradykinesia in 55.2 percent, and resting tremor in 41.4 percent of subjects with TD; more significant rigidity occurred in 41.4 percent, bradykinesia in 31.0 percent, and resting tremor in 20.7 percent Concurrence rates of neurological conditions with TD subsyndromes were distributed rather evenly according to condition prevalences, except for an association of cervicotruncal TD with bradykinesia (perhaps because of ventromedial striatal presynaptic and postsynaptlc D2 blockade, respectively). These findings, as well as the occurrence of equal gender ratio and relative underrepresentation of bipolar and alcohol disorders in subjects with definite TD, are discussed.

Psychiatry Research, 2003

Increased serum inorganic phosphorus associated with elevated serum calcium has been demonstrated... more Increased serum inorganic phosphorus associated with elevated serum calcium has been demonstrated to coincide with the onset of agitation and mania in periodic psychoses and bipolar disorders. We tested the hypothesis that unexplained transient hyperphosphatemia (UTHP) is more common in patients with psychiatric disorders than in controls with medical or surgical conditions. We studied 100 patients admitted to a psychiatric ward and 100 controls admitted to a medical-surgical ward. All subjects (patients and controls) underwent acute admission to the same general hospital. The serum phosphorus was measured upon admission and, if elevated, followed during the hospital course. Twenty patients (20%) with psychiatric disorders had unexplained hyperphosphatemia compared with four medical-surgical controls (4%). UTHP occurred in six patients with psychiatric disorders and no controls. Hypophosphatemia did not occur in subjects with psychiatric disorders. This study shows an increased incidence of UTHP in acutely ill, hospitalized patients with psychiatric disorders relative to acutely ill, hospitalized controls with medical-surgical conditions. These data extend previous findings by linking UTHP to acute psychiatric disturbances across varied psychiatric diagnoses independent of hypercalcemia. Potential explanations include trazodone administration and transient hypocalcemia.

Neurocase, 2010

Sequential therapeutic trials for catatonoid frontal signs in clinically-evident frontotemporal d... more Sequential therapeutic trials for catatonoid frontal signs in clinically-evident frontotemporal dementia (n = 2) revealed differential benefits for lorazepam, amantadine, memantine, pramipexole, aripiprazole, quetiapine, citalopram, and donepezil, although certain signs also worsened. Citalopram and donepezil were poorly tolerated. Ramelteon was without effect. While memantine appeared to improve cognition in case 1, this remains to be established by more reliable neuropsychological testing. Parkinsonism (case 2) responded to pramipexole, but not amantadine or levodopa. Possible relationships of catatonoid signs requiring future confirmation include insufficient GABA-A (multiple signs) and D2 (mutism) and excessive NMDA (immobility, rigidity), D2/D3 (mannerisms, verbal perseveration), and 5HT1a (staring) receptor stimulation. Low-dose lorazepam and quetiapine required close monitoring.

Journal of Neuropsychiatry, 2007

This report reviews the state of the literature and opportunities for research related to the cog... more This report reviews the state of the literature and opportunities for research related to the cognitive correlates of functional status. The prediction of functional capacity on the basis of cognitive test performance is an important aspect of neuropsychological assessment. Moreover, functional impairment or "disability" is an essential part of dementia case finding. Nevertheless, relatively little attention has been given to the empirical study of the specific cognitive correlates of functional outcomes. What literature is available suggests that 1) the variance in functional status that can be specifically attributed to cognition is surprisingly modest; 2) some cognitive domains may be more relevant to functional capacity than others; 3) some measures of executive control function are relatively strong correlates of functional capacities, particularly medical or financial decision-making; and 4) "general" cognitive screening tests are surprisingly strong correlates of functional status. These findings are of particular significance to dementia case finding, epidemiology, and treatment. The extensive literature on functional status has yet to be integrated with the equally extensive literature on cognitive assessment. Better integration of cognitive and functional assessments would offer greater clinical utility. However, psychometric batteries may have to be redesigned to maximize their capacity to capture the variance in functional outcomes.

Journal of Neuropsychiatry, 2009

Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with vario... more Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with various neurological disorders. It is characterized by the presence of episodic and contextually inappropriate or merely exaggerated outbursts of laughter and/or crying without commensurate feelings. This review provides an in depth analysis of the neuroanatomy of lesions seen in patients with this clinical condition, discusses the relevant functional neuroimaging and electrophysiological stimulation studies in human subjects, and summarizes the current treatment options. It concludes with a presentation of the remaining questions and directions for future research.

Journal of Neuropsychiatry, 2008

The Committee on Research of the American Neuropsychiatric Association conducted a review of the ... more The Committee on Research of the American Neuropsychiatric Association conducted a review of the noncognitive neuropsychiatric manifestations of frontotemporal dementia. The Committee on Research searched reviews and several online databases for all pertinent publications. Single case reports without pathology were excluded, except for psychosis, where single cases made up much of the literature. The strongest evidence supports an association of frontotemporal dementia with the following behaviors: apathy-abulia; disinhibition-impulsivity; loss of insight and self-referential behavior; decreased emotion and empathy; violation of social and moral norms; changes in dietary or eating behavior; and repetitive behaviors. Frontotemporal dementia is less frequently associated with anxiety and mood disorders, which may be a prodrome or risk factor, and rarely presents with delusions or hallucinations. The results of this review highlight the distinct neuropsychiatric manifestations of frontotemporal dementia and the need to reconsider the current diagnostic criteria for this disorder.

Journal of Neuropsychiatry, 2006

The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical ... more The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical psychiatry and describe specific techniques, including visual analysis, spectral analysis, univariate comparisons to normative healthy databases, multivariate comparisons to normative healthy and clinical databases, and advanced techniques that hold clinical promise. Controversial aspects of each technique are discussed, as are broader areas of criticism, such as commercial interests and standards of evidence. The published literature is selectively reviewed, and qEEG's applicability is assessed for disorders of childhood (learning and attentional disorders), dementia, mood disorders, anxiety, panic, obsessive-compulsive disorder, and schizophrenia. Emphasis is placed primarily on studies that use qEEG to aid in clinical diagnosis, and secondarily on studies that use qEEG to predict medication response or clinical course. Methodological problems are highlighted, the availability of large databases is discussed, and specific recommendations are made for further research and development. As a clinical laboratory test, qEEG's cautious use is recommended in attentional and learning disabilities of childhood, and in mood and dementing disorders of adulthood.

Journal of Neuropsychiatry, 2010

In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotecti... more In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

Cognitive and Behavioral Neurology, 2008

Cognitive and Behavioral Neurology, 2010

The authors studied mood disorder and neurobehavioral correlates of solitary focal cerebellar (CB... more The authors studied mood disorder and neurobehavioral correlates of solitary focal cerebellar (CB) lesions. CB function has been correlated with cognitive, behavioral, and psychiatric conditions. Systematic study of uncomplicated CB pathology can further our understanding of these correlates. Magnetic Resonance Images were blindly selected from 20,000 scans for solitary focal CB lesions after excluding other pathology. "Secondary" conditions (developing after lesion onset) were determined using structured clinical interviews (DIS and SCID) for psychiatric diagnoses while blind to MRI findings. Clinical correlates of lesions and a priori hypotheses were examined in 13 participants while controlling for alternative attributions (atrophy, hyperintensities, ventriculomegaly, disability, etc.). Bipolar disorders after CB lesions were more common than expected in normal populations (OR 28.62, 95% CI 3.51 < - >233.34, P=0.0001), replicating a previous finding. Secondary DSM-III and -IV depressive disorders correlated with posterolateral lesions of the right CB posterior lobe (P=0.0035); severity correlated with lesion size. Other lesion correlates included hypomania (anterolateral left CB posterior lobe), apathy (medial left anterior lobe, anterolateral right posterior lobe), disinhibition and dysexecution (medial left anterior lobe), agitation (central left and anterolateral right posterior lobe), and elation (anterolateral right posterior lobe). Although other structural cerebral and psychosocial variables did not explain the findings, much larger sample sizes will be needed to adequately control for these variables. Review of the literature reveals support for these findings, suggesting CB control of mood, behavior, and frontal cognition.

Biological Psychiatry, 2005

Background: Among patients with tic disorders, a distinctive clinical profile of obsessive-compul... more Background: Among patients with tic disorders, a distinctive clinical profile of obsessive-compulsive symptomatology has been described. The present investigation was designed to document the phenomenology of obsessive-compulsive symptoms (OCS) among patients with Sydenham chorea (SC), the neurologic variant of rheumatic fever. We hypothesized that OCS occurring in association with SC would be similar to those among patients with tic disorders. Methods: The authors studied the presence of OCS in 73 patients with SC by using the Yale-Brown Obsessive-Compulsive Scale at the Results: The most frequent symptoms observed among subjects with comorbid SC and OCS were aggressive, contamination, and somatic obsessions and checking, cleaning, and repeating compulsions. A principal component factor analysis yielded a five-factor solution (accounting for 64.5% of the total variance), with contamination and symmetry obsessions and cleaning compulsions loading highly. Conclusions: The symptoms observed among the SC patients were different from those reported by patients with tic disorders but were similar to those previously noted among samples of pediatric patients with primary obsessive-compulsive disorder.

Journal of neuropsychiatry and clinical neurosciences, Jun 2012

Disruptions in sleep and sleep-wake cycle regulation have been identified as one of the main caus... more Disruptions in sleep and sleep-wake cycle regulation have been identified as one of the main causes for the pathophysiology of depressive disorders. The search has been on for the identification of an ideal antidepressant that could improve both sleep disturbances and depressive symptomatology. Melatonin, the major hormone of the pineal gland, has been shown to improve sleep and is involved in the regulation of the sleep-wake cycle. Identification of high concentrations of MT1 and MT2 melatonergic receptors in the suprachiasmatic nucleus of the anterior hypothalamus, the structure concerned with regulation of circadian rhythms and sleep-wake cycles, has led to the development of melatonergic agonists with greater potency and longer durations of action. Agomelatine is one such melatonergic agonist that acts specifically on MT1/MT2 melatonergic receptors and at the same time exhibits 5-HT2C antagonism, a property that is utilized by current antidepressants that are in clinical use. Agomelatine has been shown to be effective in a number of animal models of depression. Clinical studies undertaken on patients with major depression, bipolar disorders, seasonal affective disorder, and generalized anxiety disorder have all shown that agomelatine is also very effective in ameliorating depressive symptoms and manifesting early onset of action with a good tolerability and safety profile. It improved sleep efficiency and also resynchronized the disrupted circadian rhythms. Hence, the melatonergic modulation by agomelatine is suggested as one of the mechanisms for its antidepressant effect. Agomelatine's action on dendritic neurogenesis in animal models of depression is also identified as yet another action.

Therapeutic Value and Neuroprotection, 2014

Sleep-wake rhythm regulation

The Neurologist, 2007

Dextromethorphan (DM) is a widely-used antitussive. DM's ... more Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism. Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM's protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM's limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed. Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders.

Alzheimer Disease & Associated Disorders, 2012

Psychotropics are widely prescribed in Alzheimer disease (AD) without regard to their pathobiolog... more Psychotropics are widely prescribed in Alzheimer disease (AD) without regard to their pathobiological effects. Results summarize a comprehensive survey of psychotropic effects on messenger ribonucleic acid (mRNA) expression for 52 genes linked to AD. Pending future investigations, current data indicate that atypical antipsychotics, lithium, and fluoxetine reduce AD risk, whereas other drug classes promote risk. Risk may be attenuated by antipsychotics and lithium (down-regulate TNF), atypical antipsychotics (down-regulate TF), risperidone (down-regulates IL1B), olanzapine (up-regulates TFAM, down-regulates PRNP), fluoxetine (up-regulates CLU, SORCS1, NEDD9, GRN, and ECE1), and lithium coadministered with antipsychotics (down-regulates IL1B). Risk may be enhanced by neuroleptics (up-regulate TF), haloperidol (up-regulates IL1B and PION), olanzapine (down-regulates THRA and PRNP, up-regulates IL1A), and chlorpromazine, imipramine, maprotiline, fluvoxamine, and diazepam (up-regulate IL1B). There were no results for dextromethorphan-plus-quinidine. Fluoxetine effects on CLU, NEDD9, and GRN were statistically robust. Drug effects on specific variants, polymorphisms, genotypes, and other genes (CCR2, TF, and PRNP) are detailed. Translational AD risk applications and their limitations related to specific genes, mutations, variants, polymorphisms, genotypes, brain site, sex, clinical population, AD stage, and other factors are discussed. This report provides an initial summary and framework to understand the potential impact of psychotropic drugs on AD-relevant genes.

Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly... more Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly prescribed to treat Huntington's disease (HD). In HD preclinical models, while no psychotropic has convincingly affected huntingtin gene, HD modifying gene, or huntingtin protein expression, psychotropic neuroprotective effects include upregulated huntingtin autophagy (lithium), histone acetylation (lithium, valproate, lamotrigine), miR-222 (lithium-plus-valproate), mitochondrial protection (haloperidol, trifluoperazine, imipramine, desipramine, nortriptyline, maprotiline, trazodone, sertraline, venlafaxine, melatonin), neurogenesis (lithium, valproate, fluoxetine, sertraline), and BDNF (lithium, valproate, sertraline) and downregulated AP-1 DNA binding (lithium), p53 (lithium), huntingtin aggregation (antipsychotics, lithium), and apoptosis (trifluoperazine, loxapine, lithium, desipramine, nortriptyline, maprotiline, cyproheptadine, melatonin). In HD live mouse models, delayed disease onset (nortriptyline, melatonin), striatal preservation (haloperidol, tetrabenazine, lithium, sertraline), memory preservation (imipramine, trazodone, fluoxetine, sertraline, venlafaxine), motor improvement (tetrabenazine, lithium, valproate, imipramine, nortriptyline, trazodone, sertraline, venlafaxine), and extended survival (lithium, valproate, sertraline, melatonin) have been documented. Upregulated CREB binding protein (CBP; valproate, dextromethorphan) and downregulated histone deacetylase (HDAC; valproate) await demonstration in HD models. Most preclinical findings await replication and their limitations are reviewed. The most promising findings involve replicated striatal neuroprotection and phenotypic disease modification in transgenic mice for tetrabenazine and for sertraline. Clinical data consist of an uncontrolled lithium case series (n = 3) suggesting non-progression and a primarily negative double-blind, placebo-controlled clinical trial of lamotrigine.

Evidence-based medicine, 2013

Journal of Neuropsychiatry and Clinical Neurosciences, 2010

... Kerry L. Coburn, Ph.D. Edward C. Lauterbach, MD Nash N. Boutros, MD Kevin J. Black, MD David ... more ... Kerry L. Coburn, Ph.D. Edward C. Lauterbach, MD Nash N. Boutros, MD Kevin J. Black, MD David B. Arciniegas, MD C. Edward Coffey, MD LETTERS E4 http://neuro. psychiatryonline.org J Neuropsychiatry Clin Neurosci 22:1, Winter 2010

Parkinson's Disease, 2012

Neuroprotective treatments in Parkinson&a... more Neuroprotective treatments in Parkinson's disease (PD) have remained elusive. Psychotropics are commonly prescribed in PD without regard to their pathobiological effects. The authors investigated the effects of psychotropics on pathobiological proteins, proteasomal activity, mitochondrial functions, apoptosis, neuroinflammation, trophic factors, stem cells, and neurogenesis. Only findings replicated in at least 2 studies were considered for these actions. Additionally, PD-related gene transcription, animal model, and human neuroprotective clinical trial data were reviewed. Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms) include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R), although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided. The most promising neuroprotective investigative priorities will involve disease-modifying trials of the safest agents alone or in combination to capture salutary effects on H3 histone deacetylase, gene transcription, glycogen synthase kinase-3, α-synuclein, reactive oxygen species (ROS), reactive nitrogen species (RNS), apoptosis, inflammation, and trophic factors including GDNF and BDNF.

Schizophrenia Bulletin, 2001

Of 49 state hospital patients referred for movement disorder consultation for tardive dyskinesia ... more Of 49 state hospital patients referred for movement disorder consultation for tardive dyskinesia (TD), 11 (23.9%) of 46 meeting inclusion criteria had movement disorders other than TD. These other disorders led to a false diagnosis of TD in 6 subjects (12.2%). Between-day dyskinesia variability affected TD ascertainment in only 3.2 percent of subjects. Prevalences of other neurological conditions in the 30 patients identified with definite TD were parkinsonism (90%), dystonia (25%), akathisia (16%), cerebellar signs (40%), dysmetria (23%), cerebellar tremor (17%), tardive dystonia (3.3%), and tardive akathisia (33%). Concurrence rates of parkinsonism with TD varied significantly according to which clinical signs were used to define parkinsonism. Using a rating score threshold of at least mild, rigidity occurred in 793 percent, bradykinesia in 55.2 percent, and resting tremor in 41.4 percent of subjects with TD; more significant rigidity occurred in 41.4 percent, bradykinesia in 31.0 percent, and resting tremor in 20.7 percent Concurrence rates of neurological conditions with TD subsyndromes were distributed rather evenly according to condition prevalences, except for an association of cervicotruncal TD with bradykinesia (perhaps because of ventromedial striatal presynaptic and postsynaptlc D2 blockade, respectively). These findings, as well as the occurrence of equal gender ratio and relative underrepresentation of bipolar and alcohol disorders in subjects with definite TD, are discussed.

Psychiatry Research, 2003

Increased serum inorganic phosphorus associated with elevated serum calcium has been demonstrated... more Increased serum inorganic phosphorus associated with elevated serum calcium has been demonstrated to coincide with the onset of agitation and mania in periodic psychoses and bipolar disorders. We tested the hypothesis that unexplained transient hyperphosphatemia (UTHP) is more common in patients with psychiatric disorders than in controls with medical or surgical conditions. We studied 100 patients admitted to a psychiatric ward and 100 controls admitted to a medical-surgical ward. All subjects (patients and controls) underwent acute admission to the same general hospital. The serum phosphorus was measured upon admission and, if elevated, followed during the hospital course. Twenty patients (20%) with psychiatric disorders had unexplained hyperphosphatemia compared with four medical-surgical controls (4%). UTHP occurred in six patients with psychiatric disorders and no controls. Hypophosphatemia did not occur in subjects with psychiatric disorders. This study shows an increased incidence of UTHP in acutely ill, hospitalized patients with psychiatric disorders relative to acutely ill, hospitalized controls with medical-surgical conditions. These data extend previous findings by linking UTHP to acute psychiatric disturbances across varied psychiatric diagnoses independent of hypercalcemia. Potential explanations include trazodone administration and transient hypocalcemia.

Neurocase, 2010

Sequential therapeutic trials for catatonoid frontal signs in clinically-evident frontotemporal d... more Sequential therapeutic trials for catatonoid frontal signs in clinically-evident frontotemporal dementia (n = 2) revealed differential benefits for lorazepam, amantadine, memantine, pramipexole, aripiprazole, quetiapine, citalopram, and donepezil, although certain signs also worsened. Citalopram and donepezil were poorly tolerated. Ramelteon was without effect. While memantine appeared to improve cognition in case 1, this remains to be established by more reliable neuropsychological testing. Parkinsonism (case 2) responded to pramipexole, but not amantadine or levodopa. Possible relationships of catatonoid signs requiring future confirmation include insufficient GABA-A (multiple signs) and D2 (mutism) and excessive NMDA (immobility, rigidity), D2/D3 (mannerisms, verbal perseveration), and 5HT1a (staring) receptor stimulation. Low-dose lorazepam and quetiapine required close monitoring.

Journal of Neuropsychiatry, 2007

This report reviews the state of the literature and opportunities for research related to the cog... more This report reviews the state of the literature and opportunities for research related to the cognitive correlates of functional status. The prediction of functional capacity on the basis of cognitive test performance is an important aspect of neuropsychological assessment. Moreover, functional impairment or "disability" is an essential part of dementia case finding. Nevertheless, relatively little attention has been given to the empirical study of the specific cognitive correlates of functional outcomes. What literature is available suggests that 1) the variance in functional status that can be specifically attributed to cognition is surprisingly modest; 2) some cognitive domains may be more relevant to functional capacity than others; 3) some measures of executive control function are relatively strong correlates of functional capacities, particularly medical or financial decision-making; and 4) "general" cognitive screening tests are surprisingly strong correlates of functional status. These findings are of particular significance to dementia case finding, epidemiology, and treatment. The extensive literature on functional status has yet to be integrated with the equally extensive literature on cognitive assessment. Better integration of cognitive and functional assessments would offer greater clinical utility. However, psychometric batteries may have to be redesigned to maximize their capacity to capture the variance in functional outcomes.

Journal of Neuropsychiatry, 2009

Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with vario... more Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with various neurological disorders. It is characterized by the presence of episodic and contextually inappropriate or merely exaggerated outbursts of laughter and/or crying without commensurate feelings. This review provides an in depth analysis of the neuroanatomy of lesions seen in patients with this clinical condition, discusses the relevant functional neuroimaging and electrophysiological stimulation studies in human subjects, and summarizes the current treatment options. It concludes with a presentation of the remaining questions and directions for future research.

Journal of Neuropsychiatry, 2008

The Committee on Research of the American Neuropsychiatric Association conducted a review of the ... more The Committee on Research of the American Neuropsychiatric Association conducted a review of the noncognitive neuropsychiatric manifestations of frontotemporal dementia. The Committee on Research searched reviews and several online databases for all pertinent publications. Single case reports without pathology were excluded, except for psychosis, where single cases made up much of the literature. The strongest evidence supports an association of frontotemporal dementia with the following behaviors: apathy-abulia; disinhibition-impulsivity; loss of insight and self-referential behavior; decreased emotion and empathy; violation of social and moral norms; changes in dietary or eating behavior; and repetitive behaviors. Frontotemporal dementia is less frequently associated with anxiety and mood disorders, which may be a prodrome or risk factor, and rarely presents with delusions or hallucinations. The results of this review highlight the distinct neuropsychiatric manifestations of frontotemporal dementia and the need to reconsider the current diagnostic criteria for this disorder.

Journal of Neuropsychiatry, 2006

The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical ... more The authors evaluate quantitative electroencephalography (qEEG) as a laboratory test in clinical psychiatry and describe specific techniques, including visual analysis, spectral analysis, univariate comparisons to normative healthy databases, multivariate comparisons to normative healthy and clinical databases, and advanced techniques that hold clinical promise. Controversial aspects of each technique are discussed, as are broader areas of criticism, such as commercial interests and standards of evidence. The published literature is selectively reviewed, and qEEG's applicability is assessed for disorders of childhood (learning and attentional disorders), dementia, mood disorders, anxiety, panic, obsessive-compulsive disorder, and schizophrenia. Emphasis is placed primarily on studies that use qEEG to aid in clinical diagnosis, and secondarily on studies that use qEEG to predict medication response or clinical course. Methodological problems are highlighted, the availability of large databases is discussed, and specific recommendations are made for further research and development. As a clinical laboratory test, qEEG's cautious use is recommended in attentional and learning disabilities of childhood, and in mood and dementing disorders of adulthood.

Journal of Neuropsychiatry, 2010

In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotecti... more In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

Cognitive and Behavioral Neurology, 2008

Cognitive and Behavioral Neurology, 2010

The authors studied mood disorder and neurobehavioral correlates of solitary focal cerebellar (CB... more The authors studied mood disorder and neurobehavioral correlates of solitary focal cerebellar (CB) lesions. CB function has been correlated with cognitive, behavioral, and psychiatric conditions. Systematic study of uncomplicated CB pathology can further our understanding of these correlates. Magnetic Resonance Images were blindly selected from 20,000 scans for solitary focal CB lesions after excluding other pathology. "Secondary" conditions (developing after lesion onset) were determined using structured clinical interviews (DIS and SCID) for psychiatric diagnoses while blind to MRI findings. Clinical correlates of lesions and a priori hypotheses were examined in 13 participants while controlling for alternative attributions (atrophy, hyperintensities, ventriculomegaly, disability, etc.). Bipolar disorders after CB lesions were more common than expected in normal populations (OR 28.62, 95% CI 3.51 < - >233.34, P=0.0001), replicating a previous finding. Secondary DSM-III and -IV depressive disorders correlated with posterolateral lesions of the right CB posterior lobe (P=0.0035); severity correlated with lesion size. Other lesion correlates included hypomania (anterolateral left CB posterior lobe), apathy (medial left anterior lobe, anterolateral right posterior lobe), disinhibition and dysexecution (medial left anterior lobe), agitation (central left and anterolateral right posterior lobe), and elation (anterolateral right posterior lobe). Although other structural cerebral and psychosocial variables did not explain the findings, much larger sample sizes will be needed to adequately control for these variables. Review of the literature reveals support for these findings, suggesting CB control of mood, behavior, and frontal cognition.

Biological Psychiatry, 2005

Background: Among patients with tic disorders, a distinctive clinical profile of obsessive-compul... more Background: Among patients with tic disorders, a distinctive clinical profile of obsessive-compulsive symptomatology has been described. The present investigation was designed to document the phenomenology of obsessive-compulsive symptoms (OCS) among patients with Sydenham chorea (SC), the neurologic variant of rheumatic fever. We hypothesized that OCS occurring in association with SC would be similar to those among patients with tic disorders. Methods: The authors studied the presence of OCS in 73 patients with SC by using the Yale-Brown Obsessive-Compulsive Scale at the Results: The most frequent symptoms observed among subjects with comorbid SC and OCS were aggressive, contamination, and somatic obsessions and checking, cleaning, and repeating compulsions. A principal component factor analysis yielded a five-factor solution (accounting for 64.5% of the total variance), with contamination and symmetry obsessions and cleaning compulsions loading highly. Conclusions: The symptoms observed among the SC patients were different from those reported by patients with tic disorders but were similar to those previously noted among samples of pediatric patients with primary obsessive-compulsive disorder.

Journal of neuropsychiatry and clinical neurosciences, Jun 2012

Disruptions in sleep and sleep-wake cycle regulation have been identified as one of the main caus... more Disruptions in sleep and sleep-wake cycle regulation have been identified as one of the main causes for the pathophysiology of depressive disorders. The search has been on for the identification of an ideal antidepressant that could improve both sleep disturbances and depressive symptomatology. Melatonin, the major hormone of the pineal gland, has been shown to improve sleep and is involved in the regulation of the sleep-wake cycle. Identification of high concentrations of MT1 and MT2 melatonergic receptors in the suprachiasmatic nucleus of the anterior hypothalamus, the structure concerned with regulation of circadian rhythms and sleep-wake cycles, has led to the development of melatonergic agonists with greater potency and longer durations of action. Agomelatine is one such melatonergic agonist that acts specifically on MT1/MT2 melatonergic receptors and at the same time exhibits 5-HT2C antagonism, a property that is utilized by current antidepressants that are in clinical use. Agomelatine has been shown to be effective in a number of animal models of depression. Clinical studies undertaken on patients with major depression, bipolar disorders, seasonal affective disorder, and generalized anxiety disorder have all shown that agomelatine is also very effective in ameliorating depressive symptoms and manifesting early onset of action with a good tolerability and safety profile. It improved sleep efficiency and also resynchronized the disrupted circadian rhythms. Hence, the melatonergic modulation by agomelatine is suggested as one of the mechanisms for its antidepressant effect. Agomelatine's action on dendritic neurogenesis in animal models of depression is also identified as yet another action.

Melatonin and Melatonergic Drugs in Clinical Practice, 2014

The efficacy of melatonin in promoting and maintaining sleep has been demonstrated in most of the... more The efficacy of melatonin in promoting and maintaining sleep has been demonstrated in most of the clinical studies. However, because of its short half-life, its sustained effect in improving sleep quality could not be demonstrated uniformly in all the studies that have been undertaken so far. The development of slow-release melatonin preparation Circadin has been found effective in reducing sleep onset time and also for improving sleep quality. This was followed by the introduction of another melatonergic drug ramelteon, a melatonin receptor agonist that has high selectivity for MT 1 receptors than MT 2 receptors and therefore targets sleep onset more specifically than melatonin. Clinical trials undertaken in different countries of European region and Japan have conclusively demonstrated that ramelteon in various doses (from 4 to 32 mg/day) reduced sleep onset latency, increased total sleep time, and sleep effi ciency and quality in patients suffering from chronic insomnia. Besides acting as a sedative-hypnotic drug, ramelteon also demonstrated its ability as a drug with chronobiotic properties and has been found useful in resetting the disturbed circadian rhythms. The action of ramelteon in improving sleep effi ciency is dose independent and hence acts differently from melatonin. It has a promising value in treating patients with chronic insomnia as it does not have any of the adverse effects like next-day hangover and dependence associated with the usage of other conventional hypnotic drugs.

Melatonin and Melatonergic Drugs in Clinical Practice , 2014

Numerous clinical studies have shown that melatonin is involved in the pathogenesis of mood disor... more Numerous clinical studies have shown that melatonin is involved in the
pathogenesis of mood disorders like major depressive disorder, bipolar
disorder, and seasonal affective disorder or winter depression. Many clinical symptoms seen in depressive patients suggest that disturbances of sleep and circadian rhythms play an important role in the pathophysiology of mood disorders. Disturbances of sleep-wake rhythms and circadian rhythms are linked to malfunctioning of SCN-pineal-melatonin axis. As a rhythm regulating factor and as a hormone involved in the physiological regulation of sleep-wake rhythm, melatonin plays an important role in regulating sleep and circadian rhythm disturbances of mood disorders. Melatonin receptors, namely, MT 1 and MT 2 , are found expressed in the suprachiasmatic nucleus of the hypothalamic region, an area concerned with the regulation of various circadian rhythms and sleep-wake rhythm. Although pharmacotherapy of mood disorders has long been associated
with the modulation of monoaminergic systems of neuronal circuits in different regions of the brain that are involved in the regulation of mood,
attention has been paid in recent years for the development of drugs that
can shift, reset, and stabilize the circadian rhythms and improve the quality of sleep. In this context agomelatine, a novel antidepressant with MT 1/MT 2 agonistic and 5-HT 2c antagonistic properties, has been introduced. Having proved its effi cacy as an effective antidepressant in various animal models of depression, agomelatine has been introduced as an antidepressant for treating patients with major depressive disorders in many European countries and also in the USA. Agomelatine has also been used for treating patients with bipolar disorder, winter depression, and anxiety disorder and has demonstrated its clinical effi cacy with rapid onset of action, comparable to other antidepressants like SSRIs and SNRIs. But unlike these drugs, agomelatine does not exhibit adverse side effects like worsening of insomnia or sexual problems, and hence, it is considered as an antidepressant of choice for effective treatment of mood disorders.

Melatonin: Therapeutic value and Neuroprotection, 2014

Sleep disturbances are the most common complaint of the elderly and one of the most prevalent sym... more Sleep disturbances are the most common complaint of the elderly and one of the most prevalent symptoms of mental illness. The co-occurrence of disturbed sleep and disturbed mood also has been reported in a number of clinical studies in patients with major depressive disorder (MDD).